En Acı Haplar: Antipsikotiklerin Sorunlu Hikayesi (İngizlice kopya)
Table of Contents
Title
Copyright
Contents
List of Tables and
Figures
List of
Abbreviations
Preface and
Acknowledgements
1 Cure or Curse:
What Are Antipsychotics?
2 Chlorpromazine:
The First Wonder Drug
3 Magic Bullets:
The Development of Ideas on Drug Action
4 Building a House
of Cards: The Dopamine Theory of Schizophrenia and Drug Action
5 The Phoenix
Rises: From Tardive Dyskinesia to the Introduction of the ‘Atypicals’
6 Looking Where the
Light is: Randomised Controlled Trials of Antipsychotics
7 The Patient’s
Dilemma: Other Evidence on the Effects of Antipsychotics
8 Chemical Cosh:
Antipsychotics and Chemical Restraint
9 Old and New
Drug-Induced Problems
10 The First
Tentacles: The ‘Early Intervention in Psychosis’ Movement
11 The
Antipsychotic Epidemic: Prescribing in the Twenty-First Century
12 All is not as it
Seems
Notes
Appendix 1: Common
Antipsychotic Drugs
Appendix 2:
Accounts of Schizophrenia and Psychosis
References
Index
The Bitterest Pills
Also by
Joanna Moncrieff
THE MYTH OF THE CHEMICAL CURE
DE-MEDICALISING MISERY (co-editor)
A STRAIGHT TALKING INTRODUCTION TO
PSYCHIATRIC DRUGS
Praise for The Myth of the
Chemical Cure:
‘A revolutionary book written with the calm
assurance of someone who knows her subject matter – and the people involved –
extremely well. Essential reading for anyone interested in mental health’.
Dorothy Rowe, www.dorothyrowe.com.au
‘This is a book that should change
psychiatry forever’. Mental Health
‘This book is critically important and should
be essential reading for all psychiatrists, politicians, service providers, and
user groups. Why? Because Joanna Moncrieff’s central tenet is right, and the
implications for service delivery are profound. The book is closely argued and
well referenced. Even if you disagree with some of it’s overall premises, it is
not legitimate to dismiss it. I urge you to read it if only as a prompt to a
critical evaluation of the status quo, never a bad thing, and almost always an
illuminating exercise’. Sarah Yates, Cambridge, UK
‘This is a sober and thoughtful book. I
found it very engaging and worth the effort to be better informed about a
subject that affects many of our clients and impinges on our professional lives
as therapists’. Existential Analysis (Society for
Existential Analysis)
‘...Joanna Moncrieff, a practising
psychiatrist and academic, has produced a devastating critique of the use of
psychiatric drugs... This courageous book has the potential to revolutionise
psychiatric practice and the care of people with many forms of mental distress.
Many in the therapy professions will, I am sure, celebrate its message’. Rachel
Freeth, Therapy Today
The Troubling Story of Antipsychotic Drugs
Joanna Moncrieff
University College London, UK
© Joanna Moncrieff 2013
All rights reserved. No reproduction, copy
or transmission of this publication may be made without written permission.
No portion of this publication may be
reproduced, copied or transmitted save with written permission or in accordance
with the provisions of the Copyright, Designs and Patents Act 1988, or under
the terms of any licence permitting limited copying issued by the Copyright
Licensing Agency, Saffron House, 6–10 Kirby Street, London EC1N 8TS.
Any person who does any unauthorized act in
relation to this publication may be liable to criminal prosecution and civil
claims for damages.
The author has asserted her right to be
identified as the author of this work in accordance with the Copyright, Designs
and Patents Act 1988.
First published 2013 by
PALGRAVE MACMILLAN
Palgrave Macmillan in the UK is an imprint
of Macmillan Publishers Limited, registered in England, company number 785998,
of Houndmills, Basingstoke, Hampshire RG21 6XS.
Palgrave Macmillan in the US is a division
of St Martin’s Press LLC, 175 Fifth Avenue, New York, NY 10010.
Palgrave Macmillan is the global academic
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the world.
Palgrave® and
Macmillan® are registered trademarks in the United States, the
United Kingdom, Europe and other countries.
ISBN 978–1–137–27742–8 hardback
ISBN 978–1–137–27743–5 paperback
This book is printed on paper suitable for
recycling and made from fully managed and sustained forest sources. Logging,
pulping and manufacturing processes are expected to conform to the
environmental regulations of the country of origin.
A catalogue record for this book is
available from the British Library.
A catalogue record for this book is
available from the Library of Congress.
Typeset by MPS Limited, Chennai, India.
To my life-long companions Sarah, Richard
and Madeline
List of Tables and Figures
List of Abbreviations
Preface and Acknowledgements
1 Cure or Curse: What Are Antipsychotics?
2 Chlorpromazine: The First Wonder Drug
3 Magic Bullets: The Development of Ideas
on Drug Action
4 Building a House of Cards: The Dopamine
Theory of Schizophrenia and Drug Action
5 The Phoenix Rises: From Tardive
Dyskinesia to the Introduction of the ‘Atypicals’
6 Looking Where the Light is: Randomised
Controlled Trials of Antipsychotics
7 The Patient’s Dilemma: Other Evidence on
the Effects of Antipsychotics
8 Chemical Cosh: Antipsychotics and
Chemical Restraint
9 Old and New Drug-Induced Problems
10 The First Tentacles: The ‘Early
Intervention in Psychosis’ Movement
11 The Antipsychotic Epidemic: Prescribing
in the Twenty-First Century
12 All is not as it Seems
Notes
Appendix 1: Common Antipsychotic Drugs
Appendix 2: Accounts of Schizophrenia and
Psychosis
References
Index
List of Tables and Figures
Tables
1.1 Models of drug action
1.2 Positive and negative symptoms of
schizophrenia
6.1 Randomised trials of antipsychotic
treatment of an acute psychotic episode
6.2 Recent randomised trials of
antipsychotic discontinuation
7.1 Verbatim descriptions of subjective
effects of antipsychotics from www.askapatient.com
7.2 Changes in dimensions of psychosis
after antipsychotic treatment
10.1 Melbourne criteria for the ‘at risk
mental state’
10.2 PIER (Portland Identification and
Early Referral) programme
Figures
1.1 Kissit demonstration, UK, 2005
1.2 Trends in prescriptions of
antipsychotics issued in the community in England
3.1 Reserpine advertisement
3.2 Melleril advertisement
3.3 Stelazine advertisement
3.4 Melleril advertisement
6.1 Northwick Park first episode study:
patients remaining relapse-free on drug and placebo
7.1 Global adjustment of psychotic patients
over 15 years of follow-up
8.1 Stelazine advertisement
8.2 Stelazine advertisement
8.3 Clopixol acuphase advertisement
9.1 Incidence rate of sudden death in
people taking antipsychotic drugs compared with people not taking them
|
ADHD |
attention deficit hyperactivity
disorder |
|
APA |
American Psychiatric Association
|
|
BPRS |
Brief Psychiatric Rating Scale |
|
CATIE |
Clinical Antipsychotic Trial of
Intervention Effectiveness study |
|
CT |
computerised tomography |
|
D1, D2 |
dopamine 1 and 2 receptors |
|
DSM |
Diagnostic and Statistical
Manual of Mental Disorders |
|
ECG |
electrocardiogram |
|
ECT |
electro-convulsive therapy |
|
FDA |
Food and Drug Administration |
|
LSD |
lysergic acid diethylamide |
|
MRI |
magnetic resonance imaging |
|
NAMI |
National Alliance for the
Mentally Ill |
|
NICE |
National Institute of Health and
Clinical Excellence |
|
NIMH |
National Institute of Mental
Health |
|
PACE |
Personal Assessment and Crisis
Evaluation clinic |
|
PANSS |
Positive and Negative Syndrome
Scale |
|
PET |
positron emission tomography |
|
PIER |
Portland Identification and
Early Referral programme |
|
PTSD |
post-traumatic stress disorder |
|
SSRI |
selective serotonin reuptake
inhibitor |
|
TIPS |
Early Identification and
Treatment of Psychosis programme |
|
VA |
Veterans Affairs |
|
5-HT2a |
5-hydroxytryptamine receptor 2a |
I have been interested in the drugs used to treat
psychiatric problems ever since, as a junior psychiatrist in the 1990s, I
realised how completely drug treatment dominated psychiatric practice, and how
inadequate were the current theories for explaining the effects these drugs had
on people in real life. Since their introduction in the 1950s, what we now call
‘antipsychotics’ have become psychiatry’s most iconic treatment, symbolising
everything that modern psychiatry wishes to portray of itself. They are a
simple, easy to administer, seemingly specific medical treatment that, it is
claimed, target the underlying biological basis of the most serious and
debilitating family of psychiatric conditions, the ‘psychoses,’ including the
most frightening and disabling of all forms of madness, schizophrenia. Discovered
by chance, so the story goes, and introduced against resistance from an
unwilling and psychoanalytically inclined profession, antipsychotics helped to
place psychiatry on a sound medical footing, revealing the true nature of
psychiatric disorders as diseases of the brain, and enabling patients to be
discharged in droves from the old asylums back into normal life.
This book will challenge this common
perception of the revolutionary nature of antipsychotics by setting them in the
context of the physical interventions that preceded them, procedures like
insulin coma therapy, now mostly discredited, and also by reinstating an
understanding of these substances as drugs, in other words as potentially toxic
chemicals that change the way the body functions. It will explore the
characteristic alterations that antipsychotics induce, particularly their
‘psychoactive’ effects, that is the way they modify normal processes of
thinking and feeling. Exploring the history of antipsychotics reveals that the
clinicians and researchers who first prescribed these drugs were interested in
these effects and how they impacted on people with mental disturbances of
various sorts. As the drugs became transformed in official circles into
disease-specific, targeted treatments, however, this knowledge was lost from
view. The ideas represented here form an attempt to reclaim this way of
understanding the effects of antipsychotic drugs and their potential role
within mental health services.
The book also charts the effects of
this metamorphosis of antipsychotics into restorative treatments. The
belittling of the drugs’ serious neurological side effects, the denial of their
use to control unwanted behaviour and the lack of interest in properly
researching their long-term effects all derive from a bias that sees the drugs
as essentially benign because they work by rectifying an underlying disease.
When the limitations of the older
drugs started to be acknowledged in the 1980s, a new range of antipsychotics
was launched, which was promoted first to people with psychotic disorders and
then to a much wider portion of the population with the mantra that the drugs
help reverse a ‘chemical imbalance’ or stop an underlying process of
neurodegeneration. This book will show how these claims do not stand up to
scrutiny, yet they were successfully utilised by the pharmaceutical industry,
aided and abetted by the psychiatric profession, with the result that the new
antipsychotics have become multi-million dollar blockbusters, as lucrative as
antidepressants and statins.
It is important to state straight
away that I am a practising psychiatrist, and that I believe that
antipsychotics have a role in helping to suppress the manifestations of severe
mental disturbance. I have seen people who are locked into an overwhelming
psychotic state, which can sometimes be sufficiently suppressed by
antipsychotics of one sort or another that they are able to regain some contact
with the outside world again. This suppression comes at a price, however, as
other thoughts and emotions are also slowed and numbed, but for some people
this price is worth paying, at least initially. The cost–benefit analysis of
long-term treatment, especially in people who have recovered from their acute
episode, is more difficult to fathom.
One of the problems with writing a
critical book on mental health issues is the question of terminology. Commonly
used terms like ‘mental illness’, ‘patient,’ ‘treatment’ and, of course,
‘antipsychotic’ carry connotations that a critically-minded observer might wish
to challenge. Yet, as the medical view of mental health problems is so deeply
entrenched in the general psyche and forms the basis of the modern mental
health system, it is sometimes difficult to make sense if these terms are not
used. Alternatives that have general currency and acceptance simply do not
exist, and one risks becoming incomprehensible, or at least extremely
cumbersome, if one tries to avoid them altogether. I made a decision, for
example, to use the term ‘antipsychotic’ in preference to the more descriptive
term ‘neuroleptic’ throughout this book when a student asked me what a
‘neuroleptic’ was. Similarly, although I acknowledge that the concept of
schizophrenia is highly contested, so much of the research I have looked at
accepts this label at face value that it is virtually impossible to avoid the
use of the term when looking at this research in any detail without adding
endless caveats.
I apologise, therefore, if the
language I use is insufficiently critical of concepts and views that I, as well
as others, believe are inadequate, misleading, and need dissecting and
challenging. Whatever my reservations about current approaches, however, I do
accept that some people suffer from severe, disabling and occasionally
persistent forms of mental distraction, which can manifest in bizarre,
dysfunctional and sometimes dangerous behaviour, whose origins currently remain
mysterious and possibly always will. It is for these people above all others
that I offer this reappraisal of antipsychotic drugs and their history.
Many other authors have covered
parts of the story I have presented in the following pages. I have drawn, in
particular, on the work of Peter Breggin, David Cohen, Sheldon Gelman, David
Healy, Judith Swazey and Robert Whitaker. I would like to thank Richard Bentall
and other anonymous reviewers for their encouraging comments on the initial
proposal for this book; Michael King, my head of department at University
College London; and Martin Orrell, head of Research and Development at the
North East London Foundation Trust for their support; and Sonu Shamdasani and
the staff and students of the University College London Centre for the History
of Psychological Disciplines for discussing and developing ideas with me.
Special thanks are due to all the librarians at the North East London
Foundation Trust library for tracing obscure articles; to Doreen, Liz and Irene
for help tracking down copyright holders; and to Olivia Middleton and Nicola
Jones at Palgrave for their enthusiasm for the project. I am also grateful to
all those service users, carers, doctors, nurses, psychologists, social workers
and other professionals who have debated with me at meetings and conferences
over the last few years, and to all members of the Critical Psychiatry Network
for their understanding and assistance. Finally, I would like to thank my
mother and father for their hard work proof reading, and for their lifelong
support and encouragement.
1 - Cure or
Curse: What Are Antipsychotics?
Antipsychotic
drugs, otherwise known as neuroleptics and sometimes major tranquillisers, were
introduced into psychiatry in the 1950s. Many people believe these drugs were
the first really effective treatment for the severely mentally ill, and they
have been referred to as ‘miracle’ or ‘wonder’ drugs that were said to
represent a medical advance as significant as antibiotics (Time Magazine, 1954,
1955; Shorter, 1997). Their introduction is frequently credited with
transforming the care of the mad or ‘insane’, enabling the closure of the old
Victorian asylums and ushering in the possibility of more humane care based in
the community. According to this view, people who would have languished in the
back wards of institutions for the whole of their lives could be restored,
through drug treatment, to lead normal lives in the outside world. The drugs
were said to have brought about the ‘social emancipation of the mental
patient’, and to have changed the nature, purpose and location of psychiatric
practice (Freyhan, 1955, p. 84). The introduction of antipsychotics and other
modern drugs into psychiatry was heralded as a ‘chemical revolution’ that
constituted one of the ‘most important and dramatic epics in the history of
medicine itself’ (F. Ayd cited in Swazey, 1974, p. 8).
Antipsychotics are not simply
believed to be more effective than previous treatments, however. They are
believed to be something quite distinct and unique. In contrast to the drugs
that came before them, which were regarded merely as a crude means of
controlling agitated or challenging behaviour, antipsychotics are thought to
work by cleverly targeting an underlying disease or abnormality. They are
thought to exert their beneficial or therapeutic effects by counteracting the
brain processes that give rise to the symptoms of the most devastating and
burdensome of mental conditions—that known as ‘schizophrenia’. With the introduction of antipsychotics, psychiatrists
believed they could, at last, alter the course and outcome of a major mental
illness, and that ‘for the first time, public mental institutions could be
regarded as true treatment centres, rather than as primarily custodial
facilities’ (Davis and Cole, 1975, p. 442). The idea that there were proper
medical treatments for mental disorders that acted on underlying diseases in
the same way as antibiotics or cancer drugs helped to lift psychiatry out of
the doldrums, transforming it from a neglected form of social work into what
was perceived as a properly scientific activity, and restoring it to its
rightful place within the medical arena (Shorter, 1997; Comite Lyonnais de
Recherches Therapeutiques en Psychiatrie, 2000). By this account, the
introduction of antipsychotics is a story of untainted medical progress.
Yet, for others, antipsychotic drugs
are the embodiment of psychiatric oppression, equivalent to the shackles and
manacles of previous eras. They have replaced electro-convulsive therapy (ECT)
and lobotomy as the main target of criticism of the psychiatric system, and are
viewed by detractors as a chemical straight jacket, used to facilitate the
control of unwanted behaviour. Many people who have taken the drugs describe
the experience as highly unpleasant, like a ‘living hell,’ ‘sheer torture’ or
being in a ‘drug prison’ (Breggin, 1993a, p. 57; Anonymous, 2009b). People
describe feeling like ‘zombies’ under the influence of the drugs, with their
mental capacities dulled and their emotions blunted (Wallace, 1994). For those
who are forced to take antipsychotics against their will, the experience is
particularly traumatic. Former patient turned campaigner David Oaks, reflecting
on his experience of the mental health system in early adulthood, described how
the effect of coerced antipsychotic drug treatment ‘felt like a wrecking ball
to the cathedral of my mind’ (Oaks, 2011, p. 190). Mental health advocacy
groups have argued that such activity constitutes a breach of human rights.
Demonstrations against forced drug treatment have become a regular occurrence
outside major psychiatric conferences in the USA (Mindfreedom, 2012), and
campaigns have also been conducted in England (Figure 1.1), Ireland and Norway. Even those who feel
the drugs have been helpful often describe the high price they have had to pay
for these benefits. ‘It makes you sane, but you’re not much better off’,
commented one antipsychotic user on a medication website (Anonymous, 2009a).
Critics from within the mental
health professions have also challenged the view that antipsychotic drugs are a
restorative and benign medical treatment. Psychiatrist Peter Breggin claims
that antipsychotics induce a form of ‘chemical lobotomy’ and cause permanent
brain damage, leading to a form of drug-induced
dementia (Breggin, 2008). Furthermore, Breggin and others suggest that the
‘brain disabling’ effect of these drugs is not an unintended side effect, but
the intended consequence of drug treatment. This view
of antipsychotics as a chemical cosh that stifles mental and physical activity
goes back to the time of their introduction in the 1950s, when many clinicians
welcomed the new drugs’ ability to suppress normal brain function. Others,
however, commented on how the new tranquillisers, later to become known as
antipsychotics, had replaced the noise and disturbance of the asylum with the
‘silence of the cemetery’ (Comite Lyonnais de Recherches Therapeutiques en
Psychiatrie, 2000, p. 29; attributed to Racamier or Lacan).
Figure 1.1 ‘Kissit’
demonstration, UK, 2005 (Reproduced courtesy of Anthony Fisher Photography)
While criticising antipsychotics was
once regarded as the territory of a few extremists, the reputation of these
drugs has recently become more widely tarnished through revelations about the
activities of the companies that market them. In 2009, Eli Lilly reached the
record books for incurring what was at the time the largest fine in US
corporate history for the illegal marketing of its blockbuster antipsychotic
drug, Zyprexa (olanzapine), in situations in which it had not been licenced.
AstraZeneca, Pfizer and Johnson & Johnson have also been found guilty of
illegally promoting their atypical antipsychotics, and revelations that
companies had suppressed or minimised evidence of the serious side effects of these drugs, particularly their propensity to
cause weight gain and diabetes, has also come to light (Berenson, 2006). Large
settlements have been paid out to people who have alleged drug-induced effects
of this sort in North America (Berenson, 2007). Moreover, data have been
gradually accumulating from brain imaging studies that confirm earlier
suspicions that antipsychotics cause brain shrinkage. Nancy Andreason, a
leading biological psychiatrist and former editor of the American
Journal of Psychiatry, acknowledged these findings in an interview with
the New York Times in 2008 (Dreifus, 2008). In 2012,
British psychiatrist, Peter Tyrer, editor of the British
Journal of Psychiatry, went even further, admitting that there is an
‘increasing body of evidence that the adverse effects of treatment [with
antipsychotics] are, to put it simply, not worth the candle’. ‘For many’, he
suggested, ‘the risks outweigh the benefits’(Tyrer, 2012, p. 168).
Understanding how a group of drugs,
initially understood as powerful nervous system suppressants, came to be
regarded as a miraculous medical intervention that could successfully
counteract the biological origins of mental disease, helps to illuminate how a
motley collection of unpleasant and toxic substances could rise to become
modern day blockbusters. Antipsychotics started life in the asylums of the
mid-twentieth century, but 50 years later they are being prescribed to millions
of people worldwide, including children, many of whom have never even seen a
psychiatrist (Sankaranarayanan and Puumala, 2007). Aggressive marketing has
driven these powerful chemicals, once reserved for the most severely mentally
disturbed, out into the wider community. We all need to be aware now of what
these drugs are, and what they can do. Antipsychotics have become everybody’s
problem.
Use of Antipsychotics
The first drug that came to be classified as an
antipsychotic is chlorpromazine, but it is often better known by its brand
names—Largactil in the UK and Thorazine in the USA. It was first used in
psychiatry in the early 1950s, and it was regarded as so successful that in the
following years numerous other drugs aimed at treating psychosis and
schizophrenia were introduced. Haloperidol was first marketed in 1958 and, for
a long time, it was the biggest selling antipsychotic on the market. Stelazine
(trifluoperazine) and perphenazine were also introduced in the 1960s, and
Modecate (fluphenazine), the first injectable, long-acting, ‘depot’ preparation
of an antipsychotic, was released in 1969. It was followed by Haldol, a depot
preparation of haloperidol, and the still commonly
used depot injections Depixol (flupentixol) and Clopixol (zuclopenthixol) (see Appendix 1).
In the 1990s a new generation of
antipsychotic drugs was introduced, which are sometimes referred to as the
‘atypicals’. These followed on the heels of clozapine, the archetypal atypical
antipsychotic, which was reintroduced in 1990, after having been abandoned in
the 1970s when its potential to cause life-threatening blood disorders became
apparent. The success of clozapine for people who were deemed to have
‘treatment resistant schizophrenia’, along with problems that became apparent
with the older drugs, particularly the drug-induced neurological condition
known as tardive dyskinesia, encouraged attempts to develop other
clozapine-like drugs for schizophrenia and psychosis. Risperidone, also known
by its brand name Risperdal, was duly licensed and launched in 1994, and
olanzapine, or Zyprexa in 1996. Quetiapine, marketed under the name Seroquel,
was approved by the US Food and Drug Administration in 1994 and in the UK in
1997.
For the first 30 years after their
introduction antipsychotic drugs were reserved mainly for the treatment of
people with severe psychiatric problems. They were officially recommended for
the treatment of people with schizophrenia or psychosis, although they were
always administered more widely than this, and were given to many of the
inmates of the old asylums, regardless of their diagnosis. Low doses of some of
the more sedative antipsychotics were also prescribed to people with sleep
problems and anxiety, but such use was not endorsed officially, and they were
never regarded as drugs that had a mass market. Since the introduction of the
‘atypicals’, however, the use of these drugs has widened and aggressive
marketing has made some of these drugs into worldwide best-sellers. In 2010
spending on antipsychotic drugs in the USA reached a total of almost $17
billion, only just behind anti-diabetic drugs and statins, and ahead of
antidepressants (IMS Institute for Healthcare Informatics, 2011). In England,
in 2010, 7.5 million prescriptions were issued for antipsychotics in the
community alone (excluding the large number of prescriptions issued to patients
in psychiatric hospitals)—a 61% increase on the number of prescriptions issued
in 1998 (Figure 1.2). The
cost of the drugs increased by a dramatic 286% over the same period, with
antipsychotics costing the English National Health Service £282 million in 2010.
By 2007, they became the most costly class of drug treatment used for mental
health problems in England, overtaking antidepressants, which had enjoyed this
dubious honour for a decade or more (Ilyas and Moncrieff, 2012).
The success of the new generation of
antipsychotics was achieved in two ways. First, marketing campaigns attempted
to convince prescribers that the atypical
antipsychotics should replace the use of the older antipsychotics for the
treatment of people with schizophrenia or psychosis. By 2002, atypical
antipsychotics represented more than 90% of all antipsychotics prescribed in
the USA (Sankaranarayanan and Puumala, 2007), and, by 2009, they had captured
73% of the community prescription market in the UK (NHS Prescription Services,
2009). A few blockbusting drugs now occupy the majority of this market,
particularly olanzapine, quetiapine and risperidone (Zyprexa, Seroquel and
Risperdal). In 2010 these three drugs accounted for 63% of community
prescriptions of antipsychotics in England, and olanzapine and quetiapine alone
made up 76% of the costs of all antipsychotic drugs.
Figure 1.2 Trends in
prescriptions of antipsychotics issued in the community in England (data from
the National Health Service Information Centre for Health and Social Care,
1998–2010)
Second, there has been a concerted
effort to expand the indications for the use of antipsychotics in general, so
that the atypical antipsychotics could be targeted at the wider population in
the way that had proved so successful for modern ‘antidepressant’ drugs like
Prozac and Seroxat (Paxil). Companies promoted antipsychotics for use in
elderly people with dementia, targeting the staff of nursing homes and
pharmacies, despite the fact they had no licence for the treatment of dementia,
or agitation in people with dementia, and regardless of accumulating evidence
that the use of antipsychotics in dementia shortens people’s lives. Atypical
antipsychotics were also promoted for the treatment of common problems
including anxiety, depression, irritability, agitation and
insomnia (United States Department of Justice, 2009, 2010), and data from the
USA and the UK suggest that the majority of prescriptions of atypical
antipsychotics are now issued to people who are diagnosed with depression,
anxiety or, more recently, bipolar disorder rather than schizophrenia or
psychosis (Kaye et al., 2003; Alexander et al., 2011).
The expansion of the concept of
bipolar disorder has been one of the key strategies employed to expand
antipsychotic use into the wider population. Atypical antipsychotic
manufacturers successfully transformed perceptions of the condition from being
a rare and highly distinctive form of severe madness, to the common and
familiar experience of intense and fluctuating moods. In this manner they were
able to capture some of the large population that had previously identified
themselves, or had been identified, as depressed (Spielmans, 2009).
Most worryingly, antipsychotics have
been prescribed to increasing numbers of children over the last few years,
especially in the USA (Olfson et al., 2006). Much of this prescribing has also
been justified by giving children the newly fabricated diagnosis of paediatric
bipolar disorder, but the drugs are also prescribed, often in combination with
other drugs, to children diagnosed with attention deficit hyperactivity
disorder (ADHD), autism and ‘behavioural problems’. Although parents and
academics have been at the forefront of the trend to label children with
bipolar disorder and medicate them with antipsychotics, drug company money has
helped to lubricate this activity and give it respectability by funding
research programmes and cultivating leading academics as allies with generous
payments for services rendered (Harris and Carey, 2008).
What Are Antipsychotics and What Do They
Do?
This expansion in the use of antipsychotic drugs has
been dependent on a theoretical framework that casts psychiatric drugs as
specially targeted treatments that work by reversing or ameliorating an
underlying brain abnormality or dysfunction. The nature of the abnormality is
often referred to as a ‘chemical imbalance’, and drug company websites
repeatedly stress the idea that psychiatric medication works by rectifying a
chemical imbalance. The website for the antipsychotic Geodon (zisprasidone—an
antipsychotic used in the USA, but not in the UK), stated in its information
about schizophrenia in 2006 that ‘imbalances of certain chemicals in the brain
are thought to lead to the symptoms of the illness. Medicine plays a key role in balancing these chemicals’ (my emphasis)
(Pfizer, 2006). Similarly, Seroquel is ‘thought to work’, said
its manufacturers in 2011, ‘by helping to regulate the balance of chemicals in
the brain to help treat schizophrenia’ (AstraZeneca, 2011). Antidepressants
like Prozac and Paxil are also said to ‘balance your brain’s chemistry’
(GlaxoSmithKline, 2009) and information on bipolar disorder, or manic
depression, suggests the condition is triggered by ‘an imbalance in some key
chemicals in the brain’ that antipsychotics can help to ‘adjust’ (Otsuka
America Pharmaceutical, 2012).
Information produced by professional
organisations makes similar statements. The American Psychiatric Association’s
1996 leaflet on schizophrenia suggested that antipsychotic drugs ‘help bring
biochemical imbalances closer to normal’ (American Psychiatric Association,
1996). The UK’s Royal College of Psychiatrists claims that there is an
‘imbalance in brain chemistry’ in people with psychosis or schizophrenia (Royal
College of Psychiatrists, 2004) and antidepressants are said by the American
Psychiatric Association to ‘correct imbalances in the levels of chemicals in
the brain’ (American Psychiatric Association, 2005).
What sort of drugs antipsychotics
are thought to be, and how they are understood to work in people with
schizophrenia and other conditions, is fundamental to the debate about their
merits and how to use them appropriately. These descriptions of the action of
psychiatric drugs as reversing chemical imbalances embody a particular way of
understanding the action of drugs, which I have called the ‘disease-centred’
model of drug action. The disease-centred model can be contrasted with an
alternative ‘drug-centred’ model, and some of the features of the two models
are outlined in Table
1.1 (Moncrieff and Cohen, 2005; Moncrieff, 2008a).
The disease-centred model of drug
action is based on the idea that drugs work by acting on the aberrant
biological processes, be it chemical imbalances or other abnormalities, which
are assumed to produce the symptoms of a particular disorder. According to this
view, drugs make the body more ‘normal’ by helping to reverse an underlying
disease or dysfunction. This action on the disease process is the drug’s
‘therapeutic’ action, and all its other actions are designated as ‘side
effects’ and considered to be of secondary importance.
Table 1.1 Models of drug
action
|
Disease-centred
model |
Drug-centred
model |
|
Drugs correct an abnormal brain
state |
Drugs create an abnormal brain
state |
|
Drugs as medical treatments |
Drugs as psychoactive substances |
|
The beneficial effects of drugs
are derived from their effects on a presumed disease process |
The drugs alter the expression
of psychiatric problems through the superimposition of drug-induced effects |
|
Example:
insulin for diabetes |
Example:
alcohol for social anxiety |
The disease-centred model of drug
action has become the dominant way of theorising what drugs do when they are
taken by someone with a mental health problem. It is so influential that people
are not aware that there are other ways of conceptualising how drugs affect
people with mental disorders, or whether the disease-centred model is supported
by scientific evidence. But the idea that psychiatric drugs work by targeting
underlying biological processes that are specific to certain sorts of mental
health problems or symptoms is central to the way that psychiatric treatment is
administered and presented, and to the way that research on drug treatment is
designed, conducted and interpreted. The latest edition of the principle
American textbook of psychiatry (which, interestingly, opens with a four-page
colour spread of different drugs listed alphabetically under their trade
names), stresses that ‘mental disorders are true medical conditions that can
benefit from drug therapy in the same way that diabetes, asthma and
hypothyroidism, and other chronic disorders are responsive to medication’
(Sussman, 2009).
As we shall see in the following chapters,
however, this conception of how psychiatric drugs work is relatively recent.
Prior to the 1950s the drugs that were prescribed to psychiatric patients were
understood quite differently, according to what I have called the drug-centred
model of drug action. This model is so named because it suggests that
psychiatric drugs need to be understood first and foremost as drugs, that is as chemical substances that alter the way
the body functions. Moreover, psychiatric drugs are a
special type of drug known as psychoactive drugs,
which are substances that affect brain functioning, and which, as a
consequence, alter mental experience and behaviour. According to the
drug-centred model, rather than reversing some underlying brain abnormality,
psychiatric drugs themselves create an abnormal or altered state of physical
and mental functioning.
Psychoactive drugs, by definition,
are chemicals that act on the body’s central nervous system and by doing so
produce changes in perception, mood, consciousness and behaviour. The most
familiar psychoactive substances are recreational drugs like alcohol, nicotine,
heroin, cannabis and LSD. When we think of recreational drugs we refer to the
altered mental states they produce as ‘intoxication’. Some drugs, such as
alcohol, produce profound and easily identifiable states of intoxication,
whereas the intoxication produced by drugs like nicotine and caffeine is more
subtle. Psychiatric drugs also produce states of intoxication whose features
vary according to what sort of drug is taken. Just as the effects of cannabis
differ from those of alcohol or heroin, so the effects produced by
‘antipsychotics’ are different from those produced by drugs like Valium, which
differ again from the effects of the so-called antidepressant drug Prozac, for
example. The characteristic features of the intoxicated or drug-induced state
depend on the chemical structure and nature of each drug. Recreational drugs
produce effects that some people find pleasurable or enjoyable. Many other
psychoactive drugs, however, including the antipsychotics, produce effects that
most people find unpleasant.
One of the many and varied effects
of antipsychotic drugs is their ability to oppose the actions of the brain
chemical called dopamine by blocking certain types of dopamine receptors.1
At least five types of dopamine receptor have been identified so far, but it is
the ability of antipsychotics to block one particular type of dopamine
receptor, the D2 receptor, that gives rise to their
characteristic neurological effects and is thought, by many, to produce their
therapeutic effects. However, both the first and second generation of
antipsychotic drugs come from a number of different chemical classes, and none
of them act solely on dopamine receptors. Many antipsychotics, including
chlorpromazine, thioridazine, clozapine and olanzapine, have an extremely broad
range of actions on a large number of the brain’s chemical systems, and some of
them, such as clozapine and olanzapine have relatively weak actions on the D2
receptor. Even those drugs that target the dopamine system more precisely, like
haloperidol, have a variety of actions on other systems. Despite decades of
research and speculation, we do not fully understand the chemical basis of the
actions of antipsychotics, or whether, as a group,
they act on symptoms through the same mechanism or through a variety of
different mechanisms.
Although there is variation in
individuals’ response to all drugs, psychoactive drugs produce their
characteristic range of effects in anyone who takes them, regardless of whether
or not they have a psychological problem. Most psychoactive drugs also have
physical effects, and the physical and mental effects are often inextricably
linked. Alcohol and benzodiazepines, for example, produce a state of both
physical and mental relaxation, and stimulant drugs, like amphetamines and
cocaine, stimulate mental processes like attention and alertness, as well as
physical processes like increasing heart rate and blood pressure. The physical
and mental effects of antipsychotics are also intimately linked, as we shall
see, and it is impossible to understand one without an appreciation of the
other.
The drug-centred model suggests that
drugs can sometimes be helpful because certain drug-induced psychoactive
effects can replace or suppress the manifestations of mental disorders. An
example of this is the long-accepted benefits of alcohol in people with social
phobia or social anxiety. Alcohol is not thought to be helpful because it
corrects a deficiency of alcohol within the brain, or because it corrects
another chemical imbalance. It is thought to help because one of the
characteristic features of alcohol intoxication is that it reduces social
inhibitions, which may be helpful for someone who finds social situations
anxiety-provoking.
Following the drug-centred model of
drug action, the barbiturates and other sedative drugs that were used in
psychiatry prior to the advent of antipsychotics were understood to be acting
as chemical restraints, which sedated people and rendered them more manageable,
without affecting the underlying problem. As we shall see, the antipsychotics
themselves were also viewed in this manner at first. Perceptions changed over
the course of the 1950s and 1960s, however, and the group of chemicals that
were first known as neuroleptics or tranquillisers, came to be viewed as a
specific treatment for the symptoms of psychosis or schizophrenia. First
thought of as special sorts of sedatives, they were transformed in the minds of
those who prescribed them into psychiatry’s first real ‘magic bullet’.
Evidence for the Action of Antipsychotics
This transformation was not, however, as we shall see
in more detail in Chapter 3, the
result of an accumulating body of compelling scientific evidence,
or even of persuasive and informed debate. No studies were set up to evaluate
whether antipsychotics or antidepressants really targeted a disease process,
and whether their mind-altering properties could be deemed irrelevant to their
impact on mental health problems. When the disease-centred model of drug action
was adopted, the fact that there was another way of thinking about drug action
was swiftly forgotten, and so almost no research was conducted to attempt to
confirm or refute the idea that psychiatric drugs worked in a disease-specific
manner. Elsewhere, I have reviewed in detail the little evidence that exists on
all types of psychiatric drugs (Moncrieff, 2008a) and, in the course of this
book, we shall see what research has been conducted that might illuminate the
mode of action of antipsychotics. I shall argue that none of the evidence
justifies the presumption that antipsychotics act in a disease-specific manner
in schizophrenia or psychosis, and that the drug-centred model remains a more
compelling approach for explaining the full range of actions of
antipsychotics—both those that are intended and those that are not.
It is important to realise at the
start that no chemical imbalance or other biological process that might explain
drug action in a disease-centred way has been substantiated for any psychiatric
disorder. The serotonin theory of depression and the dopamine hypothesis of
schizophrenia, which appear to suggest that drugs act in this way, remain
merely hypotheses. Most authorities now admit that there is no evidence that
depression is associated with abnormalities of serotonin or noradrenaline, as
used to be believed (Dubovsky et al., 2001). There is also little empirical
support for the dopamine hypothesis of schizophrenia, as we shall see in Chapter 4, and many psychiatric
researchers acknowledge it is at least inadequate as an explanation for the
aetiology of schizophrenia. The fact that the theory will not die, despite
decades of contradictory findings, illustrates the importance of portraying the
action of antipsychotics in disease-centred terms. By helping to establish the
idea that antipsychotics exert a disease-specific action in schizophrenia and
psychosis as unquestioned fact, the dopamine hypothesis has helped to create
the impression that antipsychotics might have disease-specific actions in the
many other circumstances in which they are now employed.
The Zyprexa website boldly suggests that
‘antipsychotic medicines are believed to work by balancing the chemicals found naturally in the brain’ (my emphasis) (Eli Lilly, 2011).
The statement demonstrates the utility of adopting the disease-centred model of
drug action. By taking Zyprexa it is implied that you will restore some
imagined chemical harmony, whose disruption is
suggested to be the origin of your problem or symptoms. This appealing, but
entirely hypothetical, proposition conveniently disguises the fact that drugs
consist of foreign chemical substances that would be expected to alter and
disrupt the body’s normal chemical functioning, rather than restore or enhance
it.
The Nature of Psychosis and Schizophrenia
Although antipsychotics are used more widely, their
most well accepted use continues to be what they are named for—the treatment of
psychosis, or what generally used to be called schizophrenia. Schizophrenia is
a highly contested concept, of course, and even mainstream psychiatrists would
acknowledge that the label is applied to people with a variety of different
problems. The German psychiatrist, Eugene Bleuler first coined the term
schizophrenia, and described what he saw as the characteristic ‘splitting,’
disintegration or fragmentation of psychic functions (Bleuler, 1911). He also
drew attention to the withdrawal from reality that people with the disorder
show, which he referred to as ‘autism’—a term that has now, of course, been
used to designate another proposed, but also disputed, psychiatric condition
(Timimi et al., 2011). Bleuler also divided the symptoms into ‘positive’
symptoms, which consist of bizarre thoughts and experiences, including
delusions and hallucinations, and ‘negative’ symptoms. The latter denote a
state of demotivation and apathy, a loss of interest in participating in the
normal activities of life, and the blunting of emotional responses (Table 1.2).
The term ‘psychotic’ is usually
applied to the positive symptoms of schizophrenia, and an episode of ‘psychosis’
refers to an episode characterised by symptoms such as delusions and
hallucinations that indicate a loss of contact with reality. In an extreme
psychotic state people appear to be locked into an internal mental world. As
Bleuler put it: ‘one of the most important symptoms of schizophrenia is the
preponderance of inner life, with an active turning away from the external
world. The most severe cases withdraw completely and live in a dream world;
milder cases withdraw to a lesser degree’ (Bleuler, 1951, p. 397).
Table 1.2 Positive and
negative symptoms of schizophrenia
|
Positive
symptoms |
Negative
symptoms |
|
•
Hallucinations (usually auditory, ‘hearing voices’) |
• Reduced
speech |
|
• Delusions |
• Apathy or
inactivity |
|
• Feelings of
being controlled |
• Social
withdrawal |
|
• Feelings of
having thoughts read, broadcast or interfered with |
• Blunted
emotions |
|
• Incoherent
or tangential speech |
|
To illustrate the variety of ways
that people can manifest what is called psychosis or schizophrenia I have
summarised some accounts written by people who have had this experience (or
their carers) in Appendix 2. As these stories demonstrate, for some
psychotic symptoms are frightening and distressing and clearly unwanted, but
for others psychotic reality can be enjoyable and exciting. For others it is
both of these things. Some people take years to reach a state of stability, and
for many this involves a long and arduous process of coming to terms with the
unpleasant and stifling effects of antipsychotic medication. Even then, some
people continue to experience psychotic symptoms and struggle to function
independently. The final story, however, illustrates that it is possible to
make a full recovery from severe and prolonged psychotic episodes without
modern drug treatment, and to derive benefit from the experience.
There has, of course, been a vast
amount of research and debate into the nature and causes of schizophrenia. On
the one hand, mainstream biological psychiatry asserts that it is a brain
disease caused by a specific, but not yet fully identified, abnormality of
brain function, which may, in turn, be the result of a particular genetic
make-up. On the other hand, the critics of biological psychiatry have
questioned the validity of the whole concept of schizophrenia. Thomas Szasz,
for example, the psychiatrist famous for denouncing psychiatry, views all
psychiatric diagnoses, including schizophrenia, as disguised moral and political judgements about deviant behaviour (Szasz,
1970). Others have suggested that psychotic breakdowns are reactions to
traumatic situations, and recent research reveals high levels of previous
physical and sexual abuse and victimisation in people diagnosed with psychotic
disorders (Read et al., 2003; Gracie et al., 2007). This view overlaps with
theories advanced in the 1960s and 1970s by ‘antipsychiatrist’ R.D. Laing and
colleagues, who suggested that psychotic experiences could be understood as
meaningful responses to the circumstances of an individual’s upbringing and
environment (Laing, 1965). In his later writings, influenced by the 1960s
counterculture, Laing suggested that psychosis might even represent a ‘sane
response to an insane world’ (Laing, 1967).2
Other psychological analyses, without necessarily contradicting the possibility
of understanding the condition at a biological level, have underlined the
relation between psychotic symptoms, like hearing voices and paranoid
delusions, and normal mental processes (Freeman, 2007; Waters et al., 2010).
Szasz and other writers have
emphasised the difference between a ‘mental illness’, such as schizophrenia,
and an ordinary bodily disease. British psychiatrist Alec Jenner described
schizophrenia, as ‘closer to a life process than to an illness’ (Jenner et al.,
1993, p. 61). According to this view, the tendency to have psychotic breakdowns
or a longer lasting mental condition can be understood as part of the variety
of human nature or a set of ‘ways of being human’ (Jenner et al., 1993). This
does not mean that it is a desirable state of affairs, but it does mean that,
like other aspects of human character and behaviour, madness or mental disorder
results from a complex interaction of biology, environment and agency, and that
disentangling the precise contributions of these different factors may well be
impossible.
In this book I wish to largely
side-step the question of the nature of schizophrenia, as it is already the
subject of many other books. Nor is it immediately relevant to the subject of
what antipsychotics do and how they do it. The analysis of antipsychotic drugs
presented here is applicable whatever position you take on the nature of
schizophrenia. A drug-centred model of drug action is compatible with the idea
that schizophrenia is a brain disease, as well as with other models of the
nature of schizophrenia. The drug-centred model merely suggests that current
psychiatric drugs do not work by acting on an underlying disease process. It
does not necessarily deny that there is an underlying disease, although it does
weaken the current case that such an entity exists because the idea that
antipsychotics have a disease-specific action has long been an important part
of the evidence for this position.
It
is necessary to point out, however, that despite the claims of much official
information, current evidence does not allow us to conclude that schizophrenia
is a brain disease in the simple sense in which we usually understand the term
‘disease’. No biological factor, whether it be a genetic, biochemical or
anatomical deviation, has been found that is consistently and specifically
related to schizophrenia, despite more than half a century of recognisably
modern research efforts. Moreover, what was thought to be one of the most
reliable indications that schizophrenia arises from a defective brain, namely
the finding that people with the diagnosis have smaller brains and larger brain
cavities than people without, turns out, as we shall see in Chapter
10, to be at least partially a
consequence of antipsychotic drug treatment.
Whatever its nature, however, and
whether it is best understood as a brain disease, as social deviance, a
response to trauma, a way of being human or a combination of these ideas,
schizophrenia, psychosis or madness remains a serious problem for many of the
people who go through it, their families and carers, and for society as a
whole.
Antipsychotics and Mental Health Policy
Antipsychotic drugs were introduced during a period of
transformation in the nature of mental health services in the Western world,
when the care of people deemed mentally disturbed moved out of the Victorian
institutions and into the community. Whether or not the introduction of
antipsychotic drugs facilitated this process, and whether the drugs worked by
restoring people to normality or through chemical suppression, has been the
subject of much debate, but they undoubtedly played a symbolic role, if nothing
else (Gronfein, 1985).
Psychiatry has changed in other ways
over the decades since the introduction of antipsychotics. The once influential
ideas of psychoanalysis have almost disappeared from mainstream teaching and
practice, and in their place has risen a renewed and increasingly dogged
biological psychiatry. In this new psychiatry, people are given medical-type
diagnostic labels derived from manuals like the American Diagnostic
and Statistical Manual (the DSM), which are
regarded as designating underlying diseases, and treatment is applied according
to the label or the diagnosis, with little regard for the personal history and
particular circumstances of the individual. The skill of the practitioner, and
the importance of the therapeutic relationship, once thought central to being a
good psychiatrist, have been relegated to the shrinking specialism of
psychotherapy, and replaced with a guideline-driven, shallow imitation of general medical practice. Drugs, especially
when understood as acting according to a disease-centred model, fit nicely with
this new approach, providing the basis for quick, cheap and apparently
evidence-based therapy.
In the following chapters I will
describe how antipsychotic drugs have been central to the transformation of the
image of psychiatry in the minds of its practitioners and the public over the
last few decades. The acceptance that these drugs could target the basis of
schizophrenia conferred on psychiatry a level of respect it had never had
before. Coupled with the use of technology, such as brain scans, for example,
psychiatry acquired all the appearances of being a high-powered, cutting-edge
scientific activity in which a variety of brain abnormalities could be detected
and rectified with highly specific and targeted interventions. Having a
psychiatric diagnosis lost its stigma, and people actively sought to be
labelled and treated with the new products of this sophisticated branch of
medicine.
The new image of psychiatry is
exemplified in the portrayal of the use of drugs for the control of challenging
or aggressive behaviour. No longer regarded as the equivalent of the shackles
and manacles that were used to restrain the ravings of the mad in times past,
the use of antipsychotics to reduce disturbance in psychiatric institutions is
portrayed as a benign, therapeutic intervention administered for the health and
benefit of the patient. Despite the fact that the same drugs are routinely
employed as animal tranquillisers, the view that antipsychotics work in a
disease-centred fashion has helped to present psychiatric activities as
fundamentally therapeutic rather than coercive.
As early as the 1950s, Thomas Szasz
pointed to the dangers of presenting the forcible control of unwanted behaviour
as a medical treatment. The use of drugs conceals the power relation that
enables one group of people to force their will on another, and removes the
natural checks that exist when the reality of the situation is acknowledged. As
Szasz observed in 1957, ‘restraint by chemical means does not make us guilty;
herein lies the danger to the patient’ (Szasz, 1957, p. 91). Behavioural
control using drugs does engender guilt, however, albeit less directly and
immediately than mechanical restraint, and the rise of the disease-centred
model of antipsychotic action is a testimony to the persistence of that guilt
into the modern pharmacological era. As long as antipsychotic drugs were
understood according to a drug-centred model, the qualities that made them
useful restraints could not be ignored. It was only with the disease-centred
model that forcible drugging could be presented as a treatment for the
patient’s underlying disease, and the guilt could truly lift.
An Alternative View of Antipsychotics
The account I offer in the rest of this book suggests
that antipsychotic drugs can be regarded as implements of social control, but
that they can also help individuals gain relief from intense and intrusive
psychotic experiences or destructive emotional states. The neurological
inhibition they induce helps to reduce psychotic thought processes, and calm an
agitated mind and body. Sometimes, when people are locked into an internal
reality they cannot escape, this chemical suppression can bring them back into
contact with the real world, and enable them to resume some normal activities
and re-establish relations with other people. These benefits come at a price,
however. Some people simply feel a little sedated, or numb or stiff. But others
complain that their whole personality has been altered by the drugs. They feel
they have lost their motivation and interest in the world, their originality,
their emotional intensity; in short, the very things that make us human.
The same pharmacological properties
that suppress psychotic experiences are what make antipsychotic drugs effective
in tranquillising the challenging, aggressive patient and subduing the frenzied
activities of the individual gripped by mania. In the long term the drugs can
be used to modify behaviour that others find threatening, disturbing or
antisocial. Taking a drug-centred approach to the nature of antipsychotics
therefore reveals how they can be both effective chemical restraints and
useful, therapeutic interventions.
By suggesting that social control is
still at the heart of psychiatry, the drug-centred model of antipsychotic drugs
opens up issues that the psychiatric profession had hoped to close, however.
This book will chart the way that this mode of understanding was successfully
buried, and how its replacement with the disease-centred model of drug action helped
to divert attention from the pharmacological properties of psychiatric drugs
and their potential application for the modification of unwanted behaviour. I
hope the book will enable readers to re-evaluate the story of antipsychotic
drugs as it is usually told, and appreciate the many dangers they present, as
well as the opportunities they provide some people in the grips of a severe
mental disorder. It is intended to throw a sceptical light on the acres of
research literature and marketing material that presents these drugs as a
practically untarnished boon to humankind, but also to show, through first-hand
accounts, how the drugs might be distinctively helpful in some situations. It
should also raise questions about the consequences of long-term treatment, and
why, six decades after their introduction, we still cannot be sure if
antipsychotics help or harm people who take them for long periods of time.
Chlorpromazine: The First Wonder Drug
Since the 1950s, drugs have been regarded as the
principle form of treatment for people with psychiatric conditions. Alongside
the introduction of chlorpromazine and other so-called ‘antipsychotics’ in the
1950s, lithium was suggested as a treatment for people diagnosed with mania or
manic depression, drugs that are referred to as ‘antidepressants’ started to be
used and, in the 1960s, the benzodiazepines—a class of sedative drugs that
includes such household names as Valium, Librium and Ativan—were developed for
the treatment of anxiety. Nowadays, the central, and often the only, aspect of
treatment most people with mental health problems receive is drug treatment.
When one drug fails to resolve a person’s difficulties, another one is started,
and then another, and then drugs are needed for the side effects of the first
drugs and so on. Many people end up taking multiple substances in what is often
an endless quest based on the belief that the right drug or drug combination
can reverse the underlying problem.
A large proportion of psychiatric
research and theory has also been inspired by the introduction of new drug
treatments. When the disease-centred theory of drug action took hold, newly
discovered drug-induced effects were interpreted as a clue to the underlying
basis of the mental disorder the drug was thought to treat. So when
antipsychotics were found to block dopamine receptors, acres of research were
devoted to locating dopamine abnormalities in people with schizophrenia, as we
shall see in Chapter 4. In a similar
fashion, the effects of stimulants and some early ‘antidepressants’ on
noradrenaline, and later the effects of drugs like Prozac on the serotonin
system, inspired a vast research effort to investigate levels of noradrenaline
and serotonin in people with depression—research that has yielded even less
that is conclusive or enlightening than the research on dopamine in
schizophrenia. Although critics consider this research
activity a waste of resources and a dangerous distraction from the real nature
of psychiatric drugs (Breggin, 2008; Kirk et al., 2013), many scientists
believe that modern drug treatments are helping them to unlock the secrets of
mental illness.
Psychiatry in the Early Twentieth Century
The use of drugs has a long history in psychiatry, but
the idea that they are an important intervention and that their action relates
to the nature of the underlying condition is more recent. In the early
twentieth century there was plenty of interest in the possible biological
factors underlying mental disorders, with frequent articles discussing their
proposed hereditary, biochemistry and histology, but there was little focus on
treatment. At this time, psychiatric care took place in large state asylums
that catered for ‘pauper lunatics’—that is people whose families had no money to
pay for their care—and smaller private asylums for private patients. There was
no care or follow up once people left the asylum. Many of the pauper lunatics
came from, and returned to, the local workhouse—the institution that provided a
minimal level of subsistence for those who had no other means.
The usual account of early
psychiatry suggests that few people recovered and that, after being admitted to
an asylum, people were rarely discharged. This picture has been challenged,
however, by a considerable amount of historical research, which shows that
40–60% of people admitted to asylums in England and Wales were discharged
within a year. By the last years of the nineteenth century, two thirds of
patients admitted stayed less than two years (Wright, 1997; Ellis, 2006).
As far as there was any conception
of ‘treatment’, it consisted of fresh air and the structured routine of the
asylum, which included jobs within the asylum system that patients were set to
do as soon as they were thought fit (Henderson and Gillespie, 1927; Anonymous,
1990). There was experimentation with various physical procedures, like
surgery, to remove potential sites of infection, which was thought, at one
point, to be a cause of chronic mental disturbance (Scull, 1994), but there
were no widely accepted interventions for particular conditions. Various
sedative drugs were prescribed liberally during this period; ‘doled out by the
bucketful’, in the words of one retired psychiatrist (Rollin, 1990), but they
aroused little interest among psychiatrists, and official recommendations were
to use them ‘as sparingly as possible’ (Henderson and Gillespie, 1927, p. 154).
It seems these early drugs were regarded merely as ‘chemical restraints’, which
fulfilled the same purpose as the mechanical restraints—the
straight jackets and manacles—which were also in use at the time (Braslow,
1997). Staff of the mental asylums at the beginning of the twentieth century
believed they were, at best, helping to promote a natural recovery and, at
least, providing a long-term residence for people who required on-going
assistance or containment.
Physical Treatments
In the late 1920s, the idea that inducing malaria might
cure or benefit people suffering from the severe neurological degeneration seen
in some people with late-stage syphilis infection (known as general paralysis
of the insane, or GPI) was suggested, and ‘malarial therapy’ started to be used
in asylums. Patients were deliberately infected with malaria using mosquitoes
bred in the grounds of the asylums. As it was never subjected to controlled
evaluations, it remains uncertain whether this technique had any beneficial
effect, although we know that it was hazardous. It was generally accepted as a
major medical innovation, however, and its inventor, Austrian psychiatrist
Wagner Jauregg, was awarded the Nobel prize for medicine, despite the
objections of one member of the committee about the ethics of giving people
malaria (Austin et al., 1992). Regardless of its actual efficacy, malarial
therapy encouraged the idea that apparently incurable conditions might be
treatable, and it gave the staff of asylums a sense of having a truly medical
purpose (Braslow, 1997).
From the early 1930s onwards a range
of other physical techniques, including insulin coma therapy, chemical and then
electrically-induced shock therapy and lobotomy, were introduced into
psychiatry and all became standard and accepted forms of treatment. Like
malarial therapy, these interventions were based partly on the prevalent belief
that there was a mutual antagonism between certain diseases and that some
mental conditions could be reversed or eliminated by inducing another sort of
disease.
Insulin coma therapy was the first
physical procedure to come into widespread use that was aimed at people who would
conventionally be said to suffer from a mental disorder, rather than a
neurological disease like neurosyphilis. It was proposed and promoted by
Manfred Sakel, an Austrian psychiatrist, who had started experimenting with the
use of insulin in people addicted to morphine. Insulin was isolated in 1922,
and its discovery, along with the synthesis of thyroid hormone in 1927,
inspired interest in the role and use of hormones in many areas of medicine.
When Sakel noticed that insulin induced a state of calm in his morphine-addicted patients, he started to try it out
in patients diagnosed with acute schizophrenia. In these patients he devised a
regime that consisted of using insulin to induce hypoglycaemic comas. The
patient was kept in the state of coma for 2–3 hours, and then dramatically
awakened by an injection of glucose. The comas were given every week-day
morning and continued for weeks at a time. The procedure was both degrading and
dangerous. Patients sweated profusely during the comas, and were often doubly
incontinent. Afterwards they would be confused and disorientated, with the
confusion lasting for several days after prolonged treatments. The death rate
was between 5 and 10% (Ebaugh, 1943; Fink and Karliner, 2007).
Although there were never any well-accepted
theories about how insulin coma therapy produced improvement, there was a
general belief that it did so by acting on the underlying biological basis of
schizophrenia. One psychiatric textbook described how ‘hypoglycaemic treatment
obviously touches the physical basis of schizophrenia more closely than all
earlier modes of physical attack’ (Mayer-Gross et al., 1954, p. 286). Sakel
himself claimed that insulin coma therapy selectively killed diseased brain
cells like ‘fine microscopic surgery’ (Sakel, 1958, p. 334). Others proposed
that it worked by correcting faulty brain circuits or correcting hormonal
imbalances (Fink et al., 2007). A German psychiatrist, looking back at the
introduction of insulin coma therapy from the 1960s felt that it was ‘the decisive
step from a purely symptomatic to a curative therapy of the “endogenous”
psychoses’ (Ehrhardt, 1966, p. 838).
In 1953 Harold Bourne, a young
doctor from New Zealand, published an article in The Lancet
entitled ‘The Insulin Myth’. He pointed out that the effects of insulin coma
therapy were likely to be due to a placebo effect produced by the particularly
dramatic nature of the procedure. A subsequent randomised controlled trial that
compared insulin-induced comas with an anaesthetic procedure using barbiturates,
found no difference between the two (Ackner et al., 1957). However, a
comparison between insulin coma therapy and chlorpromazine, the first
antipsychotic drug, also showed no difference (Fink et al., 1958). The author
Robert Whitaker has suggested that, like lobotomy, insulin coma therapy may
have been effective in calming patients by inducing a form of brain damage,
which may explain its similarity to antipsychotic treatment (Whitaker, 2002).
In the end insulin coma therapy faded out of use and was replaced by the new
antipsychotic drugs in the 1950s. Psychiatrists, ‘like a large shoal of
fish...simply switched direction to follow the lights of the more fashionable
pharmacotherapy of schizophrenia’, according to British psychiatrist Michael Shepherd
(Shepherd, 1994). Today, insulin coma therapy is
almost entirely forgotten. It stopped being recommended in the 1960s and is no
longer regarded as effective.
Following the proposal that
hypoglycaemic comas might cure or improve schizophrenia, came the idea that
inducing epilepsy might relieve people of their madness. ‘Convulsive’ therapy
reflected not only the idea that mental disorders might be cured by the
presence of a physical disease, it was also a product of a longstanding notion
that people could be shaken out of their mental disturbance by violent shocks
(Frank, 1978). At first, epileptic convulsions were induced using chemical
agents, but this technique was later replaced by the use of an electrical
current applied to the brain in a procedure known as electro-convulsive therapy
(ECT). As it was easier and quicker to administer than insulin coma therapy,
and considerably less dangerous, it became the mainstay of treatment for people
with schizophrenia in the asylums of Europe and north America in the 1940s.
Although the majority of people to whom it was administered were diagnosed with
schizophrenia, it was later suggested that ECT was most effective in people
with ‘involutional melancholia’ (severe depression of old age) or manic
depression. In these conditions it was suggested that it might rectify
underlying abnormalities, such as reversing dysfunctional ‘brain circuits’
(Paterson, 1963) or an underactive pituitary gland (Sadler, 1953), but there
was, and remains, no consensus about its mechanism of action.
Treatments like insulin coma
therapy, ECT and, subsequently, lobotomy ushered in a transformation in
attitudes towards the treatment of mental health problems, and marked the
beginning of a sustained period of therapeutic zeal. Suddenly, ‘treatment’
became a topic worthy of discussion, with textbooks and academic papers
describing the application of the new physical procedures (Moncrieff, 1999).
Mental hospitals established ECT and insulin suites; X-ray facilities and
pathology laboratories were introduced; and neurosurgeons appointed to the
staff to conduct lobotomies (Anonymous, 1990). The asylums of the nineteenth
century were at last believed to be becoming true hospitals, where people would
be restored to sanity by real medical procedures. The days of waiting for
nature to take its course, and trying to limit the damage on the way, were
thought to be past.
Moreover, psychiatrists believed
that their new treatments could, at last, alter the course of mental
disturbance. Insulin coma therapy and ECT, in particular, were thought to
represent effective and specific treatments for the two major psychiatric
disorders that had been defined by Kraepelin at the end of the nineteenth
century and that structured mid-twentieth century
psychiatric thinking: schizophrenia and manic depression.
The Introduction of Chlorpromazine
Chlorpromazine, otherwise known by its trade names
Largactil and Thorazine, was the first of the drugs now referred to as
‘antipsychotics’ or neuroleptics to become an established psychiatric
treatment. It was not developed with psychiatric uses in mind, however, and the
circuitous manner in which it arrived in psychiatry has led to it being dubbed
a ‘drug in search of an illness’ (Lickey and Gordon, 1986, p. 78). It was
originally synthesised as an antihistamine; it was first used clinically in
some dubious anaesthetic procedures; it was promoted as an anti-sickness agent,
probably for morning sickness; and it was named Largactil after its ‘large
action’. But it landed in psychiatry at a propitious moment, and that is where
it stuck.
The story of chlorpromazine’s
introduction into psychiatry has been well told by a number of historians
(Swazey, 1974; Healy, 2002), but the story is worth retelling in order to
highlight a number of issues that are not well recognised. The adoption of
insulin coma therapy, ECT and lobotomy already illustrates that psychiatry was
ready to embrace highly intrusive and dangerous procedures in the name of
providing mental patients with what seemed like medical ‘treatments’. The use
of chlorpromazine in psychiatry also emerged out of a bizarre and dangerous
experimental technique for the prevention of surgical shock, known as
‘artificial hibernation’, based on long-outmoded theories about the origins of
shock that contradicted conventional treatment practices both then and now.
Confidence in physical treatments in general encouraged psychiatrists to
embrace the new chemical approach to treatment, which also happened to promise
an alternative for the containment of the mentally ill that was cheaper than
long-term confinement in the asylum system.
Chlorpromazine’s early history also
illustrates the drug-centred framework within which drugs were understood at
this time. The clinicians who used chlorpromazine in its early years were
fascinated by the peculiar way the drug modified human emotions and behaviour,
and recorded their observations in detail. Simultaneously, however, the story
indicates the circumstances that lead to the transformation of ways of understanding
the new drugs. The seeds of the disease-centred view are already apparent in
the enthusiasm with which they were greeted and the desire to view them as
something quite distinct from the sedatives that were in use before their
arrival.
After the demonstration in 1910 that histamine could
produce an acute allergic shock reaction when injected into mammals (Dale and
Laidlaw, 1910), work began to develop a drug that could counteract the effects
of histamine. A group of chemicals called the phenothiazines, which had first
been synthesised and used as dyes in the chemical industry in the late
nineteenth century, were found to have this effect and, by 1941, Rhône-Poulenc,
the French pharmaceutical and chemical company patented the first antihistamine
for clinical use in humans, phenbenzamine, known as Antergan. It was closely
followed by several more, including promethazine (Phenergan) and, by the
mid-1940s, antihistamines were in widespread use for the treatment of mild
allergic conditions, including hay fever and allergic rashes. By 1950 there
were at least 20 antihistamines on the market (Emanuel, 1999).
It was immediately recognised that
one of the main effects of antihistamines was drowsiness or sedation, and
several groups of researchers began to look at these effects in more detail.
Scientists at Rhône-Poulenc identified that promethazine and other
antihistamines could prolong the sleep-producing effects of barbiturates in
rabbits, and work in the USA showed that antihistamines could also inhibit
animals’ ability to learn new behaviour. Rhône-Poulenc started to search for
antihistamine compounds with a stronger ability to suppress the activity of the
central nervous system, which they referred to as a ‘depressant’ action,
although the company was not yet sure what clinical applications such drugs
might have (Swazey, 1974).
The ‘depressant’ or sedative actions
of antihistamines lead to some of them being put to use in psychiatric practice
during the 1940s. Phenbenzamine and promethazine were tested in patients with
manic depression by French doctors who concluded that they were promising
treatments. Promethazine was described as producing helpful sedation and
drowsiness in agitated psychotic patients, and reducing the duration of manic
episodes (Guiraud and David, 1950).
The Contribution of Laborit and His Theory
of Shock
Henri Laborit was a surgeon who worked for the French
navy and, like many of his colleagues, he had an interest in the physiological
state known as ‘shock’. Shock is a condition that occurs when blood circulation
fails and bodily organs are deprived of oxygen, and as it can occur after
surgery and wounding, it has been a concern of doctors and surgeons throughout history. We know now that this sort
of shock is a consequence of blood loss, even if the source of the loss is not
immediately apparent, but this was not always obvious and, for much of the
nineteenth century, the cause or mechanism of shock was believed to lie in the
nervous system (Manji et al., 2009). Various contradictory theories circulated,
such as ideas that the symptoms of shock resulted from either overstimulation
or understimulation of various nervous pathways, but the most influential
proponent of the nervous theory of shock, the American George Crile, suggested
that shock was due to overstimulation of the sympathetic nervous system, the
system that increases heart rate and blood pressure, leading to exhaustion and
failure of the nervous mechanisms controlling blood circulation (Moffat et al.,
1985).
From the beginning of the twentieth
century it became clear that blood or fluid loss was the primary mechanism of
all traumatic shock, and it was believed that blood was lost because the fine
blood vessels—the capillaries—became overly permeable, but it was still believed
by some that the underlying mechanism was dysfunctional nervous impulses.
Linked with these theories was the idea that an as yet unidentified toxic
substance mediated the abnormal nervous activity that caused the increased
capillary permeability (Moffat et al., 1985). After identifying histamine as
the cause of severe allergic reactions, the famous physiologist Henry Dale
proposed that histamine might be this substance (Dale and Richards, 1918; Dale
and Laidlaw, 1919).
Following World War I, when the role
of blood loss became clear and most attention was directed to producing
effective blood and fluid replacements for people experiencing traumatic shock
(Gurd, 1955), several experiments were conducted which contradicted the nervous
stimulation hypothesis. It became more generally accepted that the activity of
the sympathetic nervous system was not the mechanism underlying shock, but the
body’s response to it (Manji et al., 2009). Following this revelation, standard
approaches to shock attempted to support the nervous system’s reaction to
shock, not suppress it.
The old nervous system hypothesis
was not abandoned by everyone, however, and in 1950, following on from work by
other French researchers, Laborit, who was based in Tunis at the time,
elaborated on the idea that shock was the result of prolonged ‘nervous
irritation’ of the sympathetic nervous system, leading to massive dilatation of
blood vessels (Laborit, 1950). Laborit proposed that histamine was one of the
endogenous chemicals that mediated the effects of this overstimulation
(Laborit, 1949), although experiments conducted in the 1930s
and 1940s had shown that histamine was not involved in the mechanism of shock
(Hunter, 1967). Based on his hypothesis, Laborit devised a complex combination
of drugs designed to counteract the effects of the chemicals that produced the
nervous overstimulation, and he included antihistamine drugs as part of what he
called his ‘lytic cocktail’ (‘lytic’ from the idea that they lysed, dissolved
or reduced the nerve-stimulating activity of these chemicals). He referred to
the overall results of the drug cocktail as ‘neuroplegia’ owing to its capacity
to inhibit nervous conduction.
In 1951, Laborit was transferred to
Paris and started collaborating with the anaesthetist, Pierre Huguenard.
Together they formulated a technique they referred to as ‘artificial
hibernation’, which was designed to prevent surgical shock by a combination of
‘neuroplegia and hypothermia’. The induction of hypothermia by surrounding the
patient with ice packs had been proposed as a way of slowing down the body’s
metabolic rate to enable long and complex operations to be conducted, but it
had also been proposed as a method of preventing surgical shock. In this case
it was to be combined with the use of Laborit’s drug cocktail (Laborit and
Hugenard, 1951).
Although some other surgeons
experimented with the use of artificial hibernation (Lazorthes et al., 1952),
and the fashion for hypothermia was widespread, Laborit acknowledged at the
time that his ideas were unorthodox, and that counteracting the action of the
sympathetic nervous system went against the prevailing view that one should
support the body’s reaction to shock, not suppress it (Laborit, 1952).
Conventional drug treatment for shock, for example, included sympathetic
nervous system stimulants like noradrenaline, which had the opposite effect of
that intended by Laborit’s cocktail (Gurd, 1955). Experiments in the late 1950s
suggested that hypothermia probably worsened shock rather than prevented it
(Beresford et al., 1956; Ferguson et al., 1958), and many surgeons were
sceptical about the artificial hibernation technique and concerned about its
safety. When Laborit was flown to the USA by Smith Kline & French to
promote the technique to US surgeons, his tour was a disaster. Most of the
animals he used died during the demonstration and US surgeons, thankfully,
showed little interest (Swazey, 1974)!
Laborit’s legacy is not in surgery,
however, but in psychiatry, owing to his observations of the novel sedative
quality of the antihistamine drugs he was employing, and his intuition that
these might be useful in subduing psychiatric patients. His suggestions may
have fallen on deaf ears had psychiatrists had the same attitude to artificial
hibernation as the US surgeons, but the parallels between Laborit’s technique and the physical treatments in use in psychiatry at the
time helped to smooth the passage of chlorpromazine from surgery to psychiatry.
The psychiatric procedure most closely analogous to artificial hibernation was
‘deep sleep’ therapy, sometimes known as ‘continuous narcosis’. This highly
dangerous procedure was popularised by Swiss psychiatrist Jakob Klaesi in 1920
and involved putting the patient into a state of deep sleep induced by high doses
of barbiturates, which could be continued for up to 10–12 days. The rationale
behind ‘deep sleep’ therapy represented a curious blend of biological,
psychoanalytical and behavioural theories, with some proponents viewing it
simply as a physical intervention, similar to insulin coma therapy, but others
suggesting that the prolonged sleep could regress the patient to an earlier
stage of development, from which they could relearn more adaptive habits and
behaviours (Greenson, 2012). Sleep therapy was particularly popular in France,
Switzerland and Russia, but was widely used across Europe and less frequently
in North America. In the UK there is evidence that it was being conducted up
until the 1970s (Gittins, 1998), and a modified version was used to treat
American soldiers in the Vietnam war (Bloch, 1970). Deep sleep therapy was also
the precursor to the idea of ‘abreaction’, the technique that aimed to elicit
repressed memories from people during periods of barbiturate-induced
intoxication, a procedure that is still occasionally employed to this day. In
the 1950s, the fact that deep sleep therapy was a widely accepted treatment
meant psychiatrists willingly embraced the idea of artificial hibernation as
transferable into psychiatry, along with the drugs used to achieve it.
Laborit was in close communication
with Rhône-Poulenc, and the company was persuaded by his ideas that an
antihistamine drug with strong sedative properties might be useful in
anaesthesia, as well as other areas. In December 1950 company scientists
synthesised a new molecule by adding a chlorine atom to the phenothiazine drug
promazine to produce what was later called chlorpromazine. It quickly became
apparent that the new substance had a strong effect on the central nervous
system, as identified by animal screening tests, and, only four months after
its synthesis in April 1951, it was tested in humans with a variety of
complaints, including some psychiatric patients. It was noted to enhance the
effects of barbiturates in these patients, and psychiatric uses were included
among Rhône-Poulenc’s list of prospective indications. But the company was
prepared to try it for almost any purpose, long before its full profile of
effects was established, such was the laxity of drug regulation at the time.
The proposed indications also included epilepsy and muscle spasm, for example,
even though subsequent observations indicated that
the drug could induce epileptic fits and that it caused, rather than prevented,
muscle spasm and rigidity (Swazey, 1974).
Laborit was given some samples of
the drug in June 1951, and started to use it as part of his lytic cocktail in
the artificial hibernation experiments he was conducting with Huguenard. In
their first report, they were enthusiastic about the new drug’s ability to
facilitate the state of hibernation, and also noted how the patient, once
injected with chlorpromazine, entered a ‘twilight state’ (Laborit and Hugenard,
1951). In a later paper published in 1952, they commented on how patients who
had taken it showed a ‘disinterestedness’ in the things that were going on
around them, and they suggested, on this basis, that it might be useful in
psychiatry (Laborit et al., 1952, p. 207).
First Uses in Psychiatry
Intrigued by its psychoactive properties, Laborit urged
his psychiatric colleagues to try the new drug and one young psychiatrist
agreed to take a dose of chlorpromazine in Laborit’s presence to allow further
observation of its effects. Cornelia Quarti taped and later transcribed her
experiences, describing how the drug gave her an ‘extreme feeling of
detachment’ from herself and others, and ‘muted’ her sensations and
perceptions. Later on she felt tired, weak and lethargic, and had difficulty
finding words. Although Laborit was not discouraged, the director of the
hospital, who had been told about Quarti staggering about under the influence
of the drug, suspended further use of chlorpromazine at the hospital (Chertok,
1982).
Dr Hamon, a colleague of Laborit’s
and director of the neuropsychiatry unit at the Paris military Hospital Val de
Grace, agreed to try chlorpromazine in some of his patients. The drug was duly
given to a 24-year-old highly aroused and agitated manic patient, Jacques Lh.
Although his case was reported as a demonstration of successful treatment with
chlorpromazine (Hamon et al., 1952a), at the same time as he received
chlorpromazine at relatively modest doses, he was also being given
barbiturates, pethidine and ECT (Deniker, 1989). Hamon and colleagues
acknowledged the influence of Laborit’s ideas, referring to chlorpromazine as
an autonomic ‘stabiliser’ and its use as constituting ‘artificial hibernation’,
which they proposed could become a useful technique in psychiatry (Hamon et
al., 1952b).
The people who are usually credited
with introducing chlorpromazine into psychiatry, however, are the psychiatrists
Jean Delay and Pierre Deniker, who were based at the
neurology and psychiatry hospital of Sainte Ann in Paris. Jean Delay was a
professor and the head of the psychiatric department of the University of
Paris, the most prestigious and respected job in French psychiatry. He had
trained as a neurologist before entering psychiatry, and he was firmly
committed to the idea that psychiatric disorders could be treated by medical or
biological means. Much of his early work consisted of attempts to elucidate the
mechanisms of ECT, for example, and he and Deniker had been experimenting with
the use of a variety of new drugs before they started using chlorpromazine
(Swazey, 1974).
Delay was interested in Laborit’s
ideas about surgical shock because of his own work on shock therapy in
psychiatry, and, in 1953, he and Deniker proclaimed ‘how enthusiastically we
have followed the remarkable work of our friend Laborit and his team’ (Delay
and Deniker, 1953, p. 347). Deniker had heard about Laborit’s observations on
chlorpromazine from his brother-in-law, who was a surgeon, and ordered some
samples of the drug from Rhône-Poulenc in February 1952 (Swazey, 1974). At
first, chlorpromazine was used in conjunction with ice packs to induce the
state of ‘artificial hibernation’ devised by Laborit. A junior psychiatrist who
was involved, Jean Thuillier, subsequently described how nursing staff started
to use the drug on its own because the pharmacy could not supply the ice packs
quickly enough. When this was reported to Deniker, he decided to continue using
the drug in this way (Thuillier, 2000). Deniker explained subsequently that he
and Delay decided that the artificial hibernation technique was too dangerous
(Swazey, 1974).
Between May 1952 and July 1952,
Delay and Deniker published six papers outlining their experience with the new
drug in patients with various types of ‘psychic excitation’, and Deniker made
several presentations to the 50th meeting of the French Congress of Psychiatry
and Neurology in 1952. The paper that is usually cited as being the first to
confirm the utility of chlorpromazine described the use of chlorpromazine in 38
patients with excited states of various sorts. The best results were said to have
been obtained in people who had ‘confusional states’—although this may have
included some patients who were psychotic. Only six patients were classified as
having schizophrenia in whom results were said to be mixed, although the
authors did comment that a few remissions had occurred among some of the most
‘refractory cases’ (Delay and Deniker, 1952).
Delay and Deniker’s early papers
also record their observations of the altered state produced by chlorpromazine.
In 1952, for example, they described how, after
receiving chlorpromazine, initially ‘patients spend most of their time in
sleep,’ and, although this effect lessened as treatment continued, patients
remained ‘a little sleepy and indifferent’ (Delay et al., 1952, pp. 114–5). A
subsequent paper contains a lengthy description of the general effects induced
by chlorpromazine. In an effort to distinguish the drug from barbiturates, the
report minimises the sleep-inducing effects noted in the earlier paper, but it
is worth reproducing because it remains one of the most detailed accounts of
the effects induced by antipsychotic drugs in the psychiatric literature:
Seated or lying down, the patient is motionless on his
bed, often pale and with lowered eyelids. He remains silent most of the time.
If questioned, he responds after a delay, slowly, in an indifferent monotone,
expressing himself with few words and quickly becoming mute. Without exception,
the response is generally valid and pertinent, showing the subject is capable
of attention and of reflection. But he rarely takes the initiative of asking a
question; he does not express his preoccupations, desires, or preference. He is
usually conscious of the amelioration brought on by treatment, but he does not
express euphoria. The apparent indifference, or delay in response to external
stimuli, the emotional and affective neutrality, the decrease in both
initiative and preoccupation without alteration of conscious awareness or in
intellectual faculties constitute the psychic syndrome due to treatment (Delay
et al., 1952, pp. 503–4).
Delay and Deniker had recognised that the new drug
affected some of the most fundamental human characteristics: emotion,
initiative and the ability to respond to the world around us. When the drug was
stopped and the effects wore off they noted how the patient regained ‘his
normal colour, and activity and his normal “spirit”’ (Delay et al., 1952, pp.
504).
Other clinicians who used
chlorpromazine at this time made similar observations.
Two Parisian neurologists, for
example, employed the drug as a painkiller, among other uses, and suggested
that ‘it had an effect different from other analgesics, producing an
indifference to the pain, rather than analgaesia’ (Sigwald and Bouttier, 1953,
pp. 150–1). From their experience of using the drug in patients with a variety
of psychiatric and neurological conditions, they described how it could lessen
the ‘imperative character’ of obsessional thoughts and the emotional distress
associated with hallucinations and delusions (Sigwald and Bouttier, 1953, pp.
175–6).
Chlorpromazine Reaches Other Countries
Among the first British psychiatrists to use
chlorpromazine was David Anton-Stephens, who worked in Warley hospital in
Essex. He described the main effects of chlorpromazine as ‘somnolence’ and
‘psychic indifference,’ and, like other investigators, felt its most useful
effects were the ‘lessening of disturbed behaviour’ (Anton-Stephens, 1954, p.
557). Joel and Charmain Elkes from Birmingham conducted what is generally
recognised as the first controlled experiment involving the drug. They had been
experimenting with other sorts of drugs, and the chlorpromazine study involved
27 patients with chronic psychiatric conditions who all displayed
‘over-activity’. The patients were given chlorpromazine for a few weeks,
alternating with a placebo. The Elkes judged the trial to have been a success,
with 7 of the patients showing ‘definite’ and 11 showing ‘slight’ improvement
on the drug. According to the Elkes, this improvement consisted of patients
becoming ‘quieter and more amenable to suggestion by the nursing staff’, and
the drug did not change basic psychotic phenomena. ‘Schizophrenic and
paraphrenic patients continued to be subject to delusions and hallucinations’
they commented, ‘though they appeared to be less disturbed by them’ (Elkes and
Elkes, 1954, p. 563).
The man credited with first
introducing chlorpromazine to North America is Heinz Lehmann, a German
Canadian, who was given some chlorpromazine by Rhône-Poulenc, who operated in
Canada, as well as France. Lehman soon organised a study of the new drug at the
Verdun hospital where he worked in Montreal. Like Delay and Deniker, Lehman
considered that the drug was of most value in ‘the symptomatic control of
almost any kind of severe excitement’ (Lehman and Hanrahan, 1954, p. 232), and
described results in people classed as having chronic schizophrenia as
disappointing. Lehman was also a keen observer of drug-induced effects and
reported how the drug made patients lethargic, and how ‘patients under
treatment display a lack of spontaneous interest in their environment, yet are
easily accessible and respond as a rule immediately
and relevantly to questions’ (Lehamnn and Hanrahan, 1954, p. 230).
Chlorpromazine in the USA
Chlorpromazine was introduced into the USA by the drug
company Smith Kline & French, who were approached by Rhône-Poulenc in 1952.
The company was initially concerned that American psychiatrists might not give
drug treatment the same enthusiastic welcome it was receiving in Europe owing
to the influence of psychoanalysis (Swazey, 1974). Sections of US psychiatry,
however, had never abandoned the biological approach to understanding and
treating mental illness. The principle American psychiatric journal (The American Journal of Psychiatry) showed a continual
preponderance of articles on biological theories and treatments throughout the
mid-twentieth century (Moncrieff, 2008a). On top of this, concern about poor
conditions and overcrowding in the state mental hospitals meant that many
psychiatrists were desperate to find a simple medical procedure that would help
to manage disturbed behaviour and reduce the inpatient population. Moreover,
for many psychiatrists, biological interventions and psychotherapeutic
approaches could be combined without contradiction. Psychiatrist John Vernon
Kinross-Wright, for example, who published the first report of the treatment of
hospital patients using chlorpromazine in the USA, expressed how ‘for decades
psychiatrists have searched for a simple chemical agent with which to treat
mental illness, one that would be effective without producing narcosis or coma
and at the same time increase the patients capacity to respond to
psychotherapy’ (Kinross-Wright, 1954, p. 297). N. William Winkelman, Jr, who
prescribed chlorpromazine to his outpatients and described the drug’s ability
to reduce almost any nervous complaint, also warned that ‘it should never be
given as a substitute for psychoanalytically oriented psychotherapy’
(Winkelman, Jr, 1954, p. 21).
Another US psychiatrist, Henry Brill
of New York, recalled how he ‘was searching for a treatment that was simple to
administer and so safe that it could be administered to large numbers of
patients’ (Brill, cited in Johnson, undated, pp. 7–8, cited in Swazey, 1974, p.
200). After introducing chlorpromazine into his own hospital, he organised a
meeting to report on the benefits he had seen to other New York psychiatrists
(Healy, 2002). In the late 1950s Brill published a series of papers that
documented a decrease in the numbers of mental hospital inpatients and
attributed the decline to the introduction of the new ‘tranquillisers’. Brill
claimed the figures demonstrated that these drugs
were producing a ‘revolution in the care and treatment of mental patients’,
enabling even the most chronic patients to be discharged (Brill and Patton,
1957, p. 509). For many decades these papers were cited as demonstrating beyond
doubt that the new drugs had emptied the asylums, despite the fact that several
other studies contradicted this interpretation (see Chapter 7).
Smith Kline & French’s campaign
to introduce chlorpromazine into the US was unprecedented at the time. A few
days after the company received permission to market the drug in 1954, the
president, Francis Boyer, appeared on a national television programme, The March of Medicine, to announce the arrival of
Thorazine, the company’s brand name for chlorpromazine. A Thorazine ‘Task
Force’ worked with state legislatures and the staff of mental hospitals in a
programme that was presented not as a marketing campaign, but as a ‘true
educative effort’ intended to highlight the need for more ‘intensive treatment’
of the mentally ill (Johnson, undated, cited in Swazey, 1974, p. 203). The
company organised council meetings at local mental hospitals, provided training
for psychiatric administrators on how to obtain state funding for drug
treatment, and organised and funded American Psychiatric Association symposia
to discuss the use of the drug. The task force also emphasised ‘aftercare’, or
the continuation of drug treatment after discharge. As well as extending the
market considerably by promoting the idea of lifelong treatment, the focus on
aftercare allowed the task force to deflect criticism that its drug might be
increasing discharge rates, but increasing readmission rates, leading to people
going in and out of hospital in a ‘revolving door’ fashion (Swazey, 1974).
The campaign was a huge success and
the task force remained in existence for 6 years, indicating the value that
chlorpromazine represented for the company. Within 8 months of Thorazine’s
launch, it had been given to more than 2 million patients (Swazey, 1974). At
the time, Brill pointed out that ‘no previous method of psychiatric therapy has
ever had such rapid and general acceptance’ (Brill, 1956, p. 181). Despite the
reservations of a few psychoanalytically-minded psychiatrists, he later
reflected the use of drugs ‘became almost universal. Only a few diehards
refused to use them at all’ (cited in Johnson, undated, p. 39, cited in Swazey,
1974, p. 196).
Reserpine
More or less concurrent with the introduction of
chlorpromazine into psychiatry, a drug with similar properties, originating
from a native Indian plant known as Rauwolfia serpentina (named after its use for the treatment
of snake bites) was receiving increasing attention. The plant had been used in
Indian medicine for centuries to combat fever, sickness, snake bite, insomnia
and insanity, and, during the twentieth century, it started to be used to treat
high blood pressure. Its potential as an anti-hypertensive attracted the
attention of Western drug companies, and, in 1953, researchers at the company
Ciba isolated the chief active ingredient of the plant preparation, which they
named reserpine.
In the same year The
New York Times reported on the news that an Indian
doctor, Dr R.A. Hakim, had been awarded a gold medal for the presentation of a
paper describing his successful treatment of patients with schizophrenia with Rauwolfia preparations. The report stimulated the interest
of psychiatrist Nathan Kline, recently appointed as research director at
Rockland State hospital. This large asylum had become notorious through its
portrayal in the highly critical film, The Snake Pit,
and Kline had set up a research unit to try and improve its image and boost
staff morale (Healy, 2002). Kline is an important figure in the story of modern
drug treatment because of his domineering influence over American psychiatry.
Although he had trained in psychoanalysis, he became an ardent advocate of
biological psychiatry in general and drug treatment in particular. He was also
known for his blunt manner, and Paul Janssen of Janssen pharmaceuticals, who
knew and liked him, nevertheless describes how he ridiculed and intimidated
those who challenged him. ‘By the end of his life’, Janssen recounted, ‘he
behaved like a kind of Pope ... he had this habit of coming to conferences with
a small dog on his lap and patting it all the time and attracting attention
whilst smiling to the speaker’ (Janssen, 1998, p. 60).
Kline obtained samples of reserpine
and started to give it to large numbers of inpatients. In 1954 he published a
paper claiming that the drug was responsible for a decline in the number of
assaults by patients, and he reported a slight improvement in their condition
as rated by nursing staff. He concluded that the drug had ‘a definite sedative
action’, but, in contrast to his later views, he emphasised that there was no
evidence that it altered ‘the schizophrenic process itself’ (Kline, 1954, p.
123). In a paper published the following year, Kline reported how hospital
nursing staff were convinced that the drug made ‘the patients definitely
quieter’ with fewer ‘assaults, arguments and disturbances in the wards’, and he
suggested the drug could ‘prove a tremendous economy’ by reducing disturbed
behaviour and enabling patients to be discharged earlier than before (Kline and
Stanley, 1955, p. 90).
The use of reserpine in psychiatry
was short-lived, however. It could cause a dangerous lowering of blood
pressure, and was associated with a restlessness and agitation in the early
days of treatment that was greater than that produced by similar drugs. Given
these drawbacks, it was soon swept away by competition from chlorpromazine and
other early antipsychotics. Reserpine was important, however, because it was
through studying its effects that American Steve Brody started to establish the
idea that psychiatric drugs worked through having effects on specific brain
chemicals (Healy, 2002).
A New Beginning?
The introduction of drugs like chlorpromazine and
reserpine into psychiatry is usually presented as one of the greatest
achievements of twentieth-century medicine. Henri Laborit is regarded as one of
the principle heroes of this story and shared the Lasker prize for his role in
the introduction of chlorpromazine. It is little known that his ideas about the
mechanism of surgical shock were based on theories that had already been
discredited, and that his techniques for preventing it were dangerous,
ineffective and regarded as bizarre by many of his surgical colleagues.
Psychiatrists were ready to embrace such unorthodox procedures because they
were already conducting their own hazardous treatments, such as insulin coma
therapy and lobotomy—therapies which were also based on unfounded theories and
a disregard for the safety and dignity of patients. But a simple intervention
in the form of a pill was even more appealing and
leading European psychiatrists were experimenting with various pharmaceutical
candidates. Even in the USA, where psychoanalysis was more influential, many
psychiatrists had been longing for an easily administered solution to the
problem of mental disturbance, especially one that would ease the problems
encountered in the increasingly large and overcrowded mental hospitals. In the
event, psychoanalysis never seriously challenged the biological approach to
managing mental disturbance and it presented no obstacle to the widespread
adoption of the new drug treatments.
Chlorpromazine was not the only drug
with antihistamine properties to be found useful in psychiatric patients during
the 1950s, but the prestige of Delay and his department combined with the
efforts of Rhône-Poulenc and Smith Kline & French helped chlorpromazine to
be recognised as the first new and revolutionary drug treatment in psychiatry.
A recent revival of interest in the use of promethazine, another early
antihistamine, for the emergency treatment of aggression and agitation in
psychiatric institutions suggests that other, possibly equally useful
candidates, may have been overlooked.
Despite their enthusiasm for the new
drugs, in the early days few of the clinicians that prescribed chlorpromazine
or reserpine believed that the drugs targeted the underlying psychiatric
condition. They thought they were using special sorts of sedative, and,
according to this drug-centred understanding of drug action, they were keen
observers of the nature of the altered state the drugs produced. After the
subsequent transformation of these drugs in the professional and popular
imagination into disease-specific treatments charted in the following chapter,
this sort of information disappeared from official literature. These early
accounts consistently described the state of sedation, detachment and
indifference produced by the drugs, and identified its benefits as calming
excited or disruptive behaviour, and reducing the intensity of psychotic
phenomena and emotional reactions. At this stage the idea that drugs
constituted a disease-specific treatment for schizophrenia or psychosis was
barely imagined, but the seeds of this view were present in the overwhelming
desire that existed in the old institutions to find a proper medical treatment
for severe mental disturbance.
Magic Bullets: The Development of Ideas on
Drug Action1
The inscription on the Lasker prize awarded to Deniker,
Delay, Laborit and Lehmann in 1957 read ‘for the introduction of chlorpromazine
into psychiatry and for the demonstration that a medication can influence the clinical course of the major psychoses’
(Deniker, 1989, p. 253, my emphasis). These words encapsulate the importance
that was attributed to finding a physical intervention that was more than just
a sticking plaster—to finding something that could change the very nature of
psychiatric disorders. Although chlorpromazine and other early antipsychotics
were thought to be uniquely useful, few people believed at this time, however,
that they acted on the disease or abnormality that was presumed to give rise to
schizophrenia or any other serious mental illness. The disease-centred view of
the action of antipsychotics took a while to develop and, in the meantime, the
unusual neurological effects the drugs induced were proposed to be the basis of
their action, in what was essentially a drug-centred model. But, as the
inscription on the Lasker award suggests, psychiatry was already aspiring
towards having a drug that would modify the very nature of the problems it was
confronted with.
The idea that mental conditions are
just the same as any other disease pre-dates the introduction of the early
antipsychotics, and, just as this idea generated a story about the effects of
insulin coma therapy and electro-convulsive therapy (ECT), it helped to
transform the way that drug treatment was understood. In turn, the
establishment of a disease-centred view of the nature of psychiatric drug
action strengthened and bolstered the medical model of mental disorders, and
gave psychiatry the confidence to present itself to the world as a thoroughly
medical enterprise, a view that was enshrined in the third edition of the Diagnostic and Statistical Manual, the American Psychiatric
Association’s surprising best-seller (American Psychiatric
Association, 1980a). Before this model took hold, however, interest in the
nature of the drug-induced state produced by the early antipsychotics revealed
the extent of their neurological effects. Plausible, drug-centred explanations
of their mechanism of action were proposed, which were subsequently swept away
when the disease-centred model took hold.
The Neurological Effects of the New Drugs
In 1954, two separate researchers, Professor Hans Steck
of Lausanne, and German psychiatrist Hans Joachim Haase provided the first
unambiguous descriptions of a syndrome of abnormally reduced and restricted
movement that was associated with chlorpromazine. They both remarked on the
similarity between the drug-induced effects—the decreased movement, loss of
initiative and muscular rigidity—and the symptoms of Parkinson’s disease. They
also described the drug-induced agitation known as akathisia (Hasse, 1954;
Steck, 1954). Steck compared the Parkinson’s disease-like symptoms produced by
chlorpromazine to the neurological syndrome seen after the epidemic of
encephalitis that hit Europe in the early decades of the twentieth century.
This was known as ‘encephalitis lethargica’, and its consequences are vividly
described in Oliver’s Sach’s famous book Awakenings
(Sacks, 1990). Steck referred to the drug-induced condition as an ‘akinetic
picture’ (akinetic meaning lack of movement), and noted how, as well as the
more obvious signs of slowness and rigidity, the condition was manifested in
subtle tendencies, such as walking without swinging the arms, a ‘frozen’ facial
expression and an impaired ability to initiate movement, which are also
recognised early features of Parkinson’s disease proper. Steck remarked on how
the signs of this neurological, drug-induced condition were particularly
striking when patients congregated together, conjuring an image of a ‘slightly
sad procession’ (Steck, 1954, p. 739).
Within a couple of years these
neurological effects were well recognised and were often referred to as
drug-induced ‘Parkinsonism’. Other dramatic effects, such as the sudden
muscular spasm that usually affects the head and neck muscles, now known as
‘acute dystonia’, had also been described (Kline, 1956; Hollister, 1957).
Collectively, these effects on the body’s motor system subsequently came to be
referred to as ‘extrapyramidal’ effects, after the extrapyramidal brain system
responsible for the modulation and regulation of movement.2
The term ‘extrapyramidal’ effects is also frequently used to refer simply to
drug-induced Parkinsonism, however, because this is the most common motor
effect encountered.
In early attempts to define the nature of drugs like
chlorpromazine and reserpine, Delay and Deniker stressed two aspects of the
drugs’ effects: the peculiar nature of the sedation, which, in contrast to
barbiturate-induced sedation, consisted of sleep from which people could be
easily roused, and the state of emotional indifference produced by the drugs
(Delay and Deniker, 1956; Deniker, 1956). They saw the Parkinson’s-like motor
effects as incidental to the drugs principle actions, but the sedation and
indifference were also regarded as neurological effects by virtue of being
induced by drug action on the brain and nervous system. In early papers,
following Laborit, they referred to chlorpromazine as a ‘neuroplegic’ drug
(from the Greek to paralyse), and, in 1955, they replaced this term by the term
‘neuroleptic’ (from the Greek to seize), still emphasising the sedative and
emotional effects the drugs produce rather than their motor effects (Delay and
Deniker, 1955).
In 1957, Delay and Deniker came
across a new drug called prochlorperazine (Stemetil), which was being tested in
psychiatric patients in Lyon. Prochlorperazine is a phenothiazine compound like
chlorpromazine, but is less sedating in its actions and can produce dramatic
neurological reactions that were described at the time as ‘excito-motor’
effects. These include muscular spasms, severe akathisia and other movement
abnormalities, and they were reported to occur both in psychiatric patients and
in military personnel who were given the drug to combat sea sickness (Delay et
al., 1957; Comite Lyonnais de Recherches Therapeutiques en Psychiatrie, 2000).
When Delay and Deniker started using the drug, they witnessed these striking
neurological symptoms. Deniker later recalled that the experience of using
prochlorperazine persuaded him and Delay that these characteristic effects on
movement and muscle tone were an intrinsic part of the neurological state
produced by this class of drugs (Deniker, 1989).
Henceforward, the term ‘neuroleptic’
became associated with the idea that the drugs acted through inducing a
neurological syndrome characterised by restricted and abnormal movement, and
Deniker, like Steck, started to refer to the distinctive effects of the new
drugs as ‘akinesia’. Deniker outlined the theory of neuroleptic action most
explicitly in a paper published in 1960, entitled ‘Experimental Neurological
Syndromes and the New Drug Therapies in Psychiatry.’ In this paper he suggested
that neuroleptics achieve their useful or therapeutic effects by producing a
characteristic neurological state akin to post-encephalitis-type Parkinson’s
disease. As in his other publications, Deniker described in some detail the way the drugs made patients appear and
behave. They ‘look as if they have been turned to stone’ he said and continued
‘they are usually indifferent to themselves and their environment, they are stuporous
or prostrate, even before the clinical symptom of hypertonia (rigidity)
appears’ (Deniker, 1960, p. 96). Although Deniker admitted that he had
previously found chlorpromazine useful in doses low enough not to cause marked
physical effects, he nevertheless suggested here that it was necessary to
‘resolutely and systematically aim to produce neurological syndromes to get
better results than can be obtained when neuroleptic drugs are given at less
effective doses’ (Deniker, 1960, p. 100).
The theory propounded in this paper
harks back to the idea that mental disorders could be cured by inducing a
bodily disease, and Deniker places neuroleptics alongside other examples of
treatments inspired by this idea such as ECT and insulin coma therapy. This orientation
also explains why he was not ashamed to suggest that the neuroleptic drugs
would ‘undoubtedly’ produce brain damage—irreversible changes in the brain’s
cellular structure—and why he referred to preliminary animal work demonstrating
drug-induced ‘lesions’ in various parts of the brain as positive evidence of
the drugs’ effectiveness (Cazzullo and Guareschi, 1954).
In the early days of the 1950s,
Delay and Deniker were not the only ones putting forward what amounts to a
drug-centred thesis about how the new drugs might work, although Deniker would
probably not have seen his ideas as such. Indeed, from time to time, he
speculated on how the site of neurological action of the drugs might be
involved in the pathology of the psychotic process (Deniker, 1970). German
psychiatrist Hans-Joachim Haase also proposed that the therapeutic effects of
the new drugs consisted of a mild version of the Parkinson disease-like
syndrome they induced (Haase, 1956). In 1961 Haase described the ‘handwriting
test’, which was based on the characteristic shrinking of handwriting that
occurs early in Parkinson’s disease. In Hasses’s test, patients’ handwriting
was measured each day while they were given gradually increasing doses of the
antipsychotic drug haloperidol. Haase suggested that when the handwriting size
had decreased by 20%, the ‘threshold’ dose had been reached. At the threshold
dose it was proposed that the early symptoms of Parkinson’s disease—the slowed
thinking and emotional suppression—would produce therapeutic benefits without
producing the more obvious and burdensome physical symptoms, such as slowed
movement and muscular rigidity (Haase and Janssen, 1965). The test charts the
early signs of Parkinsonism that are produced by the
drugs, and the concept of the ‘neuroleptic threshold’ attained some degree of
acceptance.
Similar views were proposed by
American psychiatrist, F.A. Freyhan, speaking at a symposium held in
Switzerland in 1957 (Freyhan, 1959). He stressed the belief that the effects of
the new drugs were not specific to any diagnostic group, but acted on signs of
over-arousal, excitement and abnormal preoccupations owing to their ability to
reduce movement and initiative, and blunt emotions. Like Deniker and Haase,
Freyhan suggested that the drugs’ useful or therapeutic effects were on a
continuum with their obvious extrapyramidal or Parkinson’s-like effects:
From the beginning it was evident that no lines of
demarcation could be drawn between therapeutic degrees of reduced psychomotor
activity and early symptoms of Parkinsonism...What we witnessed were gradual
transitions from hypermotility to hypomotility, which, in a certain proportion
of patients, progressed to the more pronounced degrees of Parkinsonian
rigidity. Clinical evidence therefore, indicated that the therapeutic function
of chlorpromazine and reserpine could not be separated from their modifying
influence on the function of the subcortical motor system in transacting
volitional, affective and intentional functions (Freyhan, 1959, p. 10).
Freyhan was still expressing these views in the early
1960s, when the tide was turning against this view of drug treatment, and
international meetings were dominated by studies of the biochemical and
cellular effects of the new drugs. Instead of trying to identify the specific
mechanism for a disease-based action of the drugs, Freyhan called for
researchers to abandon the ‘arbitrary distinction between main and side
effects’, and to conduct detailed observations of the ‘full range of effects on
psychic, vegetative, sensory, motor and other somatic functions’ (Freyhan,
1964, p. 561).
Psychiatrists in England and Canada
echoed these views (Sarwer-Foner, 1960; Denham, 1965), and there was also
support for Deniker’s suggestion that producing overt symptoms of Parkinsonism
was necessary to achieve the therapeutic benefits of the neuroleptics (Flugel,
1959; Karn, Jr and Kasper, 1959; Denham and Carrick, 1960). The ‘drug-centred’
viewpoint was summarised by participants at a symposium held in 1955, who
concluded that chlorpromazine could be used to ‘attain a neuropharmacologic
effect, not to “cure” a disease’ (Smith Kline & French Laboratories, 1955,
p. 158; cited in Whitaker, 2002, p. 146).
The discovery of haloperidol
in 1958 seemed to clinch the theory behind the concept of the neuroleptic, as
its therapeutic potency was strongly correlated with its ability to produce
Parkinson’s disease-like, neurological effects. Ironically, however, as we
shall see further in the following chapter, by giving rise to the dopamine
hypothesis of schizophrenia, haloperidol hastened the demise of this
drug-centred way of understanding the nature of the ‘neuroleptic’ drugs.
Haloperidol was synthesised by a
team led by Belgian researcher Paul Janssen, then director of part of the
family pharmaceuticals firm that his father had founded. Janssen’s team were
working on producing synthetic opiate drugs following the successful
development of Palfium (dextromoramide). During this process they attached a
molecule known as a ‘butyrophenone’ group to the compounds they were exploring,
and found that, in animal tests, drugs containing this molecule appeared to
produce the striking immobility and inertia characteristic of high dose
chlorpromazine, a state which had been named ‘catalepsy’. Janssen has also
described that they tested and were impressed by these drugs’ ability to
counteract the effects of amphetamines (Granger and Albu, 2005).
The similarity between the observed
effects of haloperidol and chlorpromazine suggested the drug might be useful in
psychiatric patients, so only 5 weeks after its synthesis in February 1958,
Janssen started to give out samples of the drug to psychiatrists he knew. Two
psychiatrists at the University of Leige, Paul Divry and Jean Bobon, prescribed
the drug to a number of patients with various forms of agitation, and, in line
with the first accounts of chlorpromazine, they reported that haloperidol was
effective in calming agitated behaviour without inducing irreversible sleep
(Divry et al., 1958). They expanded on their observations in a second paper, in
which they commented on the facility with which haloperidol produced
Parkinson’s-like effects: ‘here parkinsonism is the norm, not the incident’
(Divry et al., 1959).
At this point Janssen gave samples
of the drug to investigators in several different European countries, including
Delay and Deniker in Paris. In September 1959 he convened a conference at which
the investigators reported their findings, documenting the ability of
haloperidol to reduce psychotic symptoms, calm agitation, reduce involuntary
movements (like tics) and to produce the range of movement abnormalities
characteristic of a neuroleptic, including Parkinsonism, acute dystonia and
akathisia. A month later, in October 1959, just over 18 months since its
synthesis, haloperidol was launched onto the European market (Granger and Albu,
2005).
Janssen regarded the outcome as
evidence that the young man had genuinely had schizophrenia, which the
haloperidol had successfully kept at bay, and the story was interpreted as
demonstrating the remarkable benefits of the new drugs. The brevity of the
man’s symptoms and the lack of any previous psychiatric disturbance make this
explanation doubtful, however. An alternative interpretation of events is that
the second episode of psychosis was a result of the haloperidol itself, in what
may be one of the first recorded cases of ‘supersensitivity’ or
withdrawal-induced psychosis (Moncrieff, 2006). There is now evidence that
long-term exposure to antipsychotics may make people vulnerable to experiencing
psychotic symptoms when the drugs are withdrawn, even people with no previous
history of psychotic problems. The mechanism may be related to the drug-induced
changes that cause the abnormal movement disorder known as tardive dyskinesia.
These issues are described in further detail in Chapters 5 and 6,
but it is interesting to note here that the young man who has been held up as
evidence for the benefits of long-term antipsychotic treatment may possibly be
one of the first victims of a serious iatrogenic problem.
Paradoxically, although haloperidol
had the strongest potential to cause extrapyramidal effects and thus appeared
to confirm the neuroleptic theory of antipsychotic action, it also ushered in
the dopamine theory of schizophrenia, which, by suggesting that the drugs acted
by counteracting an underlying disease, rendered these effects less visible and
apparently less significant. Although the dopamine hypothesis was not clearly
articulated until the 1970s, its origins lay, as described in the following
chapter, in the specific effects of haloperidol on dopamine receptors—effects
that were never as clear with broader-acting drugs like chlorpromazine and
reserpine. Janssen himself subscribed to a version of
the dopamine theory of schizophrenia, believing that the condition was caused
by abnormally elevated phenylethylamine levels, an endogenous brain chemical
that causes dopamine release (Janssen, 1998).
From Tranquillisers to Antipsychotics
The idea of a neuroleptic was never accepted to the
same degree in the USA, where drugs like chlorpromazine and reserpine were
referred to as ‘tranquillisers’. The term tranquilliser was popularised by the
manufacturers of a drug called meprobamate, also known by its brand name,
Miltown, who used it to distinguish their drug from the numerous barbitu rates
on the market at the time (Janssen, 1998). By the 1960s, drugs used in
psychosis and schizophrenia started to be referred to as ‘major tranquillisers’
to distinguish them from sedatives, like meprobamate, and the newly-launched
benzodiazepine drugs, including Librium and Valium, which were increasingly
referred to as ‘minor tranquillisers’. The term ‘tranquilliser’ was appealing
for marketing purposes because its derivation from ‘tranquillity’ helped to
represent the drug-induced state as pleasant and calming, and it also indicated
the potentially wide application of such treatments. In the 1950s, for example,
reserpine was advertised as having ‘a remarkable calming action...capable of
wide application in mental illness’ (Reserpine advertisement, 1956) (Figure 3.1).
Early advertisements for the drug
Melleril (thioridazine), a drug that came to be widely used in psychiatry and
general practice, described it as a ‘tranquilliser pure and simple’, and used
the image of a lake to convey its ‘specific psychosedative action’ (Melleril
advertisement, 1960) (Figure 3.2).
Other advertisements from the same period recommended many different situations
in which the drugs’ tranquillising properties could be employed, including
anxiety, childhood behaviour problems, and agitation and aggression in the
elderly. Dartalan (thiopropazate dihydrochloride), for example, was advertised
for use in psychoses, neuroses, geriatrics and general medicine (Dartalan
advertisement, 1960).
As early as 1954, however,
participants at a psychiatric symposium in Washington, DC, clearly stated they
believed chlorpromazine and reserpine were attacking the ‘underlying
schizophrenic process’ (Kinross-Wright, 1956) and exerting a ‘specific effect
on the basic schizophrenic mechanisms’ (Sainz, 1956). A participant, who did
not share this view, bemoaned the tendency to jump from the effects of drugs to
making generalisations about the genesis of psychotic behaviour (Meyers, 1956).
In 1955, the President of the Society of Biological Psychiatry of the United
States reflected that the new drugs were of a ‘different order’ from previous drugs, and that they could ‘wipe out the
symptoms of psychotic patients just as internists can use insulin for the
elimination of the symptoms of diabetes’ (Himwich, 1955).
Figure 3.1 Reserpine advertisement
Copyright
of 3M, reproduced with permission.
Figure 3.2 Melleril advertisement
Reproduced
with kind permission of Novartis.
At the same symposium in 1957 in
which Freyhan outlined his drug-centred view of the action of the new
tranquillisers, Heinz Lehman set out the first explicit, disease-centred theory
of the actions of chlorpromazine and similar drugs (Lehmann, 1959). As well as
attempting to classify the new drugs by their physiological effects on the
nervous system in a drug-centred manner, he suggested that the effects of drugs
could also be divided into those that were ‘curative’, ‘corrective’ and
‘symptomatic’. Whereas a curative substance was one that reversed the original
cause of the disease, like antibiotics, a corrective was one that attacked a
‘nucleus of symptoms that is fairly close to the primary disturbance’, although
the primary cause of the condition need not be known. Examples of correctives
in medicine were insulin for diabetes and digitalis for heart disease, and
Lehmann identified chlorpromazine and reserpine as ‘typical corrective agents
in a number of acute and chronic psychotic conditions’ (Lehmann,
1959, p. 22). He contrasted their effects to symptomatic treatments, like
morphine for pain, barbiturates for insomnia, and chlorpromazine when it was
used for the control of behavioural excitement, which only affected symptoms
that were ‘rather remote and indirect manifestations’ of the disease process
(p. 23).
Heinz Lehmann has said that he
introduced the term ‘antipsychotic’ at a Canadian Medical Association meeting
in 1956, but that he meant it more metaphorically than literally at this time
(Lehmann, 1993). The first paper listed on the medical database Medline using
the term ‘antipsychotic’ was published in 1962, in which two psychiatrists
distinguished an ‘antipsychotic drug’ which ‘antagonises major psychotic
symptoms’ from other tranquillisers, which ameliorate the ‘symptom of anxiety’
(Mapp and Nodine, 1962, p. 458). Despite this distinction, however, the authors
did not attribute ‘curative’ or ‘corrective’ properties, in Lehmann’s terms, to
the drugs they were describing, but expressed confidence that ‘more specific
agents’ would be developed in the future, which would act on the ‘etiology of
the symptoms rather than the symptoms themselves’. Their longing for such a
discovery was conveyed by their dramatically expressed aspiration for a drug
which could ‘chemically remove’ mental symptoms, permitting the patient to
‘sever the blocking strings of the past and like some giant Gulliver, step
forth as a strong, fully productive adult’ (p. 463).
US psychiatrist, Nathan Kline, was
one of the most influential proponents of a disease-centred theory of
psychiatric drug action. In 1959 Kline described chlorpromazine and reserpine
essentially in drug-centred terms, calling them ‘ataraxics’, a term which,
according to Kline, meant a substance that relieved ‘turmoil and confusion’
(Kline, 1959, p. 398). As well as their ability to ‘restrict and inhibit’
mental disturbance, however, he believed they could also ‘remove or reverse’
symptoms, hinting at a putative disease-centred mechanism of action (p. 398).
But it was his characterisation of what later came to be known as
‘antidepressants’ in which Kline expressed the disease-centred view most
explicitly. Kline distinguished drugs that he called ‘psychic energisers’
(later referred to as antidepressants) from stimulants by claiming that they
normalised mood in those who were depressed without causing the general arousal
and euphoria associated with drugs like amphetamines (Kline, 1959). His
assertions were contradicted by data suggesting that the early antidepressants
he referred to did induce euphoria, and had stimulant
effects that were remarkably similar to those of amphetamines (Crane, 1956),
but no one pointed this out at the time, and Kline helped to establish the idea
that ‘antidepressants’ worked in a targeted, disease-centred fashion.
Sheldon Gelman has described how the
report of this trial encapsulated a new psychiatric ‘vision’, which suggested
that drug treatment was effective and specific with relatively trivial adverse
effects (Gelman, 1999). Although the results of the study were subsequently cited
to justify the disease-centred model of drug action, it appears that the
disease-centred view was already assumed in its conception. As the study
included no other type of drug, it could not demonstrate that the
antipsychotics were superior to other sorts of sedative, nor could it discount
the impact of the neurological effects the antipsychotics exerted. Moreover,
the neurological or ‘extrapyramidal’ effects, now referred to as ‘side
effects,’ were already distinguished from the drugs’ therapeutic effects and
the concept of the ‘neuroleptic threshold’, which explains that drugs with
different propensities to cause extrapyramidal effects can exert therapeutic
neurological effects at variable, ‘threshold’ doses was not considered.
The idea that drugs like
chlorpromazine could suppress a range of symptoms does not in itself
necessarily imply a disease-centred view of drug action, although, as we shall
see in Chapter 6, other studies have
not confirmed the NIMH’s findings, and have generally found that the principle
effects of antipsychotics are on reducing behavioural disturbance and
‘positive’ psychotic symptoms. The increasing separation and minimisation of
neurological ‘side effects’, however, and the broad endorsement
of the drugs suggests that they were in the process of being transformed into
drugs that were suitable for a new era in mental health care. Whereas during
the early and middle decades of the twentieth century, people felt able to do
practically anything to psychiatric patients in the name of therapy, including
putting them into dangerous comas for days at a time, by the 1960s times were
changing. There was increasing acceptance that treatments should be properly
and scientifically evaluated, and along with organised controlled trials came a
greater awareness of the ethics of treating people with mental conditions. The
idea that psychiatric therapies, including drugs, worked by inducing other
diseases, as Deniker had suggested, was no longer an acceptable basis for treatment.
Treatment had to be an unqualified good, except, of course, for troublesome,
but essentially trivial, side effects.
The Ascendancy of the Disease-Centred Model
The emergence of the disease-centred model of
psychiatric drug action was not premised on research findings, however, or on
theoretical discussion or debate. Although a few figures like Deniker and Haase
continued to reiterate a drug-centred view, in general, what is striking is
that this older conception of drug action simply faded away. Descriptions of
the neurological and physiological effects induced by antipsychotics and other
psychiatric drugs, such as antidepressants, disappeared from the literature
(Moncrieff, 2008b). Henceforth they were referred to, if at all, only as ‘side
effects’, which were regarded as an incidental nuisance, rather than an
intrinsic part of a drug’s action. Almost no papers discussed the relative
merits of different theories of drug action or attempted to justify the
disease-centred model, and no research was set up to evaluate different models.
When textbooks started to present the disease-centred view, there was little
acknowledgement that there was an alternative explanation of how antipsychotics
might work and there was no discussion of any evidence to support the
disease-centred view of drug action, with the exception of some oblique
references to the NIMH study.
Textbooks tentatively started to
convey a disease-centred view of the nature of neuroleptic or antipsychotic
drugs from the 1960s, with suggestions that ‘they appear to do more than
tranquilise’ (Henderson and Gillespie, 1962, p. 350) and ‘penetrate much closer
to the site of mechanism of the disease itself than any other procedure applied
hitherto’ (Mayer-Gross et al., 1960, p. 386). Most descriptions of drug
treatment remained only implicitly disease-centred at this period, however,
linking particular drugs with particular conditions, omitting any description
of their psychoactive or drug-induced effects, and conceptually separating
therapeutic effects from ‘side’ effects, but without any discussion about how
the drugs might affect possible disease mechanisms (Hoch, 1959; Malitz and
Hoch, 1966).
Figure 3.3 Stelazine advertisement
Reproduced
with kind permission of GlaxoSmithKline.
Hints
of a disease-centred view also started to appear in advertisements of the
1960s, where the neuroleptics or major tranquillisers were increasingly
associated with the treatment of schizophrenia. Largactil (chlorpromazine) was
said to act as a ‘psychocorrective’ in this situation, for example (Largactil
or chlorpormazine; Largactil advertisement, 1965), and Serenace (haloperidol)
was said to have a ‘profound’ action (Serenace or haloperidol) (Serenace
advertisement, 1965a). A 1965 advertisement for Stelazine, which depicts a
young man looking comfortable and relaxed below a troubled-looking older man,
seems to illustrate the idea that drug treatment could restore someone to
normal and prevent them deteriorating into a state of chronic patienthood
(Stelazine advertisement, 1965a) (Figure 3.3).
By 1970, the majority of
advertisements were aimed at people diagnosed with schizophrenia. The Melleril
(thioridazine) advertisement from this year, which consisted of two colour
pages, described the action of the drug in explicitly disease-centred terms (Figure 3.4). Melleril
‘strikes promptly at the target symptoms’, the advertisement claimed, and the
drug was referred to as an ‘anti-psychotic’. The effect on ‘target’ or
psychotic symptoms, which was said to occur after 7 days, was also
distinguished from the immediate sedative or ‘tranquillising effect’ of the
drug (Melleril advertisement, 1970).
During the 1970s, the consolidation
of the dopamine hypothesis of schizophrenia introduced a new confidence to
assertions about the nature of drug treatment for schizophrenia. Commitment to
the disease-centred view of drug action was expressed in the belief that
clarifying the drugs’ mechanism of action would reveal the underlying basis of
schizophrenia.
The Companion to
Psychiatric Studies, one of the most respected British textbooks of
psychiatry for many decades, first published in 1973, presented what is
probably the last mainstream, drug-centred account of antipsychotic action,
alongside the disease-centred view. The general chapter on pharmacology
suggested that the drugs damp down responses to stimuli and reduce spontaneity,
and, following Delay and Deniker, suggested their unique quality was their
ability to induce sedation without sleep (Roberts, 1973). The chapter on the
treatment of schizophrenia, however, written by a different author, assumed the
drugs acted in a disease-centred manner. In this chapter the drugs were
referred to as ‘anti-schizophrenic’ and it was asserted that they exert ‘a
specific therapeutic effect in schizophrenia, and that the term “tranquiliser”
is a misnomer’ (Smythies, 1973, pp. 281–2). Serotonin and dopamine were
discussed as possible candidates for the underlying basis of drug action and clarification
of this, it was suggested, would reveal the ‘biochemical lesion of
schizophrenia’ (Smythies, 1973, p. 282).
Figure 3.4 Melleril advertisement
Reproduced
with kind permission of Novartis.
By 1980, the first edition of what
has subsequently become the major American textbook of psychiatry unequivocally
asserted the disease-centred position. The section on antipsychotic drugs,
written by John Davis, stated ‘antipsychotic drugs have a normalising
effect. They lessen the typical schizophrenic symptoms, such as hallucinations
and delusions. They also normalise various other abnormal behaviours’. Davis
also stressed that ‘there is a clear cut difference between their sedative and
antipsychotic properties’ (Davis, 1980, p. 2260, my emphasis). The author of
the general section on psychopharmacology, Solomon Snyder, whom we shall meet
in the next chapter through his work on dopamine receptors, asserted that the
drugs ‘exert a selective anti-schizophrenia action’ and then provided a
detailed description of their actions on the dopamine system (Snyder, 1980, p.
161).
By the mid-1970s advertisements for
neuroleptic drugs no longer mentioned their psychoactive properties, and almost
all were targeted at the treatment of people diagnosed with schizophrenia. In
June 1975 a new drug called Redeptin was advertised for the first time, which
was said to have an ‘antipsychotic action’ that was achieved through its ‘specific
action on dopamine receptors’ (Redeptin advertisement, 1975).
Influences and Motivations
A rare discussion of alternative understandings of drug
action by Nathan Kline in 1969 reveals how much was felt to be at stake by
acknowledging the drug-centred point of view by this time. In his 1959 paper, Kline rejected the concept of a ‘neuroleptic’ on
the not unreasonable basis that the mode of action the term suggested was
unproven. Ten years later, he angrily dismissed a World Health Organization
report on psychopharmacology that had accepted the concept, presumably under
Deniker’s influence. He described the report as being ‘deGaulling’ in its
‘capitulation’ to the French point of view, and as using a ‘weasling excuse’ to
defend its position, language far removed from the sober and restrained
expression that usually characterises academic writing (Kline, 1969).
Although typical of Kline’s
forthright personality (Healy, 2002), his fury at the implications of the
drug-centred view illustrates the strength of professional interests that were
at stake in the transformation of views about the nature of psychiatric drug
treatment. Ever since the medical superintendents of the lunatic asylums
identified themselves as a profession, they had been on the defensive about the
role of medicine in caring for people deemed at that time to be ‘insane’
(Scull, 1993; Rogers and Pilgrim, 2001). After decades of impotence, as they
perceived it, physical treatments like insulin coma therapy, ECT and lobotomy
had helped psychiatrists to present a medical face to the world (Moncrieff and
Crawford, 2001). From the 1940s, however, with the introduction of penicillin
and an array of other drugs, medicine came to be identified more than anything
with drug treatment. Thus, the new drugs helped bring psychiatry further into
line with existing medical practice, and contemporaries expressed their delight
that the drugs made ‘the mental hospital a medical institution in the minds of
the public’ (Overholser, 1956). Deniker, too, described approvingly how the new
drugs had strengthened the medical and scientific approach in psychiatry
(Deniker, 1970).
The drug-centred view of how
psychiatric drugs might work was not, however, a model that could be easily
married with the increasingly specific nature of other medical treatments.
Medicine in the twentieth century was increasingly identified with the notion
of treatment that worked by targeting an underlying disease. ‘Cure by specific
therapy’ had become ‘the only really proper sphere for the physician’
(Pellegrino, 1979, p. 255). Suppressing symptoms by drugging people, even if
the characteristics of the drug-induced state were uniquely useful, as Deniker
and others argued, was not a model that could be married with the mechanisms of
antibiotics, hormones or other emerging medical therapies. So psychiatrists
borrowed the notion of specificity from their medical colleagues and soon
forgot that there was any other way to conceive of the effects of the drugs
that they used.
The consolidation of the idea that
psychiatric drugs constituted disease-specific treatments formed an important
building block for the project that has sometimes been referred to as the
‘remedicalisation’ of psychiatry, which took place during the 1970s,
culminating in the publication of the third edition of the Diagnostic
and Statistical Manual of Mental Disorders (DSM)
in 1980. The DSM-3 expunged the influence of
psychoanalysis and social psychiatry that had infiltrated twentieth century
psychiatry—quite illegitimately in the opinion of its authors—and helped to
present psychiatric practice as a thoroughly medical process in which discrete
disease entities could be identified, labelled and treated with specially
targeted interventions (Wilson, 1993). Without being able to predict treatment,
psychiatric diagnosis was an easy target, and hence the claim that psychiatric
treatments act on underlying processes was a prerequisite for the consolidation
and acceptance of the philosophy that underpinned the DSM-3.
Professional interests were not the
only drivers of the change in understandings of psychiatric drug action,
however. The disease-centred model seemed to promise that the use of properly
targeted medical treatment could resolve the age-old problem of what to do with
people who became mentally disturbed. Instead of having to be contained and
cared for, this new orientation suggested that people with psychiatric problems
could be ‘cured’ and returned to society to resume a normal life. It was a view
that was enormously appealing to politicians and policy
makers, who could now regard a complex problem of social control and welfare as
a simple situation requiring only the correct technical intervention. Moreover,
the idea that people could be cured provided a way of conceptualising mental
health care that was in tune with the liberal and progressive ideals of the
post-war world, and, co-incidentally, afforded the justification to run down
the expensive mental hospitals and replace them with cheaper ‘care in the
community’. The attempt to reframe madness as a medical problem that started in
the nineteenth century was finally cemented by the disease-centred view of the
new tranquillisers.
By 1970 the disease-centred model
was so well accepted that Deniker was forced to admit that his views were
controversial, acknowledging how unpalatable it was to many psychiatrists to
define a group of drugs by their adverse effects (Deniker, 1970, 1983).
Although he continued to stress that the ‘therapeutic effects of the
neuroleptics are inseparable from the psychomotor, neurological and vegetative
modifications which they produce’ (Deniker, 1983), he recanted on the idea that
advanced symptoms of Parkinsonism were required for the best therapeutic
effects (Deniker, 1970). He was sceptical of the dopamine hypothesis of
schizophrenia, however, and maintained that ‘neuroleptics diminish the
phenomena of schizophrenia, but do not pretend to be an etiological treatment
of these psychoses’ (Deniker, 1989). Also interesting from a drug-centred
perspective is that Deniker was one of the first people to comment on how the ‘neurovegetative’
effects of clozapine, which he acknowledged were different from those induced
by other, more ‘typical’ antipsychotics, were likely to mediate its therapeutic
effects (Deniker, 1989). We shall see how this idea is confirmed by other accounts
in Chapter 7.
When dopamine receptor blockade was
demonstrated to be the principle mechanism of both the therapeutic action of
most early antipsychotics and their propensity to induce neurological or
extrapyramidal effects, it might have seemed as though mainstream psychiatry
would have to acknowledge the truth of Deniker’s position. In the 1990s it was
established that the level of dopamine receptor blockade required to produce
therapeutic effects (65–80%) was only slightly lower than the level found to
produce overt evidence of drug-induced Parkinsonism (above 80%), in a pattern
reminiscent of Haase’s concept of the ‘neuroleptic threshold’ (Farde et al.,
1992; Nyberg et al., 1995). Somehow, psychiatry managed to maintain the distinction
between the therapeutic effects and the neurological effects of antipsychotics,
however, and the idea that these were one and the same started to become
unthinkable as the disease-centred view gained wider acceptance. The
development of the dopamine hypothesis of schizophrenia played a crucial part
in this evasion. By focusing attention on the biological nature of the
underlying disorder, and suggesting a mechanism whereby drugs might reverse a proposed abnormality, the theory consigned
the drug-centred understanding of the new drugs to history. The neurological
alterations produced by antipsychotics and described so vividly by Deniker and
others, along with the theories they inspired, slipped quietly, but thoroughly,
out of view.
Building a House of Cards: The Dopamine
Theory of Schizophrenia and Drug Action
By presenting a theory of schizophrenia suggesting that
some or all of its symptoms are caused by a biochemical abnormality that
antipsychotics happen to reverse, the dopamine hypothesis of schizophrenia is a
key part of the story of how the group of drugs we are considering came to be
understood as ‘miracle cures’—as drugs that target the basis of schizophrenia
or psychosis. Although the inadequacy and inconsistency of the theory have been
acknowledged ever since it was articulated, the dopamine hypothesis of
schizophrenia has occupied research activity for decades and consumed vast
amounts of funding. In fact, for many academics and practising clinicians, it
has long moved beyond hypothesis into the realm of fact.
The original hypothesis proposed
that schizophrenia is caused by over-activity of the brain chemical, dopamine.
The theory has existed in many different versions, however, over the course of
its life. Stephen Stahl, author of many best-selling textbooks on
psychopharmacology, presents an elaborate version of the hypothesis in his 2008
book Antipsychotics and Mood Stabilisers. Backed up
by numerous scientific-looking illustrations of brain circuits and neurons, he
suggests that schizophrenia is caused by simultaneous over-activity of dopamine
in one part of the brain, the limbic system, and under-activity in another, the
cortex. Furthermore, he postulates that atypical antipsychotics simultaneously
correct these opposing defects. No conflicting evidence is mentioned, and there
is no acknowledgement of the implausibility of a situation involving opposing
biochemical states co-existing in different, but inter-related, brain regions,
or of the idea that one drug can simultaneously act in different ways in
different areas (Stahl, 2008).
‘The history of schizophrenia
research’, said pharmacologist Les Iverson in an interview with psychiatrist
and academic David Healy, ‘is littered with the
skeletons of chemical hypotheses’ (Iversen, 1998, p. 345). Before the dopamine
hypothesis there was a thyroid hormone hypothesis of schizophrenia, a sex
hormone hypothesis, the transmethy lation and serotonin hypotheses, and many
others. Since the 1990s glutamate has come into fashion, and interest in
serotonin has been revived. The dopamine hypothesis seems to be the most
persistent, however, but, in order to survive, it has had to absorb, transform
or expel many awkward pieces of evidence. The popularity and longevity of the
theory tells us something important about the vision psychiatry wishes to
promote of itself and its treatments. The dopamine hypothesis of schizophrenia
suggests, as many psychiatrists have wanted to believe for a long time, that
psychiatric conditions are real diseases with tangible and specific biological
origins, and that antipsychotic drugs constitute a genuine and innocuous
medical treatment, which counteract the underlying defect in a highly targeted
manner.
In fact, however, the dopamine
theory was elaborated on the assumption that antipsychotic
drugs act in a disease-specific way on the underlying pathology of
schizophrenia or its symptoms. Because this view of antipsychotic action was
already unquestioned, it was presumed that the origins of schizophrenia or
psychosis could be deduced to be the opposite state from that produced by the
drugs. So, according to a recent textbook of psychiatry, ‘the fact that every
effective antipsychotic drug blocks dopamine D2
receptors is powerful evidence of the importance of dopamine in the pathogenesis
of schizophrenia’ (Wright et al., 2012, p. 272). Even in the early days of the
dopamine hypothesis, few of its proponents seemed aware that they were making
an assumption of this sort. The dopamine hypothesis of schizophrenia is a
consequence of the fact that the disease-centred model had already eclipsed
other ways of understanding drug action by the time the hypothesis was
elaborated in the 1970s.
This chapter will demonstrate that
decades of research have failed to provide evidence that the symptoms of either
schizophrenia or psychosis result from an underlying abnormality of dopamine
activity. What research has clearly demonstrated, in contrast, is that
antipsychotic drugs disturb dopamine function to a greater or lesser extent,
and that their action on the dopamine system is responsible for many of the
characteristic neurological disturbances they produce. The dopamine theory of
schizophrenia has, however, helped to ensure that such effects are decisively
relegated to the place of second fiddle behind the drugs’ proposed ability to
rectify the underlying disease. In this way, the dopamine hypothesis provided
an important bulwark against the potential threat
posed to the modern vision of drug treatment by the emergence of tardive
dyskinesia. Moreover, as we shall see in the next chapter, an adapted version
of the dopamine hypothesis was an important tool in the early marketing of the
atypical antipsychotics.
Origins of the Dopamine Hypothesis
The activity of dopamine as a neurotransmitter, or
chemical messenger, was discovered by the Nobel prize-winning Swedish
pharmacologist Arvid Carlsson, while he was investigating the chemical basis of
the action of reserpine. In the 1950s the newly described effects of the drug
lysergic acid diethylamide (LSD) made some people speculate that schizophrenia
was due to abnormalities of the serotonin system (Woolley and Shaw, 1954).
Bernard ‘Steve’ Brodie, the leading scientist at the National Institute of
Mental Health (NIMH) in the USA, under whom Carlsson worked for a period in the
mid-1950s, showed that reserpine reduced brain serotonin levels when given to
rabbits (Pletscher et al., 1955). Carlsson’s later work showed that reserpine
depleted not just serotonin but dopamine and noradrenaline as well, and that
dopamine and not serotonin was responsible for the slowing and lethargy caused
by reserpine (Carlsson et al., 1957, 1959). The similarity between the state of
reduced movement induced by reserpine and Parkinson’s disease lead Carlsson to
speculate that the latter might involve the dopamine system, and this was
confirmed in the 1960s (Ehringer and Hornykiewicz, 1960).
So, the discovery of the activity of
dopamine in the brain was a consequence of the investigation of the abnormal
state of reduced movement produced by reserpine. In other words, it proceeded
according to a drug-centred model of drug action. As the neuroleptics were
transformed into ‘antipsychotics’, this research metamorphosed into something
quite different. The drug-induced abnormalities that had been observed were
inverted and the research became focused on the origins of schizophrenia
itself. From this point on, the perturbations induced by drugs were only
interesting in so far as they indicated something about the pathology of the
disease that was presumed to lie behind the symptoms of schizophrenia, and
there was little interest in the effects of the drugs for their own sake.
Although reserpine had been shown to
deplete dopamine stores, the mechanism of action of the other antipsychotics
remained uncertain, as they could not be shown to have the same depleting
action. A Dutch researcher, Jacques van Rossum showed that haloperidol, and a
related drug, spiramide, reversed the effects of
dopamine on blood pressure in cats, confirming his hypothesis that ‘dopamine
receptor blockade is an important factor in the mode of action of neuroleptic
drugs’ (van Rossum, 1966a, p. 492). In a book published the same year he
briefly speculated that the discovery might have ‘fargoing consequences for the
pathophysiology of schizophrenia. Overstimulation of dopamine receptors could
then be part of the aetiology’ (van Rossum, 1966b, p. 327).
The dopamine hypothesis of
schizophrenia was not clearly expounded in the scientific literature until the
1970s, however, although there are indications that it was already influential
by this time. By 1974, for example, it was claimed to be a central theme in
psychopharmacology, which was ‘shared by many investigators’ and was said to
exert ‘a substantial influence on the design of experiments’ (Matthysse, 1974a,
p. 107). In spite of its increasing importance, other theories continued to be
put forward, however, particularly variants of the serotonin hypothesis of
schizophrenia, the ‘transmethylation’ hypothesis and a phenylalanine hypothesis
(Faurbye, 1968; Fischer, 1970). A deficit of noradrenline, another
neurotransmitter, was proposed to be the origin of schizophrenia (Wise et al.,
1974), and research continued into the role of noradrenaline in the effects of
stimulants and antipsychotics (Bartholini et al., 1972). As late as 1973, in
one of the first reviews of research pertaining to a possible dopamine theory
of schizophrenia, Steven Matthysse, professor of psychobiology at Harvard,
argued ‘this simple hypothesis is by no means the only possible interpretation
[of the research data]. It is not even the most plausible’(Matthysse, 1973).
Three international conferences on
dopamine and noradrenaline, also known collectively as ‘catecholamines’, had
been organised by 1973. At the third meeting, Steven Mattysse proposed a
further meeting, which took place the following year, on the role of these
chemicals in the ‘neuropathology of schizophrenia,’ in order, as he said, to
assemble the world’s most ‘critical and productive investigators in the field’
(Matthysse, 1974b, p. xiii). The two main strands of evidence that were cited
as the basis for a dopamine theory of schizophrenia in the collection of
conference papers published in 1974 were the effects of antipsychotic drugs,
and the ability of the drug amphetamine to induce psychotic symptoms. Many of
the authors highlighted the contradictory nature of the evidence, however, and
few were confident that the origin of schizophrenia or its symptoms had been
uncovered. As Mattysse pointed out in the epilogue to the volume, the state of
the evidence allowed only limited conclusions. These were simply, he thought,
that antipsychotic drugs block dopamine activity and that amphetamines can cause psychosis. In Matthysse’s view,
it had not even been established that dopamine was involved in the therapeutic
effects of antipsychotics or the psychosis-inducing effect of amphetamines
(Matthysse, 1974b).
These modest and uncontested claims
jar with the space devoted to speculation about the role of dopamine in
schizophrenia and the enthusiasm expressed about the potential of the research
being conducted. Leading psychiatric geneticist Seymore Kety summed up the
atmosphere of the conference by noting how the area was creating ‘considerable
ferment throughout the world’. There was a feeling, he suggested, that the
‘psychobiological substrates’ underpinning schizophrenia were, at last, being
laid bare (Kety, 1974, p. x). Despite his cautious assessment of the existing
evidence, Mattysse himself declared that the research being conducted would
eventually make a substantial contribution to the ‘matrix of scientific
knowledge’ on the biological nature of schizophrenia (Matthysse, 1974b, p.
xvi).
Antipsychotic Action and the Dopamine
Hypothesis
Matthysse noted that most of the contributors to the
1974 conference took as ‘axiomatic’ the idea that antipsychotics exerted their
therapeutic effects in people diagnosed with schizophrenia by acting on the
abnormalities that gave rise to the condition. The only contributor who acknowledged
that this view required justification was Solomon Snyder, a scientist already
renowned for his work on identifying and locating opiate receptors. Snyder
subsequently identified the first dopamine receptors and became one of the
principle proponents of both the dopamine hypothesis of antipsychotic action,
and the dopamine hypothesis of schizophrenia. Snyder’s main line of research
into dopamine concerned the actions of amphetamine, but, in his contribution to
the 1974 conference, he also claimed emphatically that antipsychotic drugs had
been shown to be specifically ‘antischizophrenic’, referring to the NIMH study
and the claim by its authors that the drugs affected all the ‘fundamental’
symptoms of schizophrenia (Snyder, 1974). As we have seen, however, the study
was already influenced by a disease-specific view of antipsychotic action and,
moreover, was contradicted by other studies on the effects of antipsychotics.
Having supposedly established the
disease specificity of antipsychotic action, and although he admitted that the
drugs ‘produce biochemical effects on almost every system that has been
examined’, Snyder concluded that the therapeutic effects of antipsychotics were
achieved through their effects on the dopamine system
on the basis of studies showing correlations between the dose range of various
antipsychotics and their effects on dopamine receptors (Snyder, 1974; Snyder et
al., 1974, p. 1246). Drugs with stronger actions on these receptors were active
at lower doses than those with weaker actions, and this finding has been cited
many times since to support the dopamine hypothesis of drug action and of
schizophrenia. David Healy suggested it was ‘among the most clear-cut findings
in psychopharmacology’ (Healy, 2002, p. 214).
The relationship between dopamine
blockade and therapeutic activity is not as strong or as simple as is often
suggested, however. It was already apparent in the 1970s that some drugs, such
as clozapine and thioridazine (Melleril), which had relatively weak dopamine-blocking
properties, were as effective as other antipsychotics. Several of the
presenters at the 1974 conference pointed out this discrepancy, including
Matthysse (Crow and Gillbe, 1974; Matthysse 1974a). Snyder himself acknowledged
another inconsistency: that the dopamine-blocking properties of the
antipsychotics were more strongly correlated with their propensity to induce
Parkinson’s-like or ‘extrapyramidal’ neurological effects, than their
therapeutic efficacy (Snyder, 1974). Evidence suggested there was a
‘dissociation between dopaminergic blockade and antipsychotic activity’
(Stawarz et al., 1975).
The discrepancy problem was largely
ignored, however, until the re-introduction of clozapine in the early 1990s. At
that time, receptor binding studies carried out with the new technology of
radio-actively labelling chemicals that bind to receptors in living subjects
confirmed that clozapine, at clinically effective doses, occupied a lower
proportion of the now identified dopamine D2
receptors, compared with most conventional antipsychotics. Moreover, occupancy
rates were closely associated with the presence of Parkinsonism, which
clozapine does not produce to the same degree as other antipsychotics (Farde et
al., 1992; Nyberg et al., 1995). A more recent meta-analysis of dopamine
receptor studies failed to find a statistically significant correlation between
D2 receptor occupancy levels and clinical response.
Excluding studies involving clozapine and quetipine (another antipsychotic with
low dopamine receptor blocking properties) still did not produce evidence of a
correlation between receptor occupancy and clinical response. Excluding one
other study, on the basis that it had overly high dopamine receptor occupancy
levels, did, finally, produce a statistically significant result. The authors
had to conclude, however, that ‘D2 receptor occupancy is only
part of the story regarding antipsychotic medication response’ (Yilmaz et al.,
2012, p. 216). By implication, therefore, drug action
on dopamine receptors cannot be presumed to reveal the underlying pathology of
schizophrenia or psychosis.
Another explanation offered for the
problem of clozapine is the suggestion that clozapine and some other
antipsychotics block dopamine receptors, but then rapidly detach themselves
again (Kapur and Seeman, 2001). Somehow, this transient attachment is proposed
to facilitate antipsychotic effects, but prevent the occurrence of
drug-induced, extrapyramidal effects. It seems more likely that the failure to
produce these neurological signs indicates that no clinically significant
dopamine blockade is occurring, and that the drugs’ much stronger effects on
other neurotransmitter systems account for their psychoactive effects and their
impact on psychotic symptoms.
Amphetamine-Induced Psychosis and the
Dopamine Hypothesis
Snyder and others had been conducting research to
elucidate the mechanism of action of the stimulant drug amphetamine since the
1960s, and several authors, including Snyder, drew on this line of evidence for
the dopamine hypothesis in their 1974 conference papers. Amphetamine psychosis
was first described in the scientific literature in 1938 (Young and Scoville,
1938). Although it is often indistinguishable from an unexplained psychotic
episode in a particular individual, as a group people with stimulant-induced
psychosis exhibit a slightly different range of symptoms, as Snyder himself
pointed out in 1972 (Snyder, 1972). Amphetamine psychosis is primarily a
paranoid state; therefore, although there is clearly overlap with the paranoid
delusions that characterise some episodes of schizophrenia, other sorts of
symptoms that occur in acute episodes of schizophrenic-type psychosis, such as
the verbal ramblings known as ‘thought disorder’, delusions of being
controlled, and inappropriate or flattened emotional responses, are rarely seen
in the drug-induced state. The latter is more often characterised by heightened
anxiety, and visual or tactile (sensations of touch) hallucinations may be
present, which are uncommon in episodes of schizophrenia. Some authors have
pointed out, however, that stimulant-induced psychosis can occasionally produce
symptoms more usually associated with schizophrenia, including bizarre
delusions, third person hallucinations, social withdrawal and apathy (Harris
and Batki, 2000; Batki and Harris, 2004). It seems possible to conclude both
that the psychotic state induced by amphetamines and other stimulants is
somewhat distinctive, and that it shares some features with spontaneous
psychotic or schizophrenic episodes.
The proposed association between
stereotypies, dopamine and the effects of antipsychotics led to the suggestion
that stimulant-induced stereotypy was a ‘model’ for psychosis, in other words
that it constituted an animal equivalent of a psychotic state. The ability of
drugs to counteract the motor effects of stimulants, particularly amphetamine,
was widely adopted as a method of evaluating the potential antipsychotic
activity of a chemical substance, and Janssen Laboratories, for example, was
said to be using this screening test from the early 1960s (Baumeister and
Francis, 2002).
Stereotypies are clearly not the
same thing as psychotic experiences, however, and they occur in people on
amphetamine in the absence of psychotic symptoms. Equally, drug-induced
psychosis is not necessarily accompanied by stereotypical behaviours. Moreover,
the idea that the motor effects of amphetamines in general, or stereotypies in
particular, were mediated purely by dopamine was not
firmly established, and some research suggested that noradrenaline was also
involved in stimulant-induced hyperactivity and stereotypies (Herman, 1970;
Mogilnicka and Braestrup, 1976; Borison and Diamond, 1978). It is also becoming
clear that it is difficult to map any complex behaviour to a single
neurotransmitter system, and it is likely that both noradrenaline and dopamine,
and possibly other systems, are involved in most aspects of amphetamine’s
effects (Berridge, 2006).
In the 1970s, Snyder attempted to
demonstrate that dopamine was the chemical involved in the psychosis-inducing
effects of amphetamine through studying the effects of the two different
chemical forms or ‘isomers’ of the drug. Snyder suggested that the positive
isomer of amphetamine, (+)-amphetamine, had been found to have stronger
noradrenaline-enhancing activity than the negative, (−)-amphetamine isomer,
whereas the two isomers had more equal dopamine-stimulating activity as
measured by their ability to provoke stereotypies in animals. As the two isomers
were equal in their ability to precipitate psychotic symptoms in humans, Snyder
concluded that dopamine must be responsible for this effect (Snyder, 1974).
However, he admitted that other studies had produced conflicting evidence, and
Matthysse, in his main contribution to the 1974 conference report, listed
numerous studies that contradicted Snyder’s findings on the relative effects of
the different isomers (Matthysse, 1974a). Another group of researchers, based
on their own studies of amphetamine isomers, came to the opposite conclusion
that noradrenaline and not dopamine was the system involved in the psychotic
state induced by amphetamines (Bunney et al., 1975).
In a comprehensive overview of the
evidence for the dopamine hypothesis published in 1976, the only evidence cited
to support the idea that amphetamine psychosis is mediated by dopamine was the
effectiveness of antipsychotic drugs in reducing its symptoms (Meltzer and
Stahl, 1976). In other words, the pharmacology of amphetamine played no independent
role in establishing the dopamine hypothesis by this time, and the evidence
came back, once again, to the assumption that the antipsychotics act in a
disease-centred manner.
Further difficulties for the
dopamine hypothesis of schizophrenia or psychosis are presented by the fact
that other drugs that increase dopamine activity do not produce the same sort
of schizophrenia-like psychosis as amphetamine and other recreationally used
stimulant drugs like cocaine. L-dopa, for example, the chemical precursor of
dopamine used for the treatment of Parkinson’s disease, can induce psychotic
symptoms in patients with Parkinson’s disease, but, as Snyder recognised, these are usually part of a toxic confusional state, and
not the lucid, paranoid-type symptoms seen most commonly with amphetamine
(Snyder, 1972). The drug apomorphine, which has specific dopamine-stimulating
effects and can induce stereotypies, produces some psychotic symptoms when used
in the treatment of Parkinson’s disease, but it has not been noted to produce a
psychotic state in the thousands of people in whom it has been used for other
problems, such as alcoholism, and it does not reliably provoke or worsen
psychotic symptoms in people diagnosed with schizophrenia (Depatie and Lal,
2001).
Cannabis also presents a difficulty
for the dopamine hypothesis of schizophrenia and psychosis. It is well known
that heavy and prolonged use of cannabis can induce a psychotic state,
involving paranoid delusions, that resembles both stimulant-induced psychosis
and schizophrenia. Cannabis, however, does not elevate dopamine to the same
degree as stimulant drugs and does not produce stereotypies.
Despite the folklore, therefore, the
occurrence of psychosis following the ingestion of amphetamine or other
stimulants has not been demonstrated to be attributable to the effects of these
drugs on dopamine. The ambiguous nature of the evidence was forgotten, however,
and what passed down into psychiatric thinking was the idea that the effects of
amphetamine in general are attributable principally
to the drug’s effects on dopamine. This view was stated repeatedly in
authoritative reviews and textbooks over subsequent decades, and the fact that
the drug had profound effects on a whole range of other brain chemicals just
stopped being mentioned (Crow, 1987; Lieberman et al., 1990; Wright et al.,
2012).
The Mirage of Dopamine Receptors
Efforts went on throughout the 1970s and 1980s to
demonstrate abnormalities of dopamine activity in people diagnosed with
schizophrenia. Dopamine can only be measured directly after death, so dopamine
concentrations in post-mortem brain specimens were sampled, levels of dopamine
metabolites in blood, urine and cerebro-spinal fluid were measured, and studies
were conducted to assess the status of the hormones that are related to
dopamine activity—growth hormone and prolactin. Although some early studies
reported differences between people diagnosed with schizophrenia and ‘healthy’
controls, these were not confirmed in further studies, and, in the end, none of
these areas yielded evidence that suggested there were any abnormalities of
dopamine activity in people with schizophrenia (the evidence is well reviewed
in Kendler and Schaffner, 2011).
The debate replayed in a similar
form in the late 1980s and 1990s when it became possible to visualise dopamine
receptors in the living brain using positron emission tomography (PET) scans.1
In 1986 a study published in Science reported that
ten young people with schizophrenia who had received no drug treatment showed
higher D2 receptor density then a control group of people of
similar age and gender without schizophrenia (Wong et al., 1986). The analysis
involved various complex and unreliable assumptions, however, and, as Barry
Zeeberg and colleagues from Washington DC demonstrated, the data were
compatible with a number of different conclusions, including that there was no
difference or even decreased density of dopamine receptors in the group with
schizophrenia (Zeeberg et al., 1988). In any case, several subsequent studies
showed no difference in dopamine receptor density in untreated people with a
diagnosis of schizophrenia compared with controls (Farde et al, 1987; Martinot
et al., 1990; Pilowsky et al., 1994).
Just as the link between amphetamine
psychosis and dopamine survived contradictory data, psychiatrists found it hard
to give up on the only demonstrable abnormality of dopamine that had so far
conclusively been shown in people with schizophrenia, and showed a tendency to
minimise, or even ignore, the evidence that the finding was attributable to
antipsychotic treatment. Thus, two meta-analyses concluded that elevated
dopamine receptors in people diagnosed with schizophrenia indicated an
underlying disease process, despite demonstrating a
statistically significant relationship between antipsychotic drug exposure and
receptor density (Zakzanis and Hansen, 1998; Kestler et al., 2001). Only when
other evidence was acquired that was thought to support the dopamine hypothesis
did it start to be widely acknowledged that changes in dopamine receptors are
accounted for entirely by prior drug treatment (Guillin et al, 2007; Howes et
al., 2012).
The Revival
Although it was never completely abandoned, by the
1990s the dopamine hypothesis looked increasingly tenuous. None of the many
areas of research that had attempted to detect dopamine abnormalities in people
with schizophrenia had yielded any confirmatory data, and the reintroduction of
clozapine was a stark reminder of the limitations of conventional,
dopamine-blocking antipsychotic drugs. They were often ineffective, and even
when they helped reduce ‘positive’ psychotic symptoms, many people continued to
show considerable impairments.
In this context, Kenneth Davis and
colleagues tried to rescue the hypothesis by outlining a version in which
positive symptoms were said to originate from increased
dopamine in the brain stem area and negative symptoms from reduced
dopamine activity in the frontal lobe of the brain (Davis et al., 1991). The
theory was founded on studies that demonstrated that the frontal lobes of the
brains of patients with chronic schizophrenia showed lower levels of activity
than those of healthy controls (as measured by blood flow and energy
consumption) (Franzen and Ingvar, 1975; Jacquy et al., 1976). This research was
claimed to indicate that ‘hypofrontality’ was a characteristic of
schizophrenia. Most of the studies, however, involved patients who had been
medicated for many years, and antipsychotic drugs have been shown to reduce
activity in the frontal lobe, as well as other areas (Ngan et al., 2002; Lane
et al., 2004). Moreover, studies with unmedicated patients did not detect the
same abnormalities (Volkow et al., 1986). This new version of the dopamine
hypothesis proposed the unusual and biologically improbable situation that the
condition of schizophrenia arises from the development of simultaneous,
opposing biochemical deviations in different brain regions. Despite its
implausibility, it remains a popular conception and continues to be promulgated
by textbooks of psychopharmacology, such as those of Stephen Stahl (Stahl,
2008).
Other attempts to rescue the
dopamine hypothesis involved combining it with a serotonin and later a
glutamate hypothesis of schizophrenia, as other brain chemicals went in and out
of fashion (Huttunen, 1995; Meltzer, 1995; Carlsson,
2006; Winterer, 2006). Then, in the 1990s, a group of researchers based in
Columbia University headed by Professor Marc Laruelle started giving
amphetamine to people with schizophrenia and indirectly measuring the dopamine
that was subsequently released using single photon emission computed tomography
(SPECT) scans. The group reported that people with schizophrenia released more
dopamine than the control sample, including the small number of people, seven
in total, who had had no previous antipsychotic treatment (Laruelle et al.,
1999). Starting around the same time, studies were conducted that looked at the
rate at which a radioactively-labelled preparation of L-dopa (the chemical from
which dopamine is synthesised), was taken up into various brain regions by
people diagnosed with schizophrenia. Some, but not all, of these studies
indicated increased uptake of L-dopa in some parts of the brain, suggesting
that synthesis of dopamine was accelerated. The results for different brain
regions were highly inconsistent across individual studies, however (Moncrieff,
2009). The study reporting the largest effects was conducted exclusively with
patients who were taking antipsychotics (McGowan et al, 2004), and the largest
study of drug-naive subjects (14 in total) found no effect (Nozaki et al.,
2009). Moreover, a study of healthy volunteers confirmed that treatment with
haloperidol enhances L-dopa-uptake (Vernaleken et al., 2006), indicating that,
as with other attempts to identify dopamine abnormalities in people with
schizophrenia, current studies probably reflect changes induced by drug
treatment.
However, many factors other than
prior drug treatment might influence the results of the L-dopa uptake and
amphetamine challenge studies. To interpret the differences between people
diagnosed with schizophrenia and controls properly, we need to understand
something of the various functions of dopamine. These have not been fully
mapped out, but numerous human and animal studies suggest that dopamine is
involved in motor activity, attention and arousal, and that it is released in
response to various stressful stimuli, such as pain, hypoglycaemia and
examination stress (Frankenhaeuser et al., 1986; Breier, 1989; Rauste-von
Wright and Frankenhaeuser, 1989; Finlay and Zigmond, 1997; Adler et al., 2000;
Goerendt et al., 2003; Nieoullon and Coquerel, 2003; Sawamoto et al., 2005;
Berridge, 2006). One study of a milder stressor—mental arithmetic—did not show
increased dopamine activity, however (Montgomery et al., 2006). As we saw in Chapter 3, we know from observations of
the dopamine deficiency state seen in drug-induced and normal Parkinson’s
disease that dopamine is involved in movement, speed of thinking and mood
(Laruelle et al., 1997; Verhoeff et al., 2001;
Voruganti and Awad, 2006). There is also some evidence that dopamine is
affected by smoking, including one study that showed increased uptake of L-dopa
in smokers compared with non-smokers (Salokangas et al., 2000). People
diagnosed with psychosis or schizophrenia, especially those who are acutely
psychotic, are likely to differ from controls in many of these factors. They
may be agitated and therefore be more physically active; they may be in a state
of heightened arousal; they may be overly attentive to their delusional ideas
or hallucinations; they are more likely to be long-term smokers; and research
indicates that people in an acute psychotic state are more stressed than
controls (Tandon et al., 1991; Pariante et al., 2004).
It was pointed out in the 1970s that
increased dopamine activity in psychosis may reflect increased movement rather
than anything specific about psychosis (Van Praag and Korf, 1975), but there
has been little consideration of the non-specific factors that might influence
measures of dopamine action in the amphetamine-induced dopamine release and
L-dopa uptake studies (Moncrieff, 2009). Nevertheless, they are now considered
to constitute ‘compelling’ evidence of a dopamine abnormality in the latest
version of the dopamine hypothesis of schizophrenia (Kapur, 2003, p. 14). This
new version, first proposed in 2003 by psychiatric researcher Shitij Kapur,
proposes that dopamine is responsible for the ‘salience’ of events—the degree
to which events appear as personally significant and important—and that
psychosis is a state of abnormally increased salience caused by a defect of the
dopamine system. Kapur’s argument was once again built up from the effects of
antipsychotic drugs, assuming that they act in a disease-centred manner. He
cited the older literature on the psychoactive effects of antipsychotics—the
first time in many years that these descriptions had appeared in the pages of
an academic journal—to illustrate how the drugs reduce the salience of events,
which he attributed to their ability to block the effects of dopamine. He
concluded from this that psychosis must represent the opposite state of
heightened salience and increased dopamine activity (Kapur, 2003).
The new version of the dopamine
hypothesis represents a restatement of the early position, except that it links
dopamine only with positive psychotic symptoms. In more recent accounts a
complex array of chemical and environmental pathways and interactions is
postulated which eventually converge to produce ‘dopamine hyperfunction’, which
produces psychotic symptoms (Howes and Kapur, 2009, p. 556).
Kapur’s ideas captured the
psychiatric imagination and sparked another revival of interest in the dopamine
theory of schizophrenia. In 2006 a large
international conference organised at the Institute of Psychiatry in London had
the dramatic title ‘Dopamine – Tempter and Tormenter of the Soul’, and
presentations included one entitled ‘Why dopamine is psychiatry’s favourite
transmitter’! In 2009 leading British psychiatrist Robin Murray described the
latest version of the dopamine hypothesis in a keynote address to an audience
of thousands at the conference of the World Psychiatric Association in Italy.
Decades of contradictory findings notwithstanding, the hypothesis remains at the
heart of the psychiatric conception of schizophrenia and antipsychotic action.
A Smokescreen
Although its proponents admire the ability of the
dopamine hypothesis to ‘evolve’ (Howes and Kapur, 2009, p. 549), others have
commented that the contortions and transformations the theory has undergone to
accommodate or side-line contradictory evidence makes it look very much like
the philosopher Karl Popper’s idea of a pseudoscience (Kendler et al., 2011).
For Popper, a pseudoscience, like psychoanalysis in his view, was a theory that
could not be refuted because it could explain everything—but to explain
everything is, in fact, to explain nothing. In view of the considerable
evidence that the only dopamine abnormalities in people with schizophrenia are
caused by antipsychotic treatment, it is hard to think what evidence could
convince the promoters of the dopamine theory of schizophrenia or psychosis
that the theory is mistaken.
The particular tenacity of the
dopamine hypothesis can be explained by the way that it appears to validate a
disease-centred model of drug action. Despite the fact that the hypothesis was
premised on the assumption that the drugs act in a disease-centred manner, the
theory has itself become a crucial plank of support for the idea that psychiatric
drugs in general, and antipsychotics in particular, represent a targeted
treatment for a particular disease process. The longevity of the dopamine
theory in the face of decades of contradictory and conflicting evidence
testifies to the importance of keeping this belief afloat. Other theories in
biological psychiatry come and go, but theories that present psychiatric
treatment as a medical enterprise, and clearly distinguish it from the physical
and chemical restraint that took place in earlier periods, cannot be easily
abandoned without risking the whole intellectual framework within which
psychiatric care and ‘treatment’ now takes place.
By focusing on the basis of the
disease the drugs were presumed to treat, the dopamine hypothesis also conveniently
diverted attention away from the effects of the drugs
themselves. As David Healy has suggested, the hypothesis blurred the boundaries
between the ‘illness and the effects of the treatments given for it’ (Healy,
2002, p. 218). In this way the dopamine hypothesis played its part in
mitigating the consequences of the emerging evidence that antipsychotic drugs
cause permanent brain damage. The story of tardive dyskinesia, as we shall see
in the next chapter, illustrates how the dopamine hypothesis kept the
antipsychotic bandwagon afloat.
The Phoenix Rises: From Tardive Dyskinesia
to the Introduction of the ‘Atypicals’1
By the 1970s the rose-tinted spectacles were securely
in place. The new tranquillisers, now increasingly referred to as
‘antipsychotics’, were widely believed to be the first truly specific treatment
for schizophrenia—a view that appeared to be confirmed by the emergence of the
dopamine hypothesis. By this time public mental health systems had become
dependent on the widespread use of these drugs both within hospitals and after
discharge. Psychiatrist George Crane, whom we shall meet shortly, commented
that the trend towards the management of more and more patients in the
community had ‘generated the feeling that drug therapy is indispensable’. The
primary purpose of community psychiatric services had become to dispense and
administer medication, and almost everyone diagnosed with severe mental illness
was taking antipsychotics (Crane, 1973, p. 125).
As their use became the norm, and as
they came to be seen as targeting an underlying disease, the wide range of
serious adverse effects induced by antipsychotic drugs were sapped of their
significance and relegated to the status of relatively trivial ‘side effects’.
A new ‘vision’ of drug treatment was cemented, as described by author Sheldon
Gelman, exemplified by the National Institute of Mental Health study report,
which proclaimed the ‘anti-schizophrenic’ properties of the drugs, while declaring
that unwanted effects were ‘generally mild or infrequent’ (National Institute
of Mental Health Psychopharmacology Service Center Collaborative Study Group,
1964, p. 255; Gelman, 1999). These conclusions threw a veil over previous
observations of the neurological impairment the drugs produced, and evidence of
other harmful effects. The emergence of enduring involuntary movements in
people on long-term treatment was more difficult to ignore, however. The
gradual recognition of what came to be known as tardive dyskinesia2
threatened to destroy the ‘study vision’, thrusting
the dangerous nature of the drugs back into public view. The anxiety it
provoked laid the foundations for the introduction of the atypical
antipsychotics.
As we saw in Chapter 3, movement disorders that arise immediately or
shortly after starting treatment with antipsychotics, including Parkinsonism
and acute dystonia, had been identified soon after chlorpromazine was first
introduced into psychiatric practice. Then, in 1956 and 1957, two German papers
described the occurrence of distinctive mouth and facial movements that began a
few weeks after the start of antipsychotic treatment (Kulenkampff and Tarnow, 1956;
Schoenecker, 1957). One of these papers described abnormal movements in three
women, which persisted for several weeks after the drug was discontinued
(Schoenecker, 1957). In 1959, Sigwald, the French neurologist, described
involuntary movements of the tongue, lips, jaw and facial muscles in four women
aged 54–69 years who had been treated with antipsychotics for between 3 and 18
months. The movements persisted for more than 2 years after the drug was
stopped in one patient, and for 6 months or more in the others (Sigwald et al.,
1959).
In 1960 two Danish psychiatrists
described 29 patients with abnormal involuntary movements of the mouth muscles,
which were associated, in some severe cases, with abnormal twisting and rocking
movements of the body and restless, akathisia-like movements of the feet. The
movements persisted in most patients in whom the medication was stopped, and in
some cases the movements started only after medication was withdrawn, a
phenomenon known as ‘unmasking’ (Uhrbrand and Faurbye, 1960).
In 1964 the Danish group proposed
the term ‘tardive dyskinesia’ to denote the characteristic abnormal,
involuntary movements that occurred after a period of antipsychotic therapy,
and the syndrome was reported by clinicians in the USA and the UK in the first
half of the 1960s (Kruse, 1960; Druckman et al., 1962; Faurbye et al., 1964;
Hunter et al., 1964a). Despite the fact that the disorder was reported in
younger people, and in people who were prescribed the drugs as outpatients for
depression, anxiety and pain (Sigwald et al., 1959; Evans, 1965), the view
emerged that the condition was uncommon and restricted to elderly people with
pre-existing brain disease. Nevertheless, the syndrome was recognised as a form
of brain damage in its own right and a British psychiatrist suggested it should
be regarded as a chemical form of ‘encephalitis’ (Hunter et al., 1964b). It was
American psychiatrist George Crane who eventually changed perceptions about the
disorder, however, establishing and publicising its frequency and significance,
although not without considerable resistance from
much of the rest of the psychiatric world (Gelman, 1999).
The story of tardive dyskinesia
reveals the psychiatric profession in a state of denial about the effects of
its treatments. Leading psychiatrists argued that the condition was infrequent
and unimportant. They suggested the movements were a pre-existing feature of
schizophrenia, and nothing or little to do with antipsychotic medication, even
though the syndrome had been clearly recognisable to those who first observed
it as something distinct and new. Finally, the full nature of tardive
dyskinesia has never been properly acknowledged, particularly the fact that the
condition is characterised by intellectual decline, as well as abnormal
movements. Although some early reports referred to tardive dyskinesia as ‘brain
damage’ (Anonymous, 1965; Schmidt and Jarcho, 1966), to this day it continues
to be understood as a usually trivial disorder limited to the presence of
involuntary movements
Minimising the Problem
In 1967 and 1968 George Crane published papers
suggesting that up to a quarter of patients in psychiatric hospitals suffered
from tardive dyskinesia, that antipsychotic drugs were most probably its cause
and that it was frequently irreversible. He described the abnormal movements of
tardive dyskinesia in considerable detail in order to distinguish them from
other types of unusual movements occasionally seen in long-term psychiatric
patients (Crane, 1967, 1968). Crane was immediately criticised by Nathan Kline,
among others, who challenged Crane’s claims about the frequency and persistence
of the condition, and asserted that the majority of cases occurred in people
with pre-existing brain damage. Despite Crane’s meticulous observations, Kline
also suggested that Crane had mistaken movements that were inherent in
schizophrenia itself for drug-induced movements and he concluded that tardive
dyskinesia was ‘not of great clinical significance’ (Kline, 1968, p. 51). The
dispute became personal with Kline accusing Crane of causing ‘another epidemic
of side effects’ without solid scientific evidence (N. Kline, cited in Crane,
1967, p. 218). Another American psychiatrist accused Crane of making ‘sweeping,
generalised conclusions that would undo the past 15 years of work’ and also
called for ‘sober, unemotional, objective and unbiased observations’, implying
that Crane’s work was none of these things (H. Denber cited in Crane, 1967, p.
218).
At the time that Kline and others
were decrying Crane’s findings other psychiatrists and neurologists, who
believed the link with antipsychotic drugs was well
established, were surprised that a contrary ‘consensus’ had survived ‘despite
many observations that contradict it’ (Schmidt and Jarcho, 1966, p. 373). An
editorial in no lesser place than the Journal of the
American Medical Association warned that a reappraisal of the benefits
and indications of antipsychotic drugs was necessary (Anonymous, 1965).
In 1973, the first of three US ‘Task
Forces’ on tardive dyskinesia gave the official stamp of approval to the
condition’s existence. However, the Task Force report asserted, without citing
any studies, that prevalence rates were low, at between 3 and 6%, and concluded
that, generally, the drugs could be ‘used with confidence’ and should continue
to be prescribed for most people with schizophrenia (Freedman, 1973, p. 463).
The report referred to tardive dyskinesia as the ‘unavoidable price to be paid
for the benefits of prolonged neuroleptic therapy’ (p. 464). Crane was a member
of the Task Force, but in a paper published around the same time as the report,
he argued much more forcefully that the benefits of antipsychotics had been
overstated, that they were given indiscriminately to far too many people and he
referred to how ‘permanent neurological disorders have become very common among
patients treated with neuroleptics’ (Crane, 1973, p. 127). He criticised the
psychiatric community which was, in his opinion, ‘completely unconcerned’ about
the problem, and he expressed his anxiety about the situation in which the
public mental health system of the USA had come to depend on widespread,
long-term drug treatment to the detriment of patients’ welfare.
A few years later the general
attitude towards tardive dyskinesia was said to have ‘shifted from curiosity
and mild concern to panic’ in the face of rising litigation (Gardos and Cole,
1980, p. 776). In 1974 Smith Kline & French settled a claim for
chlorpromazine-induced tardive dyskinesia for $1 million, and more cases
followed (Healy, 2002). Often, it was shown that the treating psychiatrists had
not noticed or had ignored the symptoms (Gelman, 1999). A second Task Force was
set up in 1980, under the auspices of the American Psychiatric Association,
which estimated from existing prevalence studies that around 20% of adults
might develop tardive dyskinesia, rising to 40% or more in the elderly.
Reviewing the evidence on the reversibility or otherwise of the condition, the
Task Force concluded that in people who had been on long-term medication,
symptoms persisted after drug withdrawal in two thirds of cases. The Task Force
produced sensible guidelines for minimising the occurrence of tardive
dyskinesia, including careful consideration of whether long-term drug treatment
was really justified, the use of minimally effective
doses, constant monitoring and attempts to withdraw medication in long-term
hospital patients who were clinically stable. It stopped short of recommending
this course of action for patients in the community, however, because of the
‘ubiquitous and critical shortage of aftercare systems’ (American Psychiatric
Association, 1980b, p. 170).
Despite concern over litigation,
increasing publicity and the American Psychiatric Association’s exhortations,
antipsychotics continued to be prescribed to ever increasing numbers at
increasingly high doses throughout the 1980s. In 1986, two leading
psychiatrists concluded that the Task Force recommendations about careful and
cautious prescribing had been ‘honored more in the breach than in the keeping’
(Gualtieri et al., 1986, p. 206). The increasing popularity of antipsychotic
use seemed unstoppable, even in the face of almost certain drug-induced brain
damage.
Blaming Schizophrenia
When prevalence rates could not be ignored, another
tactic of denial was adopted that helped to defuse the tardive dyskinesia time
bomb. Suggestions that the abnormal movements, now labelled as tardive
dyskinesia, pre-dated the use of antipsychotic drugs and were a feature of
schizophrenia, had been made by Kline in the 1960s, and periodically
thereafter. Reference was frequently made to the observations of Kraepelin and
other early psychiatrists that patients with ‘dementia praecox’ or
schizophrenia showed abnormal movements long before the introduction of
antipsychotic drugs. These claims were revived and widely publicised in a paper
by a group of researchers based at Northwick Park hospital on the outskirts of
London.
In 1982, psychiatrist David
Cunningham Owens and colleagues reported on rates of abnormal movements in a
group of long-term hospital patients. What was novel about the study was that
47 out of the 411 patients studied had never been exposed to antipsychotic
drugs. These patients had been resident in a ‘therapeutic community’ within the
hospital, where the emphasis was on psychotherapy and family therapy, and drugs
and physical treatments were avoided, although several of the patients were
said to have had electro-convulsive therapy (ECT), insulin coma therapy or a
lobotomy in the past (Owens et al., 1982).
The study reported that rates of
abnormal movements were just as high among the non-drug treated group as among
those who had received drug treatment, and, based on these results, the
researchers questioned whether tardive dyskinesia existed at all (Crow et al.,
1983). Little attempt was made to differentiate the
movements that characterise tardive dyskinesia from other sorts of movements,
however. In fact, the paper revealed that more patients on drugs had the
specific movements suggestive of tardive dyskinesia, such as grimacing and
tongue movements, whereas movements that are not a feature of tardive
dyskinesia, like head-nodding, were found to be more common in those who were
not on medication. The drug-naive patients were also 10 years older than the
drug-treated patients, and the rate of spontaneously developing movement
disorders is known to increase with age.
In 1985 Owens modified his
conclusion, suggesting that antipsychotic medication did increase rates of
abnormal movements, but that it did this by revealing an underlying tendency
inherent in the condition and, in this sense, the drugs could not be held to
cause the disorder directly (Owens, 1985).
Owens’ claims were revived in the
1990s by a group of US researchers, including psychiatrist Richard Wyatt, who
went on to develop influential theories about schizophrenia causing progressive
brain damage (see Chapter 11).
First, Wyatt published a review of studies such as Owens’, concluding that many
cases of tardive dyskinesia were a result of the underlying mental illness
rather than drug treatment (Khot and Wyatt, 1991). Second, the group conducted
a retrospective study of the case notes of patients who had been admitted to
Chestnut Lodge, a psychiatric therapeutic community hospital, who, like Owens’
sub-sample, had not received antipsychotics. Twenty-three per cent of the
patients were reported to have shown abnormal movements of some sort, with 15%
showing abnormal mouth or face movements considered to be equivalent to tardive
dyskinesia (Fenton et al., 1997). However, the majority of patients had
received ECT and insulin coma therapy, which have been found to be associated
with higher rates of tardive dyskinesia in some studies (although not this one).
Moreover, a selection of excerpts from the case notes indicates that few of the
abnormal movements resembled tardive dyskinesia and that the majority of
patients were highly psychotic at the time the movements were noted (Fenton et
al., 1994). Tardive dyskinesia, in contrast, is most clearly observable in
patients who are mentally stable. Overall, therefore, it appears that this
study identified the many bizarre mannerisms and movements that people can
demonstrate when they are severely mentally disturbed, which are quite
different from the involuntary twitching or writhing character of tardive
dyskinesia (Paulson, 2005).
Animal studies and evidence from
populations of patients without schizophrenia have confirmed that
antipsychotics cause tardive dyskinesia. Although
rats and mice do not show exactly the same picture as humans, antipsychotic
treatment can produce pointless or ‘vacuous’ and repetitive chewing movements,
tongue protrusions and facial twitches similar in nature to tardive dyskinesia
(Kulkarni and Dhir, 2011). Studies conducted in the 1970s revealed that
primates and monkeys develop signs of tardive dyskinesia indistinguishable from
those shown in humans when given antipsychotics on a long-term basis (Gunne and
Barany, 1976; Barany et al., 1979; Domino, 1985). Many studies have shown that
people with mental handicap or learning disability, and people diagnosed with
mood disorders, like depression and manic depression, develop tardive
dyskinesia when treated with long-term antipsychotics just as commonly as
people diagnosed with schizophrenia (Wolf et al., 1983; Youssef and Waddington,
1988).
The idea that tardive dyskinesia
might be part of the underlying mental condition of schizophrenia was
enormously appealing to a profession that was finding that its central and most
celebrated form of treatment caused brain damage. A final Task Force on tardive
dyskinesia, which reported in 1992 and confirmed that the disorder developed in
around 15–20% of long-term antipsychotic users, placed great emphasis on the
Northwick Park study (Gelman, 1999). The findings were described in detail and
the report repeated Owens’ later conclusion that antipsychotics might bring out
an inherent vulnerability to abnormal movements latent in some people with
schizophrenia. The very suggestion that the drugs might not be responsible for
tardive dyskinesia, however tenuous, allowed psychiatrists to continue to go
about their business, without having to fully confront the now long-buried
facts that the drugs they used were neurological poisons.
Ignoring Mental Impairment
The most persistent and effective strategy to deflect
attention from the importance of tardive dyskinesia has been the neglect of its
‘cognitive’ or mental component. In mainstream psychiatric literature, tardive
dyskinesia is described simply as a movement disorder, and although it is
sometimes acknowledged to represent a form of brain damage or malfunction, the
full consequences of that damage are rarely explicated. Coupled with the
evidence that many patients are unaware of the abnormal movements, it is easy
to see how the condition could be regarded as inconsequential. Of course, some
patients do care about the disfiguring nature of the movements, which
immediately mark them out, but there is a more worrying aspect to tardive
dyskinesia. Numerous studies show that people who
develop the condition have lowered intellectual capacity, suggesting that
mental impairment may be a feature of tardive dyskinesia. This should not be
surprising, given the interconnectedness of different areas of the brain, and
several commentators have drawn attention to the similarities between tardive
dyskinesia and other forms of generalised brain disease like lethargic
encephalitis and Huntingdon’s chorea (Wade et al., 1987; DeWolfe et al., 1988;
Breggin, 1990).
An early study found that patients
with tardive dyskinesia also had ‘dementia’ (Hunter et al., 1964b) and
subsequent research supported the view that tardive dyskinesia is only one
aspect of a wider ‘chronic neuroleptic-induced neurotoxic process’ (Wade et
al., 1987, p. 395). Mainstream psychiatric literature explained the association
between tardive dyskinesia and mental impairment by adopting Kline’s
explanation, however. Tardive dyskinesia was said to occur more frequently in
those with ‘vulnerable’ brains—people who had pre-existing brain damage or
intellectual impairment—and nothing was said about the possibility that the
condition itself might compromise mental ability. Current psychiatric textbooks
reiterate this position (Wright et al., 2012), although research has been
inconsistent, with by far the largest study finding no association between
prior mental capacity and subsequent development of tardive dyskinesia (Jeste
et al., 1995).
In the 1990s a group of researchers
from Ireland reviewed 29 studies on tardive dyskinesia and found that 23 of
these found an association between tardive dyskinesia and mental dysfunction of
some sort. The studies used different tests and measures, and found different
sorts of impairments, including deficiencies in memory, executive function
(planning and organisational abilities) and abstraction (Waddington et al.,
1993). Another review found a similar picture with 24 out of 31 studies finding
an association (Paulsen et al., 1994). The Irish group also followed a cohort
of 64 patients over a period of 5 years to explore changes in their mental or
cognitive function. They found a correlation between intellectual deterioration
and the onset of tardive dyskinesia, especially that affecting the face and
mouth, and they concluded that mental impairment is an intrinsic part of
tardive dyskinesia (Waddington et al., 1990).
In the 1980s and early 1990s several
authors suggested that tardive dyskinesia could also be associated with the
sort of personality changes that can occur following a severe brain injury,
which typically include unstable mood, loud speech, tension, aggression and
elation (Wilson et al., 1983; Mukherjee, 1984; Jones, 1985; Goldberg, 1985; Myslobodsky, 1993). Peter Breggin has also drawn
attention to the parallel between the lack of awareness of movements in tardive
dyskinesia and the denial of disability in other brain disease, like stroke,
and more generalised conditions, such as neurosyphilis (Breggin, 1993b).
Despite these indications that
long-term antipsychotic treatment leads not only to a persistent movement
disorder, but also to intellectual impairment and personality changes
characteristic of widespread brain damage, the subject has since disappeared
from the research agenda and the scientific literature. Even the Irish
researchers switched their interest to movement disorders in untreated
schizophrenia (Whitty et al., 2009). Although studies continued to examine the
mechanism of tardive dyskinesia, its prevalence and treatment, no research
programme was set up to elucidate the overall nature of the brain impairments
caused by antipsychotics. We remain uncertain about the full consequences of
long-term antipsychotic treatment, especially to what extent and how commonly
the drugs impair mental functioning.
Although research has continued to
demonstrate that tardive dyskinesia is linked with deteriorating mental
function (Byne et al., 1998), the psychiatric establishment continues to be
reluctant to acknowledge the problem. The Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) study, for example, a large and well known
randomised comparison of various antipsychotics, revealed a strong association
between mental impairment and tardive dyskinesia, but what was reported were
the results of a complex statistical analysis in which the association had
disappeared. The analysis included several variables, such as the length of
antipsychotic treatment, which should not have been included because they are
part of the putative causal mechanism. This basic statistical error, which is
likely to have wiped out the association between tardive dyskinesia and reduced
intellectual performance, apparently passed unnoticed through this high-powered
journal’s refereeing process (Miller et al., 2005).
By the twenty-first century, when
the CATIE study reported its results, psychiatry did not want to be reminded of
the evidence that antipsychotics cause generalised brain dysfunction. The
introduction of the atypical antipsychotics had thrown a welcome veil over the
powerful neurological effects the drugs produce and helped to reinforce what
had looked like an increasingly vulnerable view of these drugs as
disease-targeting treatments. The ascendance of the atypicals closed down an
opportunity to develop a proper understanding of the nature of antipsychotic
drugs and the consequences of long-term use, and returned psychiatric research
to its preoccupation with locating the pathology
underlying schizophrenia. Moreover, as we shall see in subsequent chapters, the
atypicals reinvigorated the quest to expand the use of antipsychotics far
beyond what had been achieved with the older antipsychotic drugs.
The Introduction of ‘Atypical’
Antipsychotics
Antipsychotic drug development ground to a halt in the
1980s in the face of increasing lawsuits concerning tardive dyskinesia (Healy,
2002). Revival of interest in clozapine in the late 1980s, however, suggested
that it might be possible to produce drugs with greater efficacy and lower
rates of neurological side effects, and this provided the stimulus for the
pharmaceutical industry to develop other drugs for the antipsychotic
market—drugs that are often referred to as ‘atypical’ antipsychotics.
The term ‘atypical’ has been used in
a bewildering variety of ways over the last two decades. It is commonly used to
describe drugs that are useful for the treatment of psychosis but induce lower
levels of extrapyramidal effects than older, standard antipsychotics, but it is
also used to refer to drugs that have particular chemical properties, such as
combining serotonin and dopamine receptor blockade. It has also been suggested
that the term was little more than a marketing device, deployed to convince
prescribers that the drugs were distinctive and superior (Tyrer and Kendall,
2009).
The name ‘atypical’ is first used in
a paper listed on the electronic index Medline in 1975 to describe the
properties of clozapine and two other older antipsychotics, sulpiride and
thioridazine (Melleril). Early papers on the atypical qualities of these drugs
noted that their effects on stimulant-induced movement disorders like
hyperactivity and stereo typies were weaker than the effects of the other, more
‘typical’ anti psychotics (Costall and Naylor, 1975). There were also reports that
they caused lower rates of adverse neurological or extrapyramidal effects in
humans, including tardive dyskinesia (Borison and Diamond, 1986).
Clozapine
Clozapine was synthesised in 1958, as part of a group
of compounds that were based on the chemical structure of the drug imipramine.
Imipramine was initially proposed as a treatment for schizophrenia and, like
imipramine, clozapine was found to have similar properties to chlorpromazine in
laboratory studies (Crilley, 2007). Whereas imipramine,
through the efforts of Swiss psychiatrist Roland Kuhn, came to be regarded as
an ‘antidepressant’ (although it is doubtful that it, or any other drug, has
specific antidepressant properties, see Moncrieff and Cohen, 2006; Moncrieff,
2008b), clozapine continued to be investigated as a treatment for people with
schizophrenia. German psychiatrist Hans Hippius conducted several clinical
studies, concluding that clozapine was an effective antipsychotic with a lower
propensity to induce extrapyramidal movement disorders than other
antipsychotics (Hippius, 1999). In the early 1970s a patented version of
clozapine, named Leponex, was launched in several European countries, including
Germany and Finland, and the manufacturer, Sandoz, began to plan research in
the USA (Crilley, 2007).
In 1975, however, a report in The Lancet announced that 18 patients in Finland had
developed severe blood disorders shortly after starting clozapine, nine of whom
had died (Idanpaan-Heikkila et al., 1975). Most of the blood disorders
consisted of ‘agranulocytosis’, a condition in which the white blood cells
known as granulocytes, which fight infection, are suppressed. The Finnish
government ordered clozapine to be withdrawn immediately and other European
countries followed suit. Sandoz suggested that the drug could be used safely as
long as frequent blood tests were carried out to monitor blood cell numbers,
but, in 1976, Sandoz called a halt to its clozapine research programme
(Crilley, 2007).
Clozapine continued to be used in
some parts of the world, however, and in the mid-1980s the tardive dyskinesia
epidemic, combined with rising doubts about the efficacy of the antipsychotics
in use at the time, re-ignited interest in the drug. Sandoz applied for a
licence in the USA in 1983, but the Food and Drug Administration (FDA) insisted
that the drug should be aimed at people who had failed to respond well to other
drugs because only in this population were the benefits thought to outweigh the
risks (Crilley, 2007). In 1988 a randomised trial funded by Sandoz was
published showing that clozapine produced a greater reduction in symptoms than
chlorpromazine in people with ‘treatment resistant schizophrenia’ (Kane et al.,
1988). In the same year, the company was granted a licence to market clozapine
in the USA under the trade name Clozaril.
The re-launch of clozapine revived
interest in developing new antipsychotic drugs and suggested the possibility of
finding drugs with greater efficacy than the early antipsychotics. The
‘antidepressant’ drug Prozac was launched in 1989 and it’s phenomenal success
confirmed that it was possible to make a great deal of money from drugs for
mental disorders. Prozac, or fluoxetine, was one
result of a renewed interest in the neurotransmitter called serotonion, or 5
hydroxy-tryptamine (5-HT), which started in the 1970s. Since the 1960s, it had
been suggested that serotonin might be involved in the genesis of schizophrenia
owing to the structural similarities between serotonin and lysergic acid
diethylamide (LSD), a drug which could produce hallucinations and sensory
distortions. It had been shown in the 1960s that LSD had some similar actions
to endogenous serotonin, although it also had some opposing actions (Woolley
and Campbell, 1962b). Originally, it was thought that schizophrenia might
represent a deficiency of serotonin (Gaddum and Hameed, 1954; Woolley and Shaw,
1954), but it was later proposed that schizophrenia could be due to
over-activity of serotonin (Woolley and Campbell, 1962a). Interest in serotonin
continued during the 1970s, when its role in other physiological functions was
investigated, including its effects on sleep. Paul Janssen became interested in
this area, and set out to synthesise a serotonin antagonist. At first he
produced a drug called ritanserin which, among other actions, reduced
transmission at one of the serotonin receptors thought to be influential in the
actions of LSD, the 5-HT2A receptor.
Janssen was particularly interested
in serotonin’s ability to reduce and disrupt sleep, and speculated that serotonin-blocking
drugs might therefore be useful in conditions in which sleep is disrupted, such
as chronic depression (Janssen, 1998). During the 1980s, interest also
developed in the interaction between serotonin and dopamine, with suggestions
that drugs that reduce serotonin release might inhibit the extrapyramidal
neurological effects produced by anti-dopaminergic drugs, such as haloperidol
(Waldmeier and Delini-Stula, 1979; Gerlach, 1985). Janssen and others started
to conduct studies using ritanserin added to conventional antipsychotics,
speculating that the combination would improve clinical outcome and reduce
drug-induced movement disorders (Janssen, 1998). At the same time Janssen set
out to develop a drug that would simultaneously inhibit the activity of
dopamine and serotonin. Risperidone was synthesised in 1983, and in 1988
Janssen suggested that risperidone’s actions on these two systems could combine
antipsychotic activity with beneficial effects on mood and negative symptoms,
and lower levels of extrapyramidal effects (Janssen et al., 1988). The theory
that serotonin blockade might improve mood went against the emerging serotonin
hypothesis of depression, but this inconsistency was never pointed out.
Risperidone was not launched until 1993, by which time the combined fortunes of
clozapine and Prozac made a new antipsychotic a viable and attractive
proposition.
The launch of risperidone and clozapine ushered in a
new phase in the story of antipsychotic drugs. The idea that they did not
induce extrapyramidal symptoms, later shown to be incorrect in the case of
risperidone, conveniently diverted attention from the neurological effects of
antipsychotics, including tardive dyskinesia. Moreover, the credibility of the
disease-centred theory of drug action was revived by renewed speculations about
the biochemical basis of schizophrenia and the mechanism of drug treatment.
Some claimed the ‘atypical’ antipsychotics had ushered in a whole new era in
psychiatry (Meltzer, 1995), one in which the drug-centred model could finally
be consigned to oblivion and psychiatry could get on with the business of
applying specific medical treatments to real underlying diseases. To support
such claims, an apparently coherent concept of ‘atypical’ action was moulded
out of still uncertain and inconsistent evidence, which enabled the new
antipsychotics to be presented as something quite distinct from their older
counterparts.
Although it is now only one of many
theories about the mode of action of atypical antipsychotics, in the early days
the idea that they achieved their effects through blockading serotonin, as well
as dopamine receptors, predominated, and they were frequently referred to as
‘serotonin–dopamine antagonists’ in the scientific literature and
advertisements of the time. This proposed action simultaneously rescued the
dopamine hypothesis of schizophrenia, while presenting the atypical
antipsychotics as novel and unique. US psychiatrist Herbert Meltzer, an
enthusiastic advocate of clozapine in particular, was a strong proponent of the
serotonin–dopamine antagonism hypothesis, claiming that the additional effects
of serotonin antagonism made the new antipsychotics more effective and less
toxic than their predecessors (Meltzer, 1994). Later, claims that they enhanced
cognitive function or halted the decline in mental functioning associated with
a diagnosis of schizophrenia were added, and alongside these claims came a
resurgence of interest in the role of serotonin in the aetiology of schizophrenia.
A burgeoning literature on schizophrenia and serotonin receptors appeared, and
research to develop new drugs with anti-serotonin activity flourished (Breier,
1995; Brunello et al., 1995; Remington, 2008).
As before, however, there was a
disjunction between the representation of the atypical antipsychotics and the
science behind them. Although interest in the effects of the serotonin system
survives, it is now acknowledged that the relationship between drug action and clinical effects is more complex than early accounts
allowed (Remington, 2008). In 1995, psychiatrist William Carpenter pointed out
that if serotonin antagonism counteracted dopamine blockade, and dopamine
blockade was still believed to be necessary for reducing positive psychotic
symptoms, then drugs with anti-serotonin action would be expected to be less
effective, not more effective, than other antipsychotics (Carpenter Jr, 1995).
Moreover, it is not even clear whether blocking serotonin receptors reduces
extrapyramidal effects, as claimed, as animal studies with the drug ritanserin
have yielded conflicting findings (Remington, 2008). Among atypical
antipsychotics, the proposed correlation between anti-serotonin effects and the
liability to induce extrapyrdamidal adverse effects has not been borne out. It
was clear from the time of its introduction, as Janssen himself acknowledged
(Janssen, 1998), that despite its anti-serotonergic action, risperidone causes
extrapyramidal effects at higher doses in the same fashion as the older
antipsychotics (Chouinard et al., 1993; Marder and Meibach, 1994; Kapur et al.,
1995). Moreover, the proposed benefits of the atypical antipsychotics on
negative symptoms of schizophrenia have been suggested to be a consequence of
the unduly high doses of older drugs used in comparative studies (Carpenter Jr,
1995; Geddes et al., 2000), and the much-hyped improvement in cognitive
symptoms has not materialised in well-designed studies (Green et al., 2002;
Keefe et al., 2007).
As further atypical antipsychotics
appeared, other theories were concocted, like Stephen Stahl’s idea that the
drugs somehow block the effects of dopamine in one area of the brain, the
limbic system, but not in another area, the basal ganglia (Stahl, 2008).3
The fact that most of these drugs induce neurological movement disorders, at
least at higher doses, suggests that they do affect the basal ganglia, however,
where these abnormalities originate. Moreover, no explanation was ever
satisfactorily offered for how such selective effects could come about. It was
also suggested that other dopamine receptors might be involved in atypical
antipsychotic action, such as the D1 receptor or subtypes of the D2
receptor (Meltzer, 1991). Little attention was paid to the profound effects of
clozapine and some other atypical antipsychotics on other neurochemical systems
in the brain, however, such as those involving histamine, acetylcholine and
noradrenaline.
As with the first generation of
antipsychotic drugs, the fact that the proposed mechanism of action lacked
coherence and was not supported by firm evidence did not matter. The assumption
that the drugs worked on the underlying disease was already in place, and
speculation about novel actions was all that was needed
to convince disappointed clinicians that a new miracle cure was about to
arrive. Over the last few years, however, it has become clear that the original
hopes and claims for these medications have not been fulfilled. Prominent
psychiatrists, including David Cunningham Owens (whose research had been used
to argue that tardive dyskinesia was part of schizophrenia, but who, in later
years, has become more critical of drug treatment), have started to suggest
that the story of atypical antipsychotics as a group of compounds with unique
therapeutic properties is a myth, largely constructed by the pharmaceutical
industry, and swallowed hook, line and sinker by the psychiatric profession
(Owens, 2008; Tyrer and Kendall, 2009; Kendall, 2011).
As well as its yearning for new and
effective medical treatments, the profession was won over by the results of the
first clinical trials of the atypical antipsychotics, which were rapidly set up
by the pharmaceutical companies in the USA in the 1990s. We shall look in more
detail at some of these trials in the next chapter because it is now apparent
that they were hopelessly flawed. Journalist and author of Mad
in America Robert Whitaker goes further: ‘Behind the public façade of
medical achievement’, he cautions, ‘is a story of science marred by greed,
deaths and the deliberate deception of the American public’ (Whitaker, 2002, p.
254.) But most of the psychiatric community was happily oblivious to the
machinations that propelled the atypical antipsychotics into the limelight, and
within a few years they were widely recommended as the first-line treatment for
someone diagnosed with schizophrenia (National Institute for Health and
Clinical Excellence, 2002).
Looking Where the Light is: Randomised
Controlled Trials of Antipsychotics
This chapter reviews some of the reams of evidence that
has been collected on the effects of antipsychotics in people diagnosed with
schizophrenia or psychosis, focusing on randomised controlled trials,
especially those that have compared an antipsychotic drug with a placebo. It is
important to review this data because randomised controlled trials are
universally regarded as the proper scientific method for evaluating the effects
of an intervention. They are applied throughout medicine, they are required by
drug licensing authorities and no new medical therapy would be accepted
nowadays without having passed through this testing procedure. And yet the
placebo-controlled trials of antipsychotics, both those conducted shortly after
their introduction and more recent studies, are severely limited. They provide
little information about how the drugs might impact on the experiences we call
mental disorders and whether taking them is ultimately better than not taking
them.
As we saw in Chapter 4, by the time the first large-scale,
systematic studies of antipsychotics were published in the early 1960s, there
was already a consensus developing that they constituted a disease-centred form
of treatment. The results of these studies, particularly the National Institute
of Mental Health (NIMH) study, further cemented this view, but they were also a
product of it. Instead of trying to understand how
the drugs affected the brain and behaviour, the increasing assumption that the
drugs had disease-specific effects encouraged research that simply aimed to
establish whether or not the drugs reduced symptoms. Randomised controlled
trials came to dominate research on psychiatric drug treatment and soon they
were almost the only means available with which to assess the usefulness and
safety of psychiatric medications. They continue to be regarded today as the
only credible and relevant evidence as far as drug
treatment is concerned. Although well-conducted randomised controlled trials
have an important part to play in evaluating psychiatric medications, and are
certainly preferable to anecdotal claims of miraculous recoveries, the
inadequacies of existing studies have not been properly appreciated. Moreover,
as they proliferated they eclipsed other important information on the nature of
the mental and physical alterations the drugs produce and the consequences of
long-term use.
Jonathan Cole, the psychiatrist who
became head of the Psychopharmacology Service centre at the NIMH, and conducted
the NIMH antipsychotic study, was one of the leading figures in advocating the
use of randomised trials of psychiatric treatments. Apart from a few small
randomised studies that took place in Europe, such as the Elke trial in
Birmingham, the first large-scale trials of the new drugs were conducted in the
USA. By the mid-1950s United States Congress had already earmarked $2 million
for research into new drug treatments in psychiatry, testifying to the
confidence that already existed in the potential of drugs to treat mental
disorders (Cole, 1996, p. 242).
The Limitations of Randomised Trials of
Antipsychotics
Before we look in more detail at some of the hundreds
of trials of antipsychotics that have been conducted over the last 60 years, we
need to consider some theoretical and technical problems involved in conducting
such trials. From a conceptual point of view, it is important to recognise that
measuring and categorising behavioural and emotional difficulties is an
imprecise and subjective affair. The changing ways that mental disorders have
been classified over the last century, as well as the jostling and wrangling
that occurs in the production of a system like the Diagnostic
and Statistical Manual of Mental Health (DSM),
testifies to the difficulty in achieving consensus about how such difficulties
should be understood. Supposedly homogenous conditions like ‘schizophrenia’ and
‘depression’ involve numerous and diverse experiences, follow varied patterns,
have unpredictable outcomes, their manifestations and consequences are
difficult to quantify, and they impact in different ways on different parties.
So quite apart from the issue of whether or not schizophrenia is a valid and
useful label, interpreting results of studies that involve people labelled as
having schizophrenia is far from straightforward.
Randomised trials of antipsychotics
measure the effects of the drugs using rating scales, for example, that consist
of collections of more or less randomly collated
symptoms and include many factors like anxiety, irritability and hostility that
are not specific to a psychotic syndrome or schizophrenia. Improvements in
scores do not necessarily tally with functional improvement and it is easy for
scores to improve quite a lot if someone is more subdued, and expressing their
abnormal ideas less frequently, but they might, nonetheless, remain profoundly
impaired. Occasionally, measures of social functioning are employed to address
this problem, but they, too, consist of subjective evaluations about what
constitutes normal activity in particular areas. Moreover, what counts as
improvement varies according to the perspective of the person making the
rating. In a German study of definitions of ‘remission’, for instance, it was
found that patients, their relatives and psychiatrists only agreed in 18% of
cases (Karow et al, 2012).
Technical problems are numerous, and
have been well reviewed by other authors (Leucht et al., 2008). ‘Double-blind’
studies, in which those involved are meant to be ignorant of who receives the
drug and who receives placebo, are likely to be ‘unblinded’ by the fact that
antipsychotics produce obvious physical and mental alterations, for example. In
other words, both participants and researchers are likely to be able to detect
who is receiving the drugs and who is on placebo, and non-blinded studies
produce larger differences between groups than those that are conducted double
blind (Leucht et al., 2012b). Furthermore, large numbers of people drop out of
antipsychotic trials before the end of the study, and the way this missing data
is dealt with can have an impact on study results, while many other factors can
also distort results and the way these are presented. Recent exposés have shown
how the pharmaceutical industry can cherry-pick positive findings and neglect
to mention, or fail to publish, results that do not show their drug in the best
possible light (Melander et al., 2003; Jureidini et al., 2008).
Withdrawal Effects
It is the variety of effects that can occur after
stopping antipsychotic drugs that present the greatest impediment to accepting
the results of randomised controlled trials at face value, however. Because
antipsychotics came into widespread use so early after their introduction, even
the earliest clinical trials mostly involved people who were already taking the
drugs on a long-term basis before the trial began. At the start of the study,
therefore, participants would have to be taken off their previous medication,
and those who were allocated to the drug being tested would have it replaced by
the new drug, but those allocated to placebo would
have nothing to replace it. By the 1960s there were already descriptions of the
withdrawal effects that occurred when people discontinued antipsychotics after
taking them for some time. These are known to include agitation, anxiety,
insomnia, restlessness and irritability (Brooks, 1959; Judah et al., 1961;
Lacoursiere, 1976). All these experiences can be mistaken for signs of the
underlying condition, especially if rating scales are used that contain items
referring to these behaviours, as they mostly do, and if the people making the
ratings have no awareness of the possibility that the placebo-treated subjects
might be experiencing withdrawal effects.
Occasionally, the withdrawal of
antipsychotics can itself produce psychotic symptoms that had not been present
before drug treatment started. This phenomenon was first recorded in the 1950s,
but the implications were ignored until Canadian psychiatrist Guy Chouinard
proposed the idea of ‘supersensitivity’ psychosis in the 1980s. The term
‘supersensitivity’ psychosis refers to the idea that long-term antipsychotic
treatment could make people more vulnerable to psychotic symptoms by increasing
the sensitivity of dopamine receptors, in a mechanism analogous to that which
was proposed (although not proven) to cause tardive dyskinesia. Just as tardive
dyskinesia could appear either during treatment or after drug treatment was
stopped, so Chouniard proposed that supersensitivity psychosis could occur
after drug withdrawal, or during on-going treatment, with pre-existing
psychotic symptoms re-emerging after being dormant, and new ones developing
(Chouinard and Jones, 1980).
Despite Chouinard’s work and several
other reports documenting the emergence or deterioration of psychotic symptoms
after antipsychotic discontinuation (these are described in detail in
Moncrieff, 2006), there was little interest in the area, but by the 2000s it
was becoming clear that people could become extremely psychotic when they
stopped clozapine. Moreover, several studies showed that symptoms were worse
after stopping clozapine than they had been before starting it (Diamond and
Borison, 1986; Borison et al., 1988; Apud et al., 2003). In 2002, a paper from
Hong Kong reported that two elderly men with no previous psychiatric problems
had developed a short-lived psychotic state after stopping metaclopramide, a
dopamine-blocking drug used for nausea, similar to the antipsychotic drug
sulpiride. Their symptoms rapidly subsided when they were treated with
risperidone, which was then gradually withdrawn without further problems (Lu et
al., 2002). Combining all the descriptions of withdrawal-induced psychosis
suggests that its symptoms have a slightly different profile from a typical
episode of spontaneous psychosis or schizophrenia,
and are more reminiscent of those provoked by heavy use of amphetamines or
other stimulants. Paranoid ideas, hostility and aggression are common, and
although people experience auditory hallucinations, common in schizophrenia,
some also report visual hallucinations, which are not. It seems, therefore,
that stopping antipsychotics can sometimes provoke a psychotic episode, even in
someone who does not have a history of schizophrenia or psychosis (Moncrieff,
2006).
The chemical mechanism of
withdrawal-induced psychosis is unclear, and the role of supersensitive
dopamine receptors has not been confirmed. As we saw in Chapter 5 there is, in any case, much more to the
biochemistry of antipsychotics than dopamine, and the fact that clozapine,
which has relatively weak D2 receptor-blocking properties,
is one of the most likely candidates to provoke withdrawal psychosis, suggests
that dopamine may not be the only, or even the most important, brain chemical
to be involved. The symptom profile suggests that the mechanism may be similar
to the still unknown process by which stimulant drugs, like amphetamine, induce
psychotic symptoms.
In the 1990s another potential
problem of withdrawal from psychiatric drugs was described. A group led by
psychiatrist Ross Baldessarini at Harvard medical school produced several
studies that suggested that stopping long-term psychiatric drug treatment of
various sorts may precipitate a recurrence or deterioration of the underlying condition.
In other words, stopping medication may, in itself, be a risk factor for
relapse. This effect was shown convincingly in the case of lithium treatment
for ‘bipolar disorder’ or manic depression. When an individual stops long-term
lithium treatment, the risk of that person having a relapse of manic depression
is higher than it was before they started lithium (Cundall et al., 1972; Suppes
et al., 1991; Baldessarini et al., 1999). The group’s work suggested that a
similar effect might occur in people treated with antipsychotics for
schizophrenia or psychotic disorders, and part of the evidence for this
proposal was that withdrawal studies show that relapses cluster soon after the
point of withdrawal. In one analysis, for example, 50% of relapses occurred
within 3 months of the discontinuation of the antipsychotic (Baldessarini and
Viguera, 1995). This observation suggests, however, that in many cases
‘relapse’ may have consisted of antipsychotic withdrawal symptoms, especially
in studies where relapse was defined as a small increase in score on a rating
scale.
The fact that the withdrawal of
antipsychotic medication can produce mental and behavioural difficulties,
whether or not this involves the precipitation of
relapse, potentially undermines all studies that have involved the
discontinuation of previous antipsychotic treatment in people on placebo, and
this includes almost all the placebo-controlled studies that have ever been
conducted. Although Baldessarini and his group recognised the profound implications
of withdrawal effects back in 1995 (Baldessarini and Viguera, 1995), drug
trials and reviews of research have continued more or less as if they did not
exist.
Treatment of an Acute Psychotic Episode
Despite the hundreds of randomised trials of antipsychotics
conducted with people with schizophrenia and psychosis, evidence on the effects
of drugs in people experiencing a recent, ‘acute’ episode is surprisingly
sparse. This is unfortunate because studies involving people who are
experiencing a new episode are more likely to entail the actual initiation of
drug treatment than studies with people with a chronic condition, although in
some cases the acute episode may have been precipitated by the patient
previously discontinuing long-term medication.
Table 6.1
lists randomised trials of treatment of an acute episode of psychosis or
schizophrenia that have compared antipsychotics with a placebo, another sort of
sedative drug or other sorts of treatment.
The first study of the use of
antipsychotics for acute treatment was not the NIMH study discussed in Chapter 3, but an earlier study
conducted in the late 1950s in the Veterans Affairs (VA) hospitals in the USA,
the system of hospitals reserved for veterans of the US armed forces.
Multi-site studies of anti-tuberculous drugs and of lobotomy had already been
conducted in the VA hospitals, and early attempts to create psychiatric rating
scales were made by those who were studying the effects of lobotomy (Cole,
1996). Two studies involving a number of early antipsychotic drugs were
conducted in the VA hospitals in the 1950s involving 37 hospitals and a total
of 1445 male veterans. One of them investigated the treatment of an acute episode
and one primarily involved long-term hospital patients (Casey et al., 1960a,
1960b).
The acute treatment study enrolled
640 ‘newly admitted schizophrenic men’ and is one of the largest studies of
antipsychotic drugs ever conducted, but it is little known in comparison with
the NIMH study. The control, or comparison, group took phenobarbital, the
standard barbiturate of the time, not an inert placebo as would become the norm
later (Casey et al., 1960a). At the time the study was designed, it seems it was
deemed necessary not just to show that the drugs did something rather than
nothing, but to demonstrate that they were superior to a commonly used
alternative sedative, indicating the continuing influence of the drug-centred
model at the time the study was planned. In this sense, the trial can be seen
as an attempt to quantify the descriptive comparisons made by the likes of
Deniker and others between the drug-induced state produced by antipsychotics
and that produced by barbiturates.
Table 6.1 Randomised trials
of antipsychotic treatment of an acute psychotic episode
ECT: electro-convulsive therapy; NIMH:
National Institute for Mental Health; VA: Veterans Affairs.
The only study that lasted for
longer than 12 weeks was the comparison of drug treatment and psychotherapy
conducted by the Californian-based British psychiatrist Philip May in the
1960s. This study involved people admitted to hospital with a first episode of
‘schizophrenia’ and compared treatment with antipsychotics, electro-convulsive
therapy (ECT), psychoanalytic psychotherapy and milieu therapy. The latter
consisted of all the usual activities available in the hospital at the time,
including occupational therapy and ‘industrial therapy’, and doctors were also
permitted to prescribe barbiturates and hydrotherapy.1 The
principle outcome was discharge from hospital, and the group who received drug
treatment had a clear advantage in this respect. Patients who had ECT also
fared well, and the majority of patients in all groups were discharged from the
hospital within a year. It is important to note that the trial excluded people
who were thought to have a good chance of recovery without drug treatment, as
well as those who were thought to be too chronic to benefit from it. Therefore,
the trial population probably represents patients who obtain the most benefit
from drug therapy, and not the general run of people
who experience a first episode of psychosis (May, 1968).
Whereas the NIMH study found that
antipsychotics reduced a wide range of symptoms, prompting the study authors to
comment that ‘the characterisation of these phenothiazines as agents which calm
and tranquilize excited or boisterous patients is a greatly oversimplified one’
(National Institute of Mental Health Psychopharmacology Service Center
Collaborative Study Group, 1964, p. 254), other studies found that it was
mostly ‘positive’ symptoms and behavioural disturbance that showed a specific
response to antipsychotics, although the VA hospital study also indicated signs
of improved social functioning (Table 6.1).
In the 1980s two studies compared
the effects of antipsychotics and lithium in people with different types of
acute psychosis, including those with a diagnosis of schizophrenia, mania,
psychotic depression and those with mixed features, usually given the catch-all
label of ‘schizoaffective’ disorder. Both studies clearly demonstrated that
diagnosis did not predict response to treatment. In other words, people
diagnosed with a schizophrenic or schizoaffective episode, according to a range
of diagnostic criteria, responded equally well to lithium as to antipsychotic
treatment. In one study, lithium was found to be less effective for controlling
over-activity, but the authors noted that ‘the presence of schizophrenic
symptoms did not predict a poor response to lithium’ (Braden et al., 1982). In
the other study, after dividing the sample up into small groups and applying a
complex statistical analysis, the authors claimed to show that there were
differences in the response of some symptoms and that ‘positive symptoms’
responded better to the antipsychotic drug pimozide. Differences were not
striking, however, and no direct comparison data were provided (Johnstone et
al., 1988).
A small number of studies have
compared the effects of antipsychotics and benzodiazepines. These studies are
old, mostly small and publications provide few details about their methodology,
but they do not provide convincing evidence of the superiority of
antipsychotics. Among seven comparisons, described in a review published in
1990, three found no difference between the antipsychotic and the
benzodiazepine, three found the benzodiazepine to be superior and two found
that the antipsychotic was more effective. Several trials also reported that the
benzodiazepine reduced psychotic symptoms, alongside the more familiar sedative
effects of these drugs (Wolkowitz and Pickar, 1991).
Overall, therefore, studies of the
treatment of people with a recent acute episode of psychosis or schizophrenia
show that the use of antipsychotics leads to more
improvement than a placebo, a barbiturate, psychotherapy or milieu therapy, but
in some studies people allocated to placebo or other treatments also improved
to a considerable extent. The NIMH study showed a superior effect on a wide
range of symptoms, but other studies suggest that it is the positive
‘symptoms,’ particularly hallucinations and delusions, that respond most to the
drugs (National Institute of Mental Health Psychopharmacology Service Center
Collaborative Study Group, 1964). In contrast, a later study comparing
clozapine and chlorpromazine for 31 ‘acutely schizophrenic’ patients reported
that although clozapine reduced typical psychotic symptoms, chlorpromazine did
not, and the authors concluded that it had ‘little impact on the acute
schizophrenic process in the group of patients examined’ (Shopsin et al., 1979,
p. 659). This study was conducted when clozapine was new and exciting, and
chlorpromazine was old and uninteresting, suggesting that the effects reported
in earlier studies might, at least partly, reflect investigators’ enthusiasm
for new treatments.
Two of the studies of short-term
treatment followed up participants after the trial had ended to ascertain
whether there were any lasting effects. One year after the NIMH study people
randomised to placebo were no different from people who had been treated with
antipsychotics in terms of symptoms and level of functioning, except that they
had a lower chance of being readmitted to hospital
(Schooler et al., 1967). Participants in Philip May’s study were followed up
for between two and five years after the end of the study, and there was found
to be ‘no startling difference in follow-up outcome between the five original
treatment groups’ (May et al., 1981, p. 781). On the overall measure of outcome
used, people who had had ECT performed best, and there was almost no difference
between those who had received ‘milieu therapy’ and those who had been
allocated to antipsychotics. As treatment was not controlled after the initial
admission, many participants in all groups received antipsychotics at some
point during the follow-up period, although, impressively, 51% of people
originally allocated to ECT did not use them at all, as well as 40% and 38% of
those in the psychotherapy and milieu therapy groups respectively (May et al.,
1981).
So, although studies of
antipsychotic drug treatment for an acute psychotic episode suggest that people
who receive drug treatment fare better than those who do not in the short-term,
there is little evidence that these benefits are sustained. Comparative
studies, although few in number, suggest that antipsychotics are superior to
barbiturates, but they are not differentiated from other sedative drugs like
lithium and benzodiazepines in studies conducted to
date. It is also important to note, given the emphasis now put on starting drug
treatment early in people experiencing a first episode of psychosis, that no
placebo-controlled studies of the treatment of a first episode of psychosis
have ever been conducted. May’s comparison of antipsychotics and other types of
intervention suggested that antipsychotic treatment helped people to improve
more rapidly in the short-term, although, interestingly, people who received
ECT also fared well in this respect. In the long-term, however, those who had
not received drug treatment initially improved to around the same level and
many were never subsequently exposed to antipsychotic treatment.
Long-Term Treatment
Studies of long-term treatment have two possible
objectives—they can assess the effects of drugs in people with on-going,
chronic symptoms or they can evaluate whether drug treatment helps prevent
recurrence in people who have had a discrete episode of psychosis from which
they have recovered. Unfortunately, these two situations have not been clearly
distinguished in the many hundreds of research studies that have been conducted
in this area. Although studies often purport to measure ‘relapse’ this is often
defined, if at all, as an exacerbation of symptoms and does not necessarily
indicate that the individual had previously recovered completely.
The idea that antipsychotics should
be continued on a long-term basis appears to have been established early in the
history of their use. Members of the Thorazine Task Force reminisced to Judith
Swazey that the continuation of drug treatment after discharge was the norm,
but there was concern that doses might be lowered, leading to relapse or
readmission (Swazey, 1974). Smith Kline & French quickly realised that
‘aftercare’ was a potentially profitable area, and it became a principle
component of the Thorazine marketing campaign. The task force funded regional
aftercare clinics to monitor and prescribe for recently discharged patients,
forging links between hospital and community services, and ensuring that
hospital treatment was extended beyond its walls. The task force also sponsored
symposia held by the American Psychiatric Association on caring for patients
after discharge, and it worked with the American Academy of General Practice
and with individual general practitioners and private psychiatrists to
encourage on-going prescribing. The fact that 56% of the newly admitted
patients in the VA hospitals’ acute treatment study
were already taking antipsychotics at the time of
admission suggests the policy of extending drug treatment to the community had
been widely adopted by the late 1950s.
Subsequent attempts to test whether
or not long-term continuation of treatment with antipsychotics prevents relapse
or rehospitalisation were therefore confounded by the fact that most people
were already taking the drugs. In other words, the studies could not test the
effects of starting out on long-term treatment; they could only assess the
effects of stopping it.
A recent meta-analysis of 65
randomised withdrawal studies conducted since 1960 found that 64% of people who
were withdrawn from antipsychotics met study criteria for relapse within 1 year
compared with 27% who continued the treatment. Only 26% and 10% of patients
from each group, respectively, were admitted to hospital, however. No
difference in relapse rates was detected between studies in which patients were
withdrawn from antipsychotics overnight and studies in which withdrawal was
conducted more gradually, although the average period for gradual withdrawal
was only 28 days. Moreover, in contrast to previous findings, the risk of
relapse did not appear to abate with time, except in some longer studies.
People who had not relapsed after 6 or 9 months still had higher relapse rates
if they were randomised to take placebo than if they continued on drug
treatment. Studies that lasted longer than a year, however, found that rates of
relapse in people who continued on drug treatment started to catch up with those
who had come off it. The review also revealed that studies that were conducted
double blind found smaller effects than ones that were not (Leucht et al.,
2012a, 2012b).
In contrast to the situation of
acute treatment, there is a small number of studies of the value of maintenance
antipsychotic treatment involving patients with a first episode of psychosis or
schizophrenia. As these patients are likely to have received antipsychotic
treatment for shorter periods of time than patients with a long history of
psychiatric problems, and would therefore be expected to experience less severe
withdrawal effects, these studies might provide more reliable evidence about
the real effects of taking antipsychotics on a long-term basis. Leucht et al.
identified seven placebo-controlled trials and found that overall relapse rates
in people with a first episode of psychosis or schizophrenia were similar to
those reported in other studies of maintenance treatment (Leucht et al.,
2012b). This may suggest that withdrawal-related adverse effects do not
contribute to relapse rates, but, even in these studies, patients had been
taking antipsychotic medication for up to a year after recovering from their
initial episode.
The
only sizeable study conducted until recent years was published in 1986 and
conducted at Northwick Park hospital. One hundred and twenty patients who had
recovered from their first episode of psychosis and been stable for 1 month
were randomised to continue antipsychotic medication, or have it withdrawn over
a month and replaced by placebo. They were followed up for 2 years, and, by the
end of the study, 54% of patients who continued on their antipsychotic
medication experienced a relapse, defined by requiring additional treatment or
hospital admission, which was only slightly less than the 62% of people who
relapsed while allocated to placebo. Most patients who relapsed were said to
have psychotic symptoms, but not all. Looking at the pattern of relapses (Figure
6.1) suggests a withdrawal
effect may have been present in this study despite the fact that it only
involved people with a first episode of psychosis. The majority of relapses
among the placebo-treated group occurred within the first year, whereas
drug-treated patients continued to relapse during the second year (Crow et al.,
1986). A more recent comparison of risperidone and haloperidol in people with a
first episode of psychosis found similarly high rates of relapse in both groups
of drug-treated patients, with 41% of those allocated to risperidone and 48%
allocated to haloperidol relapsing within two years (Schooler et al., 2005).
Figure 6.1 Northwick
Park first episode study: patients remaining relapse-free on drug and placebo
(reproduced with kind permission of the Royal College of Psychiatrists)
In
more recent years, three studies have been conducted using open, non-blinded
designs, and one large placebo-controlled trial has been carried out, funded by
the makers of quetiapine, GlaxoSmithKline (Table 6.2). They all reported higher rates of
relapse in people who were withdrawn from antipsychotic medication, but results
varied according to the way ‘relapse’ was defined and on the strategies
employed to manage withdrawal-related deterioration. In a study conducted in
Germany some of the patients withdrawn from antipsychotic medication were given
intermittent drug treatment if they exhibited symptoms suggestive of possible
impending relapse, such as insomnia, restlessness, poor concentration and
nervousness—symptoms which might equally have been indicative of antipsychotic
withdrawal. These first episode patients were only slightly more likely to
relapse than those who took antipsychotic medication continuously (36% vs 28%).
Patients who did not receive this early or ‘prodromal’ treatment relapsed at a
higher rate of 55%, but even in this group almost half the patients did not
relapse after medication withdrawal (Gaebel et al., 2002). Another German
study, which used a stringent definition of relapse involving a substantial
increase in symptoms, found that only a minority of patients withdrawn from
antipsychotics had a full relapse, although 57% showed some clinical
deterioration. Even so, 38% of patients were able to withdraw from medication
successfully (Gaebel et al., 2011). In contrast, only 20% of the patients in a
Dutch study were successfully withdrawn from medication without subsequent
relapse, but criteria for relapse were more inclusive (Wunderink et al., 2007).
Sixty-three per cent of patients in the placebo-controlled trial of quetiapine
were classified as having ‘relapsed’ using broad criteria, but only 16% were
hospitalised, which was only 10% more than the proportion in the drug-treated
group (Chen et al., 2010).
Again, few studies have assessed the
effects of maintenance treatment with antipsychotics compared with other sorts
of sedatives. The second VA study, which involved people with chronic symptoms,
included a group who took a barbiturate, and found that this group fared no
better than placebo (Casey, 1960b). Another study compared the effects of the
benzodiazepine drug diazepam (Valium) with the antipsychotic drug fluphenazine
for the treatment of signs of ‘exacerbation’ in 53 patients diagnosed with schizophrenia
who had been withdrawn from their previous antipsychotic regime. In contrast to
the VA study, diazepam was as effective as fluphenazine and superior to placebo
in preventing a full-blown relapse (Carpenter, Jr, et al., 1999). Similarly, in
one of the German studies short-term treatment of deterioration subsequent to
antipsychotic withdrawal with a benzodiazepine was just as effective as using
an antipsychotic (Gaebel et al., 2011).
Table 6.2 Recent randomised
trials of antipsychotic discontinuation
*As measured by PANSS positive symptom
subscale.
CGI: Clinical Global Improvement scale; GAF: Global Assessment of Functioning
scale; PANSS: Positive and Negative Symptoms of Schizophrenia scale.
Trials of Atypical Antipsychotics
As the atypical antipsychotics rapidly came to replace
the use of the older drugs for the treatment of people diagnosed with
schizophrenia or any ‘psychotic’ disorder, it is worth looking in more detail
at some of the research that forms the basis of their adoption as the principle
form of treatment for this situation. After the re-introduction of clozapine in
the early 1990s, interest in other ‘atypical’ antipsychotics accelerated. In
the US the Food and Drug Administration (FDA) requires that at least two
placebo-controlled trials are conducted to establish the efficacy of a new drug
and gain a licence for its use, and approval in many other countries is based
on evidence submitted to the FDA. Trials of atypical antipsychotics were
submitted rapidly after their development, and could only have been produced so
quickly by involving long-term patients on long-term medication.
Robert Whitaker has described in
detail the commercial structure behind these studies, and how they were
conducted by newly emerging private research
companies that tendered their services out to the pharma ceutical companies
wanting to test the new drugs. As the research companies were paid per patient
they recruited, there was an incentive to be flexible with the eligibility
criteria in order to recruit as many patients as possible. The wealth that
could be accrued through running these trials and the methods used to entice
patients into studies was revealed in enquiries into the practice of two
psychiatrists, Richard Borison and Bruce Diamond, who were involved in some of
the early studies of atypical antipsychotics, including those that formed the
basis of the FDA’s approval of risperidone. Employing aggressive selling
tactics to recruit large numbers of patients, the business netted Borison and
Diamond millions of dollars, which they used to fund extravagant lifestyles.
They were finally tried and convicted of the criminal offence of defrauding the
Medical College of Georgia, the university where they worked, to which the
profits from any trials were meant to have been paid. Richard Borison was
sentenced to 15 years in prison and Diamond to 5 years (Whitaker, 2002).
You would think that the
imprisonment of two of the principle researchers involved in the introduction
of a range of new and widely promoted pharmaceuticals would be big news,
opening up questions about the nature of the research they had conducted and
the value of the products they had tested. The medical press remained mum on
the subject, however, and, until recently, no one questioned the research base
for the new drugs.
Looking in detail at the
placebo-controlled trials that were meant to have established the efficacy of
the atypical antipsychotics confirms that they were, indeed, withdrawal
studies, involving people with longstanding difficulties, who had been taking
some sort of antipsychotic drugs on a long-term basis prior to the study. In
some studies patients were described as experiencing an ‘acute exacerbation’,
but this was never defined clearly and appeared to refer to anyone who reached
a certain level of symptom severity (Leucht et al., 2008). Despite this,
differences between atypical antipsychotics and placebo were modest, and
generally not large enough to indicate that the drugs had clinically meaningful
effects in real-life settings.
Stefan Leucht and colleagues
explored the clinical significance of changes in psychosis rating scales. They
defined a significant clinical effect as one that corresponds to a minimal
degree of improvement, as assessed by the Clinical Global Improvement scale
(Guy, 1976). They estimated that for the commonly used Positive and Negative
Syndrome Scale (PANSS), which rates 30 different items and has a maximum score of 210, a change of 15 points or more would be required
to indicate a minimally significant clinical effect. For the Brief Psychiatric
Rating Scale (BPRS), whose maximum score is 96, they suggested that a change of
10 points would be equivalent to a minimal level of improvement (Leucht et al.,
2006).
The first large study of risperidone
was set up in the USA and Canada, and involved a comparison between various
doses of risperidone, placebo and haloperidol—the latter prescribed at a fixed
dose of 20 mg per day. Like many other atypical studies, it was designed to
show risperidone in the best possible light since use of this relatively high
dose of haloperidol was bound to cause substantial rates of obvious, unwanted
‘extrapyramidal’ effects. The Canadian part of the study, which was published
in 1993, involved 135 participants who were described as having ‘chronic
schizophrenia’, and had been taking quite high doses of antipsychotics (an
average of 753 mg of chlorpromazine or equivalent doses of other
antipsychotics) prior to entering the study. No details were provided about how
this prior medication was withdrawn (Chouinard et al., 1993).
Despite the fact that many
placebo-treated patients were almost certain to have suffered from
antipsychotic withdrawal symptoms, and that 48% of participants dropped out
before the end of the study, which makes the results difficult to interpret,
only the group taking 6 mg of risperidone showed a moderate decrease in
symptoms—26 points on the PANSS. People on other doses of ripseridone (2 mg, 10
mg and 16 mg), or haloperidol, showed symptom reductions of less than 15
points. The US arm of the study was conducted with 388 patients, including a
mixture of long-term hospital patients and those who had been recently
admitted. Most participants, however, had been diagnosed many years before and
most were likely to have been on medication prior to study entry as in the
Canadian study, although the published report did not mention previous
medication. Again, only the group taking 6 mg of risperidone qualified as
showing just a minimal degree of improvement in this part of the study, with a
reduction in PANSS score of just 16 points. People on other doses of
risperidone and those taking haloperidol did not fare markedly better than
those on placebo, whose symptoms worsened somewhat in this arm of the study
(Marder et al., 1994).
Olanzapine was licensed for use in
the USA in 1996 on the basis of two studies, both of which were funded by Eli
Lilly and involved people whose condition had a ‘chronic course’. The first
trial involved a comparison of olanzapine at various doses, haloperidol (10–20
mg per day) and placebo, and lasted for 6 weeks. Three hundred and thirty-five patients were involved and they had been diagnosed with
schizophrenia for around 15 years on average, with numerous previous episodes.
They were said to be suffering from an ‘exacerbation’ of symptoms that had
lasted around 2 to 5 months before the study started. After medication was
withdrawn abruptly over 2 days, patients entered a ‘placebo lead-in phase’ of
4–7 days. During this time patients were given a placebo, and those who
responded well were excluded from randomisation. This technique has been
rightly criticised for biasing trials against placebo, but it also demonstrates
that the patients entered into the trial were almost certainly suffering from
rapidly-occurring withdrawal symptoms, as signs of the underlying condition
would be expected to take longer to reappear. After randomisation more than 50%
of patients dropped out of the study, including 50–60% of those allocated to
olanzapine.
Despite the placebo run-in bias, the
drop-out rate and the fact that patients had been withdrawn from previous
medication, the difference in improvement between people on placebo and people
taking olanzapine only just reached criteria for clinical significance in the
group taking the highest dose, where it was 12.1 points on the BPRS. People on
other doses of olanzapine and those treated with haloperidol showed an
improvement that was less than 10 points different from that shown by the
placebo-treated patients. Moreover, there was no difference between the groups
in the amount of additional medication used (lorezepam, a benzodiazepine drug,
was allowed) (Beasley, Jr, et al., 1996b).
The other trial consisted of a
simple comparison between placebo and olanzapine at two different fixed doses:
1 mg and 10 mg. It involved 152 inpatients who had been diagnosed with mental
health problems for around 15 years. Sixty-five per cent were said to be
experiencing an acute exacerbation and 78% had been taking antipsychotics in
the week prior to the study. A quarter of the patients had been on clozapine
before entering the study and, given clozapine’s potential to provoke
withdrawal-related psychotic symptoms, it is highly likely that some patients
in the placebo group would have been in a state of antipsychotic withdrawal.
This may have contributed to the fact that a phenomenal 80% of the placebo
group and 38% of the olanzapine group dropped out of the study early. Like the
previous study, this one started with a placebo lead-in phase of 4–7 days and
the double blind treatment phase lasted 4 weeks. Again, the results are
remarkable for the small difference between olanzapine and placebo, with the
group taking 10 mg of olanzapine showing a 7.7-point improvement in its BPRS
rating compared with a 0.2-point improvement in the group on placebo (Beasley,
Jr, et al., 1996a).
More recent trials have produced
even smaller differences between atypical antipsychotics and placebo. The
difference in PANSS scores between drug-treated and placebo-treated patients in
trials conducted between 1999 and 2008 was only 6 points, for example (Khin et
al., 2012), far below the threshold for clinical significance proposed by
Leucht et al. (2006). A meta-analysis conducted by Leucht and colleagues of
studies of nine atypical antipsychotics published since 1992 found that the difference
between the improvement on the antipsychotic compared with placebo was only 10
points on the PANSS and 9 points on the BPRS. Only 18% more patients taking
atypicals showed a ‘response’ to the drugs than to placebo, although response
in these studies was liberally defined as a 20–30% reduction in symptom scores,
rather than the 50% reduction that is usually regarded as representing a
clinically meaningful change (Leucht et al., 2009). The review also found
evidence suggesting the existence of unpublished negative studies and
unblinding, and the high levels of drop-out that occurred are likely to further
skew the results (Hutton et al., 2012).
Unanswered Questions
The official evidence base for the use of
antipsychotics begs more questions than it answers. We know that these drugs
improve psychotic symptoms to a greater extent than a placebo, but not how they
compare with other sedative drugs, except, perhaps, the barbiturates. In many
studies, however, the difference between antipsychotics and placebo is not
substantial, and we do not know whether suppressing symptoms with drugs in this
way helps more people to make an eventual recovery. Research suggesting that
long-term treatment with antipsychotics makes people vulnerable to various
withdrawal-induced effects when they discontinue the drugs has not been
developed, and it remains possible that such effects fundamentally undermine
the results of studies that purport to establish the value of long-term
treatment.
The principle problem with
antipsychotic trials is that the drugs were already in use before they took
place. By the 1960s most patients had been taking
these drugs for months or even years before they entered the randomised trials
that were supposed to establish whether the drugs worked. Researchers were
unaware or unconcerned about the problem this poses, however, despite the fact
that withdrawal symptoms had been clearly described by the 1960s. It is
difficult not to conclude that leading psychiatrists and researchers did not
want to think too deeply about the methodology of their studies because the
antipsychotics had already become an indispensable part of psychiatric practice
and central to the image that psychiatry was constructing of itself as a bona
fide medical speciality.
It is particularly noticeable, in
these days when special services have been set up for people experiencing a
‘first episode of psychosis’, that there are no placebo-controlled trials of
acute treatment in people undergoing a first psychotic breakdown, and only a
few studies of maintenance treatment in this group. After more than half a
century of research into the effects of antipsychotics, and despite the fact
that extended use of these drugs is universally recommended, we cannot yet say
whether taking antipsychotics in the first place is ultimately better than not
taking them or whether starting ‘maintenance’ treatment offers any real
advantages. We know at least that not everyone benefits from taking
antipsychotics on a long-term basis, but we need to look elsewhere for evidence
about what these drugs actually do that can help us weigh up the pros and cons
of taking them in different circumstances.
The Patient’s Dilemma: Other Evidence on
the Effects of Antipsychotics
By the beginning of the 1980s the data from randomised
controlled trials and the dopamine hypothesis of schizophrenia had come
together to form the foundations of a view that antipsychotic drugs were
effective and specific treatments for schizophrenia. Tardive dyskinesia and
other ‘side effects’ were considered, in most cases, a price worth paying for a
treatment that was assumed to work on the biochemical mechanism that
constituted the condition itself, whether this was the abnormality suggested by
the dopamine hypothesis, or a more complex situation involving other
neurotransmitters. The drug-centred understanding of the nature and action of
these drugs had been well and truly buried, and descriptions of the mental and
physical alterations they produced disappeared from the literature. The very
idea that psychiatric drugs, like recreational drugs, exert psychoactive
effects—alter mental functioning and the nature of consciousness—was banished
from mainstream thinking. Research was dominated by the view that these
drug-induced alterations were incidental and therefore essentially
uninteresting, and could be readily distinguished from the really significant
effects of the drugs on the underlying disease. The dopamine hypothesis of
schizophrenia ensured that the majority of attention focused on how the drugs
reversed this presumed disease, and not how they modified normal brain
function.
A countervailing view did emerge in
the 1980s, however, which reiterated and restated the drug-centred account, and
forced the drug-induced effects of the antipsychotics back into the public
domain. American psychiatrist Peter Breggin published his first book Hazards to the Brain in 1983, and his best-selling book Toxic Psychiatry came out in 1990. Breggin had started to
worry about the nature of psychiatric treatments while he was a college student
working as a volunteer at a local asylum (International
Center for the Study of Psychiatry and Psychology, 2009). He went on to
formulate a comprehensive account of what he called the ‘brain disabling’
effects of all sorts of psychiatric interventions, including electro-convulsive
therapy (ECT), lobotomy and antipsychotics, and he became a vociferous critic
of what he believed to be the ‘abusive practices’ prevalent in mainstream
psychiatry (Breggin, 1993a, p. 507).
Breggin put together scattered data
from animal research, volunteer studies, the early observations of Deniker and
others, and patients’ accounts of the experience of taking antipsychotic drugs
to construct a drug-centred account of the drugs’ effects on mental activity and
behaviour. He used the term ‘behavioural deactivation’ to summarise the
characteristics of the state produced by ingesting antipsychotics, an
expression intended to capture the generalised restriction of all aspects of
activity, from physical movement to intellectual capacity and emotional
responses. Like the theory of ‘neuroleptic action’, this view suggests that, at
lower doses, the drug-induced state is mainly manifest in the slowing of
intellectual functioning and flattening out of emotions, but at higher doses
the classical physical symptoms of Parkinson’s disease, such as increased
muscle tone and restricted movement, become more apparent. What was most
controversial about Breggin’s ideas, however, was that he resurrected the views
expressed in the 1950s that far from being unwanted ‘side effects’, it was
through these effects that the intended consequences of drug treatment
occurred. Breggin linked all physical psychiatric treatments, from lobotomy to
Prozac, by suggesting that their purpose was to obliterate troubling behaviours
by producing states of reduced brain activity. Antipsychotic drugs, like
insulin coma therapy, ECT and lobotomy before them ‘exert their primary or
intended effect by disabling normal brain function’ (Breggin, 1993a, p. 72). Treatment
is deemed successful, he explained, when someone, although not necessarily the
patient, prefers the ‘state of diminished brain function with its narrowed
range of mental capacity and emotional expression’ (Breggin, 1997, p. 4).
With typical frankness, Breggin
pointed out the parallels between the antipsychotic-induced state of
deactivation and the effects produced by surgical lobotomy. By severing
connections to the frontal lobes, the brain area responsible for
characteristics such as spontaneity and motivation, and sometimes referred to
as the ‘seat of personality’, lobotomy results in a state of apathy, emotional
disinterest and cognitive impairment. Clinicians and researchers in the 1950s
had also made the analogy between the effects of antipsychotics and lobotomy
(Lehmann, 1955), but the two states are not quite the same. Lobotomy frequently
produces disinhibited and child-like behaviour, which
is not characteristic of the antipsychotic-induced state. Like Steck and
Deniker, Breggin also compared the effects of the drugs with those of the
devastating infectious disease that hit Europe in the early twentieth century,
encephalitis lethargica. This neurological disease, which was presumed to be
caused by a virus, produced the same range of neurological abnormalities
produced by the antipsychotics. Most commonly it involved mental and physical
changes that resembled Parkinson’s disease, but it could produce other
neurological reactions like akathisia, dystonia and a tardive dyskinesia-like
condition (Breggin, 1993b).
Breggin attributed the state of
deactivation to the dopamine blockade caused by antipsychotic drugs, but even
the purest anti-dopaminergic antipsychotics affect other neurochemical systems
in complex, interacting and often unmapped ways. Chlorpromazine was given its
European brand name Largactil after its ‘large action’, but even haloperidol
and Stelazine, supposedly more specific dopamine blockers, affect numerous
other systems, and drugs like clozapine, as already noted, have relatively weak
actions on dopamine and stronger effects on other neurotransmitters. The
atypical antipsychotics consist of a diverse group of drugs, some of which are
similar in nature to some of the older drugs, and some of which appear to have
a variety of different types of action. Risperidone, for example, is chemically
related to the older drug sulpiride, and exerts a similar range of
characteristic effects, whereas olanzapine, quetiapine and ariprirazole, as we
shall see, all produce their own subtly distinctive drug-induced state.
Although we may be able to map some aspects of the alterations produced by
antipsychotics to particular chemical mechanisms, like the induction of
‘Parkinsonism’ by dopamine receptor blockade, it is rarely possible to find the
origin of a complex subjective state in a single biochemical aberration. As
philosopher of science Isabelle Stengers suggests, ‘between the richness of the
psychic effects of a drug and the hypothesis that it disturbs the effects of a
type of neurotransmitter, there exists a gulf that no contemporary theory can
cross’ (Stengers, 1995, p. 134–135, cited in Kirk et al., 2013).
The Subjective Effects of Antipsychotics
In order to understand the nature of a psychoactive
drug, whether the drug is used for recreational purposes or prescribed to treat
a condition, we have to start with the phenomenology of the drug-induced state.
We need to know what sort of physical and mental alterations different drugs
produce in people who take them, and how these alterations might vary over the course of longer periods of use.
Fortunately, although mainstream psychiatry lost interest in the nature of the
drugs it was using, some independent-minded psychiatrists bucked this trend,
and patients also continued to speak of the effects the drugs exerted on them.
They complained to their psychiatrists in large numbers, they demonstrated
their feelings by refusing to take the drugs and some put their experiences
down in writing. Put together this information provides an insight into how the
state of deactivation Breggin proposed feels from the inside—from the
perspective of the person taking the drug. Accounts by people with mental
health difficulties also convey how the drug- induced state can suppress a
range of unwanted mental experiences and disruptive or unusual behaviours,
including the symptoms associated with psychosis or schizophrenia.
Although all drugs have to be tested
in ‘healthy volunteers’ before they come to market, most published volunteer
studies provide only brief data on selected physiological parameters or
psychological tests, and do not describe the nature of the drug-induced state.
Nevertheless, the data indicate that antipsychotic drugs reduce or impair
almost all psychological and motor functions that can be measured, and that
volunteers find the drug-induced state to be highly unpleasant (Heninger et
al., 1965; McClelland et al., 1990; Fagan et al., 1991; Rammsayer and
Gallhofer, 1995; Peretti et al, 1997; Ramaekers et al., 1999).
A more informative study was
conducted by psychiatrist David Healy in the hospital where he worked in north
Wales. In this study staff from the hospital, including nurses, doctors and
psychologists, were randomised to receive 5 mg of droperidol (a
haloperidol-like antipsychotic), diazepam (Valium) or placebo in a double-blind
fashion, and they were required to perform various psychological tests under
the influence of the drug. The results of the study, which was only published
in a minor pharmacology journal, indicated that almost all of the 20 participants
who took droperidol felt heavily sedated, with a feeling that physical and
mental activity required greater effort than usual. Concentrating on even
simple tasks was difficult and one participant, who happened to be the
psychologist and author Richard Bentall, found that obtaining a sandwich from a
sandwich machine was just too complicated. All those who took droperidol
described feeling ‘disengaged’ from events around them and found it difficult
to motivate themselves to perform the tests they were set. The drug produced
feelings of restlessness, anxiety and impatience in all 20 participants, and
some felt irritable and uncharacteristically belligerent. Most people found the
experience of taking droperidol unpleasant to some degree, in contrast with
those who took diazepam who found it either neutral
or pleasant. The increased effort required to do anything, the akathisia and
the anxiety that the experience would be prolonged all contributed to these
negative feelings, and several subjects felt so distressed they entertained
suicidal feelings (Healy and Farquhar, 1998).
One of the most interesting aspects
of the experiment was that many participants did not recognise the altered
state they were in while they were under the influence of the drug. Only two
reported feelings of restlessness during the test session, even though many
more were observably restless and distressed. Others reported that although
they were vaguely aware of being in an altered state, they had an inability or
unwillingness to admit to it, in part because they found it difficult to
identify and describe its features while under the influence of the drug.
Breggin has also highlighted how people’s ability to make judgements about
their behaviour may be impaired while they are under the influence of a
psychoactive substance, an effect he has termed ‘spell-binding’ (Breggin,
2006).
The Patients’ Perspective
Despite the problem of spell-binding, and concerns that
people diagnosed with mental disorders might not be able to differentiate
between their own difficulties and the effects of drugs, patients’ accounts of
taking antipsychotics closely mirror those of non-patients. As Marjorie
Wallace, founder of the British mental health charity SANE, commented, even
people with severe symptoms remain ‘extraordinarily articulate and lucid on the
subject of their medication’ (Wallace, 1994, p. 35).
A survey conducted by SANE provided
one glimpse of patients’ views prior to the era of the Internet. Most people,
Wallace reported, disliked their drugs, whose negative effects were often
experienced as ‘worse than the illness itself’. Like Healy’s volunteers, the
respondents felt disengaged from the world around them, as if they were
separated from it by a ‘glass screen’. They described how ‘their senses were
numbed, their willpower drained and their lives meaningless’, and they often
summed up the experience as feeling like a ‘zombie’ (Wallace, 1994, p. 34, 35).
Another account of treatment with antipsychotics describes the adverse impact
on imagination and creativity. Peter Wescott, who had suffered from episodes of
extreme paranoia and psychosis, felt that his anti psychotic treatment,
although effectively suppressing his psychotic symptoms, had fundamentally
changed his personality. ‘Whereas once I lived in a fascinating ocean of
imagination, I now exist in a mere puddle of it’, he
recounted. ‘I used to write poetry and prose because it released and satisfied
something deep inside myself; now I find reading and writing an effort and my
world inside is a desert’ (Wescott, 1979, p. 990).
The Internet has revolutionised
possibilities for understanding people’s experiences of medical care and
prescription drugs. www.askapatient.com,
created by a librarian in the USA, is one of several sites that allows users to
provide their own perspective on the use of all sorts of medicines, including
those prescribed for psychiatric problems. These data are particularly useful
for evaluating the subjective effects of the atypical antipsychotics, since
there are no descriptions of these in mainstream literature. Table 7.1
lists accounts written on www.askapatient.com by people who had taken some older
antipsychotics, as well as the newer drugs risperidone and olanzapine. Comments
are artificially separated into different categories of effect, like sedation
and emotional effects, but it should be appreciated that what people generally
described was a global, drug-induced state, which had both physical and mental
aspects (Moncrieff et al., 2009).
Consistent with previous reports,
people taking the older drugs chlorpromazine, trifluoperazine (Stelazine) and
haloperidol described feeling heavily sedated, and physically and mentally
slowed or inhibited. They also depicted the deadening effect on emotions and,
like Wescott, reported feelings of having lost important aspects of their
personality such as their creativity and humour. Although many disliked these
experiences, some people acknowledged that these same effects had led to
improvements in mental symptoms. A man diagnosed with bi polar disorder, for
example, described how he thought haloperidol had ‘decreased brain activity,
slowed down racing thoughts’. A woman who had taken haloperidol for psychotic
symptoms, including hallucinations, described the suppression of interest
caused by the drug, referring to the benefits of this state, as well as a sense
of loss:
Although I felt very well, I felt as if I had
absolutely nothing to talk about. I kept wondering about whatever [it] was that
had been so interesting during most of my life that I had suddenly lost... But
I was very much in contact with reality and for that I was thankful.
Other respondents were also grateful for the effects of
the drugs. One suggested that receiving haloperidol for a few days for a manic
attack had been life-saving, for example. In contrast, many described the
experience as highly unpleasant. One man referred to haloperidol as ‘the worst
[drug] I have been exposed to’ and chlorpromazine was said to be ‘horrible
stuff’. People who had taken risperidone described a similar state, but
movement disorder was mentioned less frequently and sexual difficulties, including
loss of libido and impotence, more frequently. The latter were often linked
with the emotional flattening produced by the drug, suggesting that its effects
can be understood as a global reduction of arousal that encompasses all aspects
of motivation and desire. Again, people described how these same effects had
helped reduce troubling thoughts and disabling anxiety. A man with a diagnosis
of paranoid schizophrenia described how risperidone had ‘numbed my brain from
psychotic thoughts, flattened most of my emotions’. Another respondent with
anxiety and ‘paranoia’ described how it ‘stops my negative thoughts and feeling
being amplified and overwhelming me’, and several more commented on how the
drug had produced feelings of ‘calm’ or relief from anxiety. A woman with
depression noted how she now felt ‘too tired to be depressed’.
Table 7.1 Verbatim
descriptions of subjective effects of antipsychotics from www.askapatient.com (from Moncrieff et
al., 2009)
|
Effect |
Typical
comments |
|
Sedative effects |
‘I’m still fatigued in the
morning and can barely get out of bed some days’ (trifluoperazine) |
|
Cognitive effects |
‘low ability to make decisions’
(trifluoperazine) |
|
Emotional effects |
‘I feel absolutely nothing!! No
sadness, no joy, NOTHING’ (haloperidol) |
|
Parkinsonian effects |
‘...extremely hard to move,
think, talk’ (haloperidol) |
|
Akathisia |
‘horrible restlessness’
(haloperidol) |
|
Sexual effects |
‘I lost my ability to feel
emotions, I lost my libido, I lost my drives, I lost my ability to get an
erection’ (risperidone) |
|
Metabolic
effects |
‘ravenous,
rapacious hunger that never quit’ (olanzapine) |
People commenting on olanzapine
described an altered state consisting of profound sedation accompanied by
emotional flattening and indifference, in association with a markedly increased
appetite for food. Slow or restricted movement did not appear to be a common
feature of the drug-induced experience, in contrast to the older drugs. The
following comment by a person diagnosed with bipolar disorder typifies many,
and illustrates the close relation between the drug’s psychoactive and metabolic
effects:
I’ve never been able to eat as much as I did when I was
on Zyprexa. I gained 40 lbs in no time and my mind was in a constant fog of
lethargy and indifference. I didn’t care about anything. I just wanted to sit
around and eat.
The lethargy was not always experienced as unpleasant,
and several respondents described how olanzapine had helped reduce anxiety,
irritability and even suicidal thoughts. ‘It has a wonderful calming effect’
was how one man, with a diagnosis of bipolar disorder, described it. ‘The drug
saved my life’ commented one woman, ‘by getting me sleep so my nervous system
could rest’. Several mentioned that the drug had stopped or reduced psychotic
symptoms. It ‘stopped the psychosis and thoughts coming into my head’,
commented a man diagnosed with schizoaffective disorder. As with the other
drugs, some respondents disliked the effects intensely. An older man with
anxiety said ‘This is the most horrible drug I’ve ever used’, and a woman
commented ‘if you would not willingly undergo a lobotomy, then do not take this
drug’. Some people found the effects unpleasant, but had, nevertheless, found
the drug useful: ‘Despite its extremely negative side effects’ said one
respondent, ‘this medication does wonders for paranoia and delusional thinking
... the anxiety is non existent now, I am able to function as a normal human
being’. A woman with psychosis commented ‘It makes me feel like a veggie, but
that was better than what I was going through and it kept me out of the
hospital’.
Clozapine, now reserved for people
who do not improve on treatment with other antipsychotics because of its
dangerous effects on the immune system, was also
described as producing heavy or ‘extreme’ sedation, lethargy, weight gain and
increased appetite. In keeping with comparative clinical trials, which show
that it can reduce positive psychotic symptoms like delusions and
hallucinations better than other sorts of antipsychotics, at least in the short
term (Moncrieff, 2003), many respondents with a diagnosis of schizophrenia felt
the drug had been beneficial. ‘It saved my mind’, said a 32-year-old woman who
had been taking it for 10 years, and a 37-year-old woman, who had been on the
drug for 6 years, described how it had helped her relate and ‘connect’ to
people, which she had previously found difficult. Others commented on how the
sedating effects were useful for inducing sleep and reducing anxiety. In
contrast, several respondents had found the effects frightening and unpleasant,
and felt that the drug had changed their personalities in subtle ways which,
like the participants in Healy’s study, they were not always aware of when
under its influence. A 41-year-old woman diagnosed with depression and bipolar
disorder described how she lost her ‘personality and became like a zombie’, but
only realised the effect the drug was having when she stopped taking it and the
‘sedation wore off’. Another woman described clozapine as the ‘most EVIL med I
have ever taken’ (original emphasis), describing how it made her feel ‘100%
zoned out’.
The comments on www.askapatient.com
are consistent with a large interview study conducted in Germany involving 80
patients with a diagnosis of schizophrenia. Around a third of these patients
felt that clozapine had been helpful to them, but the most commonly cited
benefits were its ability to improve sleep and produce sensations of calmness.
The authors concluded that ‘a significant proportion of the patients viewed
clozapine more as a tranquilliser or a sleeping pill than an antipsychotic
drug’. Some patients complained of feelings of demotivation, lethargy and a
lack of interest and enthusiasm, which they attributed to the drug. When asked
how they thought the drug worked the patients reported that it had made their
voices fainter, or less frequent, or that they had disappeared completely. Two
described its effects as ‘shielding’ them from stress and ‘irritations’. Some
patients imagined that the drug suppressed the actions of the brain and nervous
system. One described how it seemed as if the drug ‘makes the nerves work more
slowly’ and another that it caused a ‘blockage of brain functions’. Like the www.askapatient.com
respondents, some patients reported that the drug had improved their ability to
function in the world (Angermeyer et al., 2001, pp. 512, 515).
Trials that demonstrate clozapine’s
facility to reduce aggressive impulses and behaviour illustrate the unusual
state of placidity this particular drug can produce
(Spivak et al., 1997b; Volavka et al., 2004; Krakowski et al., 2006). Unlike
the older drugs, where the emotional restriction appears to be part of an
overall state of physical and mental inhibition, the emotional state produced
by clozapine involves a more subtle change in emotional tenor and personality,
which people may not find so unpleasant at the time of taking the drug, but
which in retrospect might seem even more frightening.
Quetiapine, better known by its
brand name Seroquel, has become one of the best-selling drugs in its class
since its release in 1997. It shares an intense sedating effect with clozapine
and olanzapine, but its effects on weight and metabolism appear to be weaker,
although they are by no means insignificant. It is frequently prescribed for
insomnia and is said to have a modest street value as a ‘downer’, where it is
know by the slang term ‘Suzy Q’ (Wen, 2009). Respondents on www.askapatient.com,
many of whom said they were taking it for insomnia, as well as bipolar
disorder, anxiety, depression and schizophrenia, described it as sapping
motivation and sex drive, causing extreme sedation and lethargy, and sometimes
increasing appetite and producing weight gain. People reported feeling ‘drugged
up’, and having feelings of ‘passivity and ‘zombie-like periods’ while taking
it, but many people commented on its ability to induce and improve sleep.
Aripiprazole (trade name Abilify),
has been widely marketed with the curious suggestion that it has the
simultaneous ability to stimulate and block dopamine receptors. The rationale
for the benefits of this action is said to be reduced neurological adverse
effects like Parkinsonism, but why other dopamine-blocking drugs could not just
be given at reduced doses is never explained. Judging from clinical experience
and comments on www.askapatient.com,
the subjective experience of taking the drug suggests it is less sedative than
other antipsychotics, and it frequently produces an unpleasant state of
insomnia, restlessness and agitation. People also report experiences of the
sort of flattened emotions and demotivation associated with the other
antipsychotics, however.
Are Antipsychotics Useful?
Patients, volunteers and observers concur that
ingesting antipsychotic drugs produces a state of sedation, lethargy,
flattening of emotional responses, indifference and feelings of impaired mental
functioning sometimes accompanied, depending on the drug to some extent, by the
unpleasant agitation known as akathisia. The exact quality of these effects varies between the different drugs, as do the
physical effects that accompany these mental changes. So whereas the
psychoactive effects of the older drugs are closely associated with their
ability to slow and restrict movement, the placidity and indifference produced
by some of the newer antipsychotics, notably clozapine and olanzapine, appear
to be part of a global state characterised by a striking metabolic disturbance,
but less profound effects on movement. The types of mental suppression produced
by quetiapine and ariprirazole are subtly different again, but whatever the
drug, the physical effects appear to have an intrinsic relation to the mental
effects, suggesting they are, in fact, different facets of the same basic
physiological process.
It is not difficult to imagine how
these drug-induced effects might impact on symptoms of psychosis, schizophrenia
and other mental health problems, and patients describe this process from their
own perspective. The physical and mental slowing induced by the drugs reduces
agitation and helps to calm people who are highly aroused, possibly as a
consequence of hearing voices or other disturbing mental phenomena. The mental
clouding produced by the drugs may also reduce the intensity of psychotic
symptoms, but it is the distinctive ability of the drugs to dampen emotional
responses that marks them out from most other sedative, psychoactive
substances. The emotional restriction and loss of interest and motivation that
the drugs produce can reduce people’s preoccupation with intrusive ideas and
experiences, and thus also the excitation, anxiety or aggression that such
experiences might provoke. The psychotic phenomena seem to fade into the
background; they no longer demand so much attention and levels of distress can
markedly diminish. With drug treatment people are able to ignore their
psychotic symptoms, and although they will still talk about them when asked,
the symptoms no longer appear to be at the forefront of their thought.
Sometimes the abnormal ideas and experiences might dis appear altogether as
people simply lose interest in them. Deniker recognised this effect in 1960
when he suggested that the improvement that could occur in an individual’s
‘previously rigid system of delusions...is really the patient’s increasing lack
of interest and his loss of feeling for his delusional fantasies’ (Deniker,
1960, p. 99).
Although the drugs suppress mental
activity indiscriminately—not just aberrant thoughts and feelings—in cases
where someone’s mental life is dominated by psychotic processes, the dampening
down and slowing up of thinking may, by reducing the strength of the troubling
thoughts, release the affected person from their internal psychotic world, and
enable them to interact more normally with the world around
them. Thus, people who are extremely psychotic may show improved social
functioning while taking the drugs, despite also exhibiting signs of
drug-induced suppression.
Table 7.2 Changes in
dimensions of psychosis after antipsychotic treatment (data from Mizrahi et
al., 2006)
|
Dimension of
psychotic experience |
Reduction in
dimension after 6 weeks of antipsychotic treatment (%) |
|
Behavioural impact |
64 |
|
Cognitive preoccupation |
51 |
|
Emotional involvement |
56 |
|
Conviction |
25 |
|
External
perspective |
0 |
More recently, two studies led by
members of a respected research group based in Toronto have confirmed this
pattern. One study investigated patients’ views on how antipsychotics impacted
on their psychotic symptoms, and found that patients described that drug
treatment produced a state of detachment from their symptoms, rather than
eradicating them. The study included eight patients who had never taken
antipsychotics before. Initially, these individuals expected the drugs to
eliminate their symptoms, but after receiving the drugs they changed their
minds and felt the drugs merely made the symptoms less intense and troublesome
(Mizrahi et al., 2005). The second study investigated changes in five
dimensions of the psychotic experience in 17 people experiencing a psychotic
episode who were starting on anti psychotics, mostly for the first time. The
dimension that showed the most change after 6 weeks of drug treatment was the
‘behavioural impact’ of the symptoms, which referred to whether the symptoms
influenced patients’ behaviour (Table 7.2). Preoccupation with symptoms also reduced
substantially, along with patients ‘emotional involvement’ with their symptoms.
In contrast, belief in the reality of the symptoms (which the researchers
referred to as ‘conviction’) diminished little, and patients’ ‘external
perspective’, or understanding of the unusual nature of their experiences, did not
change at all (Mizrahi et al., 2006).
Long-Term Effects
The ability of antipsychotics to suppress psychotic
symptoms does not necessarily translate into a useful and lasting effect,
however. Although many psychiatrists believe that the introduction of these
drugs transformed the outlook for people with severe
mental disorders dramatically, data from research are more ambiguous. Figures
on declining hospital populations, for example, originally interpreted as
indicating that the introduction of antipsychotics had enabled people to be
discharged from psychiatric institutions more frequently than before, actually
showed that in countries like the UK and the USA, rates of discharge started
increasing prior to the introduction of antipsychotics (Shepherd et al., 1961;
Gronfein, 1985; Grob, 1994). In other places, like France and Norway, discharge
rates did not change for years after the drugs’ introduction (Odegaard, 1964;
Sedgwick, 1982). It was politics and not drugs that changed the face of mental
health care in the late twentieth century. Western governments started to
favour locating care in the community in order to reduce costs, and to combat
the neglect, brutality and demoralisation that were revealed in some
mid-century psychiatric institutions (Grob, 1983). The introduction of the new
tranquillisers, however, did provide a convenient justification for this
policy, and thereby helped to drive the community care movement forward
(Gronfein, 1985).
Ascertaining the long-term outcome
of people who experience mental health problems is fraught with difficulty
because of changing notions about the nature of these problems and varying
definitions of recovery. Thus, people diagnosed with schizophrenia in one era
and in one country may have little in common with those in other places or
other periods. Although a considerable amount of research has been conducted,
‘a clear picture of the long-term outcome in schizophrenia has not emerged’
(Warner, 2004, p. 57). Follow-up studies over the course of the twentieth century
found little evidence that outcome improved after the introduction of
antipsychotics, however. The outlook for someone diagnosed with the disorder in
the 1990s was about the same as someone diagnosed in the 1930s (Hegarty, 1994).
As we saw in Chapter 6, follow-up
studies of patients enrolled in randomised trials of acute treatment also do
not confirm that treating a psychotic episode with antipsychotic drugs confers
any long-term advantage. Robert Whitaker has proposed that far from improving
the ultimate outlook for people diagnosed with psychosis or schizophrenia,
long-term antipsychotic treatment may make it worse (Whitaker, 2010). This
could explain, he suggests, why two large international studies conducted by
the World Health Organization found that people diagnosed with schizophrenia
for the first time in the developing world, where drug treatment was often
unavailable, had fewer symptoms and functioned better socially a few years
later than those in the Western world (Sartorius et al., 1977; Jablensky et
al., 1992).
Data on the extent to which people
showed an all-round recovery, including being able to work and support
themselves, as well as remaining symptom-free, suggested that long-term
antipsychotic treatment may itself depress outcome. People who were off
antipsychotics who were diagnosed with schizophrenia, which is supposed to have
the worst outcome of all psychotic syndromes, had a better global outcome than
people with other psychotic disorders who were taking antipsychotics. This
effect could be seen from around 4 years after enrolment through to the 15-year
follow-up, when the data were presented (Figure 7.1) (Harrow and Jobe, 2007).
The authors of this study initially
postulated that the differences between drug-treated patients and those who did
not receive antipsychotics could be explained by the fact that people who have
protracted and severe problems are more likely to receive drug treatment. Only
people with the mildest difficulties would be able to avoid contact with
services and the drug therapy this usually entails. So it might be the nature
of the underlying condition that explains why people on drug treatment appear
to fare worse. Harrow and his colleagues looked at some of the factors that
might predict recovery and found that people with schizophrenia who were not
taking antipsychotics at the 15-and 20-year follow-ups were, indeed, a group
with a more favourable outlook, as judged by factors such as their level of
achievement prior to the onset of the condition. Comparing only patients with a
similar prognostic profile, however, still showed that those who were not
taking antipsychotics had a better outcome then those who were (Harrow and
Jobe, 2007). This does not rule out the prospect that there are other
unmeasured factors about the nature of the disorder that might predict both a
poor recovery and the likelihood of taking antipsychotics. It does indicate,
however, that the idea that antipsychotic treatment makes people worse has to
be considered a possibility, and one which urgently needs to be investigated
further.
Figure 7.1 Global
adjustment of psychotic patients over 15 years of follow-up—low scores indicate
better adjustment (data from Harrow and Jobe, 2007)
How antipsychotics negatively affect
the outlook of psychotic conditions, if indeed they do, remains uncertain but,
as we have seen, it has been proposed that they might make the brain more
vulnerable to psychosis by inducing changes in dopamine receptors and other
neurotransmitter systems, as in the idea of ‘supersensitivity psychosis’
(Chouinard and Jones, 1980). This mechanism would predict that some people on
long-term treatment would have higher levels of psychotic symptoms than they
might have had without that treatment. In terms of general functioning we have
seen evidence that antipsychotics can cause a decline in mental abilities, at
least in those who develop tardive dyskinesia. As American
psychiatrist Thomas McGlashan put it in an edition of the Schizophrenia
Bulletin, ‘medication may be life-saving in a crisis, but it may render
the patient more psychosis-prone should it be stopped and more deficit ridden
should it be maintained’ (McGlashan, 2006, p. 300).
The other fact that historical
studies confirm is that not everyone needs antipsychotics in order to recover
from a psychotic episode. Early follow-up studies indicate that there has
always been a proportion of people who recover from a psychotic episode
eventually, without any modern-day interventions. American psychiatrist Richard
Warner surveyed these studies in his book Recovery from
Schizophrenia. Studies in England, for example, where the diagnosis of
schizophrenia remained fairly narrow in contrast to the USA (and in that sense
similar to modern-day criteria), found that in the 1930s around 20% of people
admitted with a diagnosis of schizophrenia made a full recovery, and this rose
to more than 30% in studies of people admitted in the 1940s and early 1950s
(Warner, 2004).
Swiss psychiatrist Manfred Bleuler,
son of Eugen Bleuler who coined the term ‘schizophrenia’, followed up 208
psychotic patients admitted to a psychiatric hospital between 1942 and 1943.
Twenty-two per cent made a full recovery, which was sustained for at least 5
years, and a further 58% recovered from their initial episode, but had further
episodes interspersed with times of remission—and this was more than 10 years
before the introduction of antipsychotics (Bleuler, 1974; Modestin et al.,
2003). Moreover, Bleuler commented that none of the patients who maintained a
sustained recovery after the introduction of antipsychotics received long-term
drug treatment after the resolution of their acute symptoms (Bleuler, 1974).
Philip May’s study also showed that well over half of the patients treated with
psychotherapy or milieu therapy were discharged within a year, and the study
had excluded people with milder conditions or protective factors that suggested
they might be able to recover without drug treatment (May, 1968).
Projects that have been set up with
the aim of minimising the use of antipsychotic drugs also confirm that some
people can recover from a psychotic episode without them. The Soteria project
in the USA was established by psychiatrist Loren Mosher and funded by the
National Institute of Mental Health. It consisted of a therapeutic community,
staffed by non-professionals, but overseen by Mosher and the research team, and
it was designed to minimise the use of antipsychotics by providing a supportive
and accepting environment. In order to evaluate the project a trial was set up
in which people with an early episode of psychosis (their first or second
episode) were randomly or alternatively allocated either to the Soteria project
or to receive standard treatment at the local hospital.
A limitation of the experiment, however, was that people who were judged to be
unmanageable in the Soteria setting were excluded from allocation to the
Soteria group and a few more patients dropped out during the early stages of
the experiment. The data suggest, however, that the Soteria project was at
least as good as ‘usual care’ in terms of outcomes at 2 years for patients in
the study (Bola and Mosher, 2003). Forty-three per cent of the patients treated
in the Soteria facility received no antipsychotic treatment at all, and two
thirds (66%) had used antipsychotics either not at all or only occasionally,
compared with only 5% of the group admitted to the local hospital. When the
numbers who were excluded from the trial are accounted for, the proportion of
Soteria subjects who avoided the use of antipsychotics altogether was 32%.
A more recent study in Finland
produced similar results. In this study services for people with a first
episode of psychosis in certain areas of northern Finland were set up with the
express aim of avoiding the use of antipsychotics where possible, and
supporting patients instead with a mixture of psychotherapy and family therapy.
Results from the assessment of 84 patients treated in these ‘experimental’
areas were compared with those from 51 patients treated in other areas where
services employed antipsychotics according to usual protocols. Forty-three per
cent of patients in the experimental areas received no antipsychotic drugs
throughout the study compared with only 6% in the other areas. However, almost
a third of potential recruits in the experimental areas dropped out of the
study early. If all these patients are assumed to have received antipsychotic
treatment, then the proportion who avoided the use of these drugs altogether
falls to 34%. The patients who stayed in the study in the experimental areas
were less likely to have a prolonged hospital admission than patients from the
other areas and their global outcome ratings were superior (Lehtinen et al.,
2000). However, the replication of this trial in Sweden failed to achieve such
high levels of avoidance of drug treatment, with only 19% of patients remaining
drug free (Cullberg et al., 2002).
It is clear therefore that not
everyone undergoing a psychotic episode needs antipsychotic medication to
recover. Some people recover spontaneously and can be helped and supported
through this process without the need for chemical suppression. The
disease-centred model of drug action eclipsed this fact, however, replacing it
with the belief that people only recover because they receive the necessary and
specific treatment.
Far more research is needed into the
effects of taking antipsychotics over long periods before people can judge
whether it is beneficial to use them. Many people with psychosis find that the
drugs suppress their symptoms, although with the
advent of clozapine and its positioning for people who are ‘treatment
resistant’, it started to be admitted that up to 30% of people with
schizophrenia are not helped by the standard drugs (Meltzer et al., 1989). But
even people who obtain some relief from their symptoms may feel the price of
this relief is just too high. Majorie Wallace’s survey revealed what she called
‘the intolerable choice’ faced by sufferers ‘between being driven by voices and
delusions or drowning in agony and despair’ (Wallace, 1994, pp. 34–35). For
people who suffer from severe and protracted mental disturbance, who may spend
years locked into a frightening private world, cut off from reality and from
those who love them, the drug-induced reduction in brain function may be a
price worth paying. For others the equation is not so clear.
The balance of pros and cons is
particularly difficult to discern in relation to the idea of maintenance
treatment. Even if we put aside the difficulties in interpreting the clinical
trials and assume that the continuation of antipsychotic medication after an
acute episode does reduce the risk of relapse at least somewhat, taking a
drug-centred perspective suggests that this benefit may not be sufficient to
outweigh the day-to-day impairment the drugs produce, coupled with the serious
physical consequences associated with long-term treatment (effects we shall
explore further in Chapter 9). As
Thomas McGlashan questioned ‘Do we free patients from the asylum with D2
blocking agents only to block incentive, engagement with the world and the joie de vivre of every day life?’ (McGlashan, 2006, p.
300).
Despite the lack of well-designed
trials, guidelines continue to recommend that people should continue to receive
antipsychotic medication for 1–2 years after their symptoms have subsided
(National Collaborating Centre for Mental Health, 2010). Although it may be
difficult to distinguish who has recovered spontaneously, and who may have
residual symptoms that the drugs are effectively suppressing and that might
resurface if the treatment was stopped, a drug-centred view would suggest that
antipsychotics should be used for the shortest possible period, if they cannot be
avoided, and reduced gradually as soon as the individual shows signs of
recovery. Only after several episodes of psychotic disturbance or when episodes
involve dangerous behaviour would the possible benefits of long-term treatment
outweigh their adverse effects. If on-going use of antipsychotics is felt to be
unavoidable, we must keep in mind the loss of self this treatment can involve.
Peter Wescott poignantly expressed the patient’s dilemma when he lamented ‘In
losing my periods of madness, I have had to pay with my soul and the price of
health seems twice as high as Everest’ (Wescott, 1979, p. 989).
Chemical Cosh: Antipsychotics and Chemical
Restraint
The most controversial use of antipsychotic drugs is
when they are forcibly given to people to control and subdue agitated,
aggressive and threatening behaviour that occurs in medical and psychiatric
settings. They have been used in this way since their introduction, when they
started to replace the use of older sedatives like barbiturates, and since the
1960s antipsychotics of one sort or another have been the principle agents
recommended for the purpose of chemical restraint, or ‘rapid tranquillisation’
as it has come to be called. Haloperidol is the anti psychotic most closely
associated with this situation, and it can be given alone or in combination
with others sorts of drugs, most commonly a benzodiazepine. The related drug
droperidol, launched in 1980 and withdrawn in 2001 owing to safety concerns,
was also popular for behavioural control, and in 1990 an injectable preparation
known as Clopixol Acuphase was introduced, whose use soon became one of the
staple techniques of emergency sedation in psychiatry.
This use of antipsychotics as
chemical restraints has long been a subject of intense criticism by many who
have been its victims. Psychologist Rufus May, who was admitted to hospital
with a psychotic episode when he was 18 years old, described the ‘humiliating’
and ‘degrading’ experience of being pinned down by five or six nurses, having
his trousers pulled down and being injected in the buttock with drugs that left
him feeling drowsy and groggy for days afterwards (May, 2001). Recipients also
perceive the procedure as punitive and unnecessary, and patient-centred
organisations all over Europe and the USA have repeatedly protested against the
practice of ‘forced drugging’.1
Until recent years, the use of
antipsychotics for behavioural control was so ubiquitous that most people
admitted to psychiatric facilities were prescribed injectable haloperidol ‘just
in case’. Since concerns about haloperidol’s
dangerous and occasionally lethal effects on the heart were publicised in 2007
(Food and Drug Administration, 2007), a wider range of agents is now recommended,
including the antihistamine drug promethazine. The sole use of benzodiazepines,
such as lorazepam, which have long been employed alongside antipsychotics, is
also encouraged (Taylor et al., 2009). Haloperidol is still widely used,
however, and Clopixol Acuphase continues to be given when other measures fail.
It was used in almost a fifth of patients in secure psychiatric facilities in
one recent survey (Brown et al., 2010).
Despite the fact that there is now a
body of literature and research devoted to techniques of ‘rapid
tranquillisation’, the coercive nature of the practice is rarely acknowledged.
Most reviews and guidelines present the activity within a therapeutic framework
and studiously avoid discussing the ethics of the situation or examining the
pharmacological mechanisms that render antipsychotics suitable agents of
chemical restraint. The practice is constructed as a diagnosis-driven activity,
whose purpose is to treat an underlying disorder, rather than to modify
unwanted behaviour. Consensus guidelines on the management of ‘behavioural
emergencies’ produced by a panel of experts from the USA in 2001, for example,
presented emergency sedation for people with mental disorders (as opposed to
those with physical diseases like delirium or substance intoxication) as an
intervention that should be tailored to the suspected diagnosis.
Recommendations for ‘medication to treat agitation that appears to be due to a
primary psychiatric disturbance depend on the provisional diagnosis’ the report
stated (Allen et al., 2001, p. 16), before setting out different options for
emergency sedation in a range of disorders, including schizophrenia, mania,
psychotic depression and post-traumatic stress disorder (PTSD). The panel
explicitly rejected the notion that drugs were used for the purposes of control
or restraint. ‘The panel did not endorse the concept of “chemical restraint”’,
the report stated, continuing that instead it favoured ‘the idea that
medications are treatments for target behaviours in behavioural emergencies’
(Allen et al., 2001, p. 4).
Other experts have distinguished
between the management of aggressive or challenging behaviour when it is
exhibited by someone undergoing a psychotic episode, and situations involving
people who are not psychotic or have other diagnoses. The UK’s National
Institute for Health and Clinical Excellence (NICE) review of the ‘short-term
management of disturbed/violent behaviour’ published in 2005 recommended the
use of an antipsychotic like haloperidol or olanzapine with or without a
benzodiazepine ‘when behavioural disturbance occurs
in the context of psychosis’ and a benzodiazepine alone in other circumstances
(National Institute for Health and Clinical Excellence, 2005, p. 100). The
American Association for Emergency Psychiatry’s wide-ranging review of
emergency treatment euphemistically named ‘Best Practices in the Evaluation and
Treatment of Agitation’ published in 2012, made the same distinction,
explaining that ‘for psychosis driven agitation...antipsychotics are preferred
over benzodiazepines because they address the underlying psychosis’ (Wilson et
al., 2012, p. 30). Although the distinction implies that the use of drugs to
modify behaviour is not always a therapeutic activity, the fact that the
majority of attention is devoted to the management of people diagnosed with
psychosis or schizophrenia means the issue of forced drugging remains firmly
within the medical arena, immune from the considerations that would apply if
its coercive nature were fully acknowledged. In this way, modern practices can
be presented as distinct from the murky history of chaining up lunatics or
knocking out mental patients with a chemical cosh (Schleifer, 2011).
It was the ascendance of the
disease-centred theory of antipsychotic action that allowed the practice of
chemical restraint to be rebranded as a medical treatment, and the belief that
the forcible administration of these drugs represented a therapeutic activity
in its own right ensured that antipsychotics remained at the heart of emergency
procedures for many decades, even though other options, such as promethazine
and the benzodiazepines, have long been available. Just as adoption of the
disease-centred model of drug action drew the curtain on the modifications of
mental experience and behaviour that the drugs produce on a day-to-day basis,
so it foreclosed objective discussion about the safest, most effective and
least obnoxious method of responding to extreme agitation and aggression.
The Early History of Restraint2
Methods of restraint have been employed for at least as
long as mankind has been able to describe disturbed or unwanted behaviour. The
use of chains, shackles and fetters is documented in chronicles by Aulus Cornelius
Celsus (25 BC–50 AD) (Soreff and Bazemore, 2006), and is found in descriptions
of the management of people who were considered mad in early modern Britain
(Rushton, 1988). Although well-known nineteenth-century psychiatrists tried to
introduce humanitarian reforms, with Phillippe Pinel in France famously
removing patients’ chains, and John Connolley in England opening the doors of the Middlesex asylum, physical restraint
remained a central feature of the asylum regime well into the twentieth
century. In the memoir of his madness published in 1840, the English aristocrat
John Perceval described how he had been tied down to a bed for almost 9 months
during his time at the Brislington asylum near Bristol (Perceval, 1961).
Straight-jackets, introduced in the late eighteenth century and regarded as
kinder than chains, continued to be used in some English and American hospitals
until the 1950s, and seclusion was frequently employed to isolate and contain
disturbed individuals (Alty and Mason, 1994). Sedative drugs were used with
increasing frequency from the second half of the nineteenth century, including
opiates, bromides, chloral hydrate and paraldehyde, which were ‘welcomed for
controlling severely disturbed patients’ (Alty and Mason, 1994, p. 28).
Not everyone perceived drugs as
preferable to physical methods, however. Like Thomas Szasz more than half a
century later, Henry Maudsley, eminent psychiatrist and founder of the Maudsley
hospital in London, suggested that drugs were welcomed more because they relieved
the guilt of the custodians, than for their benefit to the patient. ‘It was
deemed better for the patient to let him have the relief and self-respect of
pretty free exercise than to keep him tied up like a mad dog’, he suggested.
But, he continued, ‘it may be doubted whether its coarse bonds did as much harm
as has been done by the finer means of chemical restraint which have been used
to paralyse the brain and to render the patient quiet’ (Maudsley, 1895, pp.
554–555, cited in Braslow, 1997).
Contemporary psychiatric literature
from the first half of the twentieth century had little to say about practices
of control and restraint, however. This reticence is typified by the coverage
provided in the first edition of Henderson and Gillespie’s
Textbook of Psychiatry. Although the authors expressed a commendable
desire to reduce the use of force in psychiatric practice, there is almost no
discussion about how to manage episodes of severely disturbed behaviour. In the
chapter on schizophrenia, for example, it was recommended that ‘episodes of
violence should be treated with explanation, suggestion, analysis or, where
necessary, by hydrotherapy3
or drugs’ (Henderson and Gillespie, 1927, p. 224), but no further details were
provided about which drugs might be employed for this purpose or how they
should be used. The chapter on Manic-Depressive Psychosis
specifically suggested the use of hyoscine hydrobromide, a sedative drug, for
use in emergencies, but no further details were provided.
Pharmaceutical companies, which, by
the 1940s, were busy advertising barbiturates and stimulants for the mass
market of ‘everyday nerves’, also apparently had no
interest in the use of their products for the management of behavioural
problems in people with severe psychiatric disorders prior to the advent of
antipsychotics. In the psychiatric literature, the subject of how to manage
disturbed behaviour continued to receive little attention throughout the 1950s
and 1960s. In 1968 a rare review of the area entitled the Comprehensive
Management of Psychiatric Emergencies made no mention of the use of
drugs or other forms of restraint specifically except to say briefly that
patients responded to ‘supportive treatment such as talking, rest, sedation
and, where indicated, food and fluids’ (Frazier, 1968, p. 7).
It is only when looking at
retrospective accounts written decades later, or speaking to people who recall
the period, that the range of techniques of chemical and physical restraint
employed in the first half of the twentieth century is revealed. Authors of an
article published in 1972 recalled ‘full restraints, maximum security chambers,
frequent ECT and heavy sedation’ as the ‘traditional methods’ of control prior
to the advent of antipsychotics (Fann and Linton, 1972, p. 478). Retired
psychiatrist John Bradley remembered the use of straight-jackets, as well as
barbiturates and paraldehyde, from the time when he worked as a psychiatrist in
the Royal Air Force in the 1950s. The use of intravenous and oral barbiturates
and the sedative drug, paraldehyde, was referred to in later editions of Henderson and Gillespie’s Textbook, supporting the idea
that use of these drugs had been widespread, despite the fact they were not
mentioned in earlier editions (Henderson and Gillespie, 1962).
Chemical Control Comes out of the Shadows
From the 1950s onwards, the therapeutic enthusiasm that
accompanied the introduction of the physical treatment procedures like ECT and
insulin coma therapy encouraged some authors to become more explicit in their
descriptions of emergency sedation, while highlighting that the procedure was a
precursor to proper therapeutic interventions. The authors of the textbook Clinical Psychiatry, who were fervent advocates of physical
treatments, stressed in the first edition, published in 1954, that ‘since the
introduction of insulin and convulsion therapy, the symptomatic use of sedative
drugs in schizophrenia has diminished in importance’. However, they believed it
was ‘still essential to know how to deal with the emergency
of an acute schizophrenic attack in the patient’s home so that he can be
transported into an observation ward or a psychiatric hospital’ (Mayer-Gross et
al., 1954, p. 278, original emphasis). They recommended an intravenous
injection of hyoscine for this purpose if the patient
refused oral medication, but mentioned various other options, including
paraldehyde and barbiturates. They also referred to the use of frequent ECT as
a form of sedation for ‘acutely excited schizophrenics’, which could be applied
once the patient had been brought into hospital (Mayer-Gross et al., 1954, p.
278).
The textbook emphasised that
chemical sedation had the therapeutic purpose of rendering patients amenable to
receive specific, targeted interventions, and, in the first edition, insulin
coma therapy was the principle treatment recommended for people who were
diagnosed with schizophrenia. By the publication of the second edition in 1960,
antipsychotics were said to be equal in effectiveness to insulin coma therapy
as a treatment for schizophrenia (Mayer-Gross et al., 1960). In their
description of the management of emergency situations, the authors still
recommended hyoscine and other older drugs and, therefore, although the last
edition published in 1969 recommended chlorpromazine as the first choice of
drug in this context (Mayer-Gross et al., 1969), antipsychotics were first
introduced as a wholly therapeutic intervention, before their use for
behavioural control was considered.
Judging from pharmaceutical
advertisements of the time, however, antipsychotics started to be used for
purposes of emergency sedation as soon as they came into use. The
pharmaceutical industry, having realised that the treatment of people with
severe mental illness could be a lucrative market, identified behavioural
management as an important component of psychiatric practice. The control of
aggression or agitation started to be listed among the many suggested uses of
antipsychotics in advertisements from the 1950s. In 1957, an early
advertisement for promazine, a close relation of chlorpromazine, made reference
to its use in ‘controlling acute agitation’, among other indications (Promazine
advertisement, 1957). In 1957 an advertisement for the new phenothiazine drug,
Pacatal, included the statement that it could be used for ‘the control of
aggression, impulsiveness and over-activity, particularly in the over-50’s’
(Pacatal advertisement, 1957).
An early advertisement for the
widely used antipsychotic drug Stelazine (trifluoperazine) promoted the drug
primarily for behavioural control by featuring an illustration of a ‘Squirrel
cage’. The caption explained that the cage was used for ‘calming mental
patients (18th Century)’, and the message of the advertisement appears to be
that Stelazine had replaced the need for mechanical restraints like the cage (Figure 8.1) (Stelazine
advertisement, 1959a). Interestingly, the advertisement was subsequently
published in a slightly amended version, with a reference, in small print, to a
preliminary report of a trial suggesting that regular oral medication with
Stelazine was superior to medication given in an emergency or on an occasional
basis (Stelazine advertisement, 1959b). This version of the advertisement could
be interpreted as suggesting that behavioural control was no longer necessary
because of the introduction of effective, therapeutic drug treatment, but, most
likely, it was intended to be ambiguous and capture markets for both long-term
and emergency treatment.
Figure 8.1 Stelazine advertisement
Reproduced
with kind permission of GlaxoSmithKline.
Subsequently,
use of Stelazine for behavioural control was advertised separately from its
long-term use, but, nevertheless, all Stelazine advertisements started to
associate its use specifically with the treatment of people with a diagnosis of
schizophrenia. One advertisement featuring a drawing of a patient being
physically restrained by two male mental health staff suggested that ‘the first
consideration in treating the violently agitated and hostile schizophrenic is
to calm, restore insight, and establish rapport’
(Stelazine advertisement, 1965b, my emphasis) (Figure
8.2). In the 1960s, advertisements
also started to portray emergency drug treatment as having the aim of rendering
the patient fit to receive more lasting, therapeutic interventions.
Advertisements for haloperidol
listed control of aggression among its many uses, and also emphasised its
rapidity of action, a vital requirement for any drug that was to be useful in
an emergency situation. The advertisements also described the effects of the
drug on psychotic symptoms and subsequent outcome, and, by implication
therefore, the utility of haloperidol for the management of aggression was
suggested to be via its therapeutic effects on the underlying condition. A 1965
advertisement, for example, described how ‘Serenace [one of the brand names
under which haloperidol was marketed] quickly controls the psychotic
manifestations of schizophrenia’ (Serenace advertisement, 1965a). Another
advertisement from this year prominently presented in large, bold text a
quotation from a 1961 study describing how ‘A very powerful, restless man,
greatly feared by all the staff for his aggressive outbreaks and
unreliability...became calm and kindly after receiving the preparation [of
haloperidol]. Nowadays he sits with a contented smile and carries out simple
hobby tasks’ (Serenace advertisement, 1965b).
The use of drugs to control
behaviour started to be discussed more frequently in psychiatric journals from
the 1970s onwards, but articles adopted various strategies in order to
emphasise the therapeutic aspects of emergency drug treatment and play down its
coercive function. Many continued to stress that the purpose of emergency
sedation was to make the patient more accessible to other, more specific and
more lasting forms of treatment. A review of the management of ‘acute
behavioural disturbance’ published in 1975, for example, described the aim of
emergency drug treatment as being the initiation of ‘a treatment programme
aimed at returning the patient to being a useful and healthy member of society’
(Freed, 1975, p. 638).
Figure 8.2 Stelazine advertisement
Reproduced
with kind permission of GlaxoSmithKline.
In 1975, a special issue of the US
journal, the Journal of Nervous and Mental Disease,
was dedicated to the management of violence in psychiatric patients. The issue
presented the management of aggression as a diagnosis-driven, therapeutic
activity that should be targeted not at the behaviour itself, but at the
underlying mental disorder (Lion, 1975). Drug treatment was not to be construed
as a ‘paralysing chemical straight jacket’ but as a specific treatment for the
condition that gave rise to the disturbed behaviour in the first place (Monroe,
1975, p. 119). Following an introductory article, the issue was divided up into
papers discussing the use of different types of drugs, each relating to
different diagnostic categories. The paper on the use of antipsychotics
therefore dealt mainly with the treatment of violence in people with
schizophrenia and psychotic disorders, although their use in people with
dementia was also discussed briefly. Antipsychotics were deemed to be an
appropriate treatment for violent behaviour committed by people with
schizophrenia because they constituted a specific treatment, and the reduction
in aggression that occurred was considered to be ‘part of their antipsychotic
properties’. The effects of antipsychotics were deemed to be ‘due to the effect the drug has on the psychosis and
not the aggression itself’ (Lion, 1975, p. 76, 79). The paper on
benzodiazepines mostly described research on the drugs’ effects on hostility
occurring in people diagnosed with anxiety, in whom the drugs were thought to
exert a disease-specific action (Azcarate, 1975). There was also an article on
the use of lithium and anticonvulsants, which proposed that some cases of
aggressive behaviour were, like epileptic fits, caused by abnormal electrical
discharges in the brain, which could be specifically treated by drugs that
lowered the epileptic threshold. In the case of lithium, which is not an anticonvulsant,
it was proposed that there was a reduction of the phenomena in some parallel
but unspecified manner. The author of this article even denied that these drugs
had any sedative or tranquillising properties, even though the well-known
benzodiazepine sedative Librium (chlordiazepoxide) was one of the
‘anticonvulsant’ drugs referred to. The only subjective effect the drugs had,
he claimed, was ‘the relief sensed by the patient in no longer losing control
when he otherwise would’ (Monroe, 1975, p. 125).
A paper published in 1972 on the use
of the antipsychotic drug perphenazine, subtitled ‘The concept of chemical
restraint,’ was unusual for its time in its explicit description of the
mechanism by which antipsychotics control excited and violent behaviour (Fann
and Linton, 1972). The authors described how the ‘drug-induced rigidity’, or
the ‘Parkinsonoid state’, produced by antipsychotics ‘may not be deleterious’
in emergency situations and that antipsychotics ‘offer an excellent alternative
to the physical measures that might otherwise be required in acute situations’
(p. 479). While still emphasising that the purpose of tranquillisation was for
the patient to be rendered able to participate in other therapeutic activities,
the authors suggested that the ‘ideal agent’ for the purpose of chemical
restraint ‘should permit definite control of the patient’s motor activity
without reducing his mentation to the point where he cannot participate in ward
activities’ (p. 479).
They went on to present two case
reports by way of illustration. One concerned a 44-year-old man who was said to
be extremely ‘threatening’ to patients and staff. After administration of
perphenazine, ‘all of his movements became slowed, and though he continued to
make verbal threats, he could no longer carry out physical violence...because
of markedly reduced movements’ (p. 480). The other concerned a 23-year-old man
who was extremely hyperactive, and threatening staff and patients with a pool
cue and pool balls. After taking perphenazine he showed ‘retardation of
hyperactive behaviour within 3 to 4 hours’ and was described as ‘markedly
slowed’, but able to continue to play pool safely (p. 480).
Research on ‘Rapid Tranquillisation’
Forcing drugs on people to curb disturbing and
challenging behaviour is a practice that rightly makes people feel
uncomfortable. In the 1975 special issue of the Journal of
Nervous and Mental Disease one author remarked that if this was the
purpose of emergency sedation, it raised ‘ethical questions as to when (if
ever) it is justified to control behaviour through this type of
chemotherapeutic intervention’ (Monroe, 1975, p. 125). But the rise of the
disease-centred model of drug action, and the idea that antipsychotics work by
rectifying an underlying disease, helped to banish the spectre of the chemical
straight-jacket and kept the genie of social control firmly inside the
psychiatric lantern. Antipsychotics had finally made the practice of forced
drugging respectable, and the control of aggression and disruptive behaviour by
chemical means could be represented as a therapeutic activity that was part of,
or a precursor to, condition-specific, restorative treatment. Neither the
introduction of the drug droperidol into the UK in 1980 nor Clopixol Acuphase
in 1990, both of which were aimed specifically at the market for short-term
sedation, fundamentally altered the mainstream view that the use of drugs to
control behaviour was driven and determined, like all psychiatric activity was
said to be, by the process of diagnosis and the administration of specific
treatment. The fact that in the early 1990s Clopixol Acuphase, a drug rarely
given with anyone’s consent, could be advertised as ‘a harmonious new way to
treat acute psychosis’ demonstrates the success of the endeavour to reconstruct
control and containment as medical treatment (Clopixol Acuphase advertisement,
1990) (Figure 8.3).
Figure 8.3 Clopixol acuphase advertisement
Reproduced
with kind permission of Lundbeck.
As
with other areas, the conviction that antipsychotics represent a
disease-specific treatment for schizophrenia and psychosis meant their use for
behavioural control went unexamined for many years. Only recently have
large-scale studies been conducted that compare different pharmacological
strategies for the management of aggression and disturbed behaviour. The
overall results of seven studies comparing an antipsychotic, mostly
haloperidol, and a benzodiazepine showed no differences in the ability of the
two sorts of drug to produce sedation, reduce aggression and improve behaviour
(Volz et al., 2007). Two large trials conducted in Brazil and India compared a
benzodiazepine with a combination of haloperidol and promethazine, a cheap and
popular mixture in these countries.4 The Brazilian study found no
difference between the haloperidol–promethazine combination and the effects of
the benzodiazepine midazolam in achieving rapid tranquillisation, and there was
no difference in the proportion of people in both groups who remained in
hospital 2 weeks later; in other words, the use of antipsychotics for emergency
sedation did not hasten improvement or discharge (TREC Collaborative group,
2003). The Indian study used lorazepam as the comparator and found that results
were the same after 4 hours, but that the haloperidol–promethazine combination
acted more rapidly, possibly owing to the fact that a relatively large 10-mg
dose of haloperidol was used, compared with 5 mg in the Brazilian study. There
were no differences in the proportion of people who required additional
medication or physical restraint, however, and having a diagnosis of psychosis
or schizophrenia did not affect how people responded to the different
medications (Alexander et al., 2004). Although few side effects were reported
in these particular studies, possibly because of the use of promethazine, in
general a higher prevalence of movement abnormalities is associated with the
use of antipsychotic drugs for rapid tranquillisation (Gillies et al., 2005).
There was one case of potentially life-threatening respiratory depression with
midazolam in the Brazilian study, and one epileptic seizure occurred in the
haloperidol–promethazine-treated group (TREC Collaborative group, 2003).
There is no doubt that antipsychotic
drugs like haloperidol can effectively tranquillise people and eliminate or
reduce aggressive behaviour. They are a staple of veterinary medicine, where
they are also used for purposes of control and restraint, and where their
ability to ‘decrease motor function and reduce awareness of external stimuli’
is well recognised (Bishop, 2005, p. 292). They are not necessarily the safest
or most benign drugs to use in this situation, however. Although there have
been few instances of cardiac complications in
randomised trials of emergency sedation, other data suggest that antipsychotics
are associated with sudden cardiac death (Ray et al., 2009), and one study
found that the risk of having a cardiac arrest or a serious irregularity of
heart rhythm (ventricular arrhythmia) with haloperidol was comparable to that
with the antipsychotic thioridazine, whose use was restricted in 2001 owing to
concern about its cardiac toxicity (Hennessy et al., 2002). The Maudsley
guidelines now recommend that everyone who is commenced on haloperidol should
receive an electrocardiogram (ECG), but this is rarely feasible in emergency
situations (Taylor et al., 2009). Benzodiazepines appear to be just as
effective in reducing disruptive or aggressive behaviour, and there is no
evidence that giving antipsychotics ultimately improves outcome in people with
a diagnosis of psychosis. Respiratory depression is a concern with the use of
benzodiazepines, however, especially midazolam.
Although the ideal agent has yet to
be found, overall the evidence does not support the idea that using
antipsychotics in the control of aggressive or disruptive behaviour is superior
to other pharmacological options for people diagnosed with psychosis or
schizophrenia, or for anyone else. Apart from the potential dangers of
antipsychotics, they are strongly disliked by recipients, but research has been
slow to identify and evaluate alternative strategies. The popularity of
antipsychotics for emergency sedation has been sustained by the perception that
they are therapeutic agents, which has allowed the dangerous and unpleasant
features of the drug-induced state they produce to be overlooked.
As Henry Maudsley suggested, we also
need to ask whether chemical restraint is really superior to other strategies
for the management of disturbed behaviour, such as mechanical restraints or
safely modified seclusion rooms. Since forcing someone to take a drug infringes
the integrity of the body and changes the person both physically and mentally,
it can be viewed as a more profound violation of an individual’s autonomy than
putting them in a straight-jacket or a padded cell. Little effort has been paid
to establishing patients’ views, but one German study conducted in the 1980s
found that most patients who had experienced some form of behavioural control
clearly preferred the use of seclusion or physical restraint to being forced to
take medication. Moreover, patients’ opinions were established when they were
in remission from the mental disturbance that had led to their confinement, so
their views were not clouded by psychotic symptoms or emotional arousal
(Schmeid and Ernst, 1983).
We have to ask, therefore, whether
chemical sedation became the norm not because it benefitted patients, but because
it suited the interests of other people, and of
institutions. Chemical restraint is easier for hospital staff, who no longer
have to wrestle patients into restraining devices or keep watch on them in
isolation rooms, for example. It may be less distressing for relatives and
friends not to have to witness the presence of people in manacles or cells, and
the public too may prefer not to have to acknowledge that we have the same
problems with managing disturbed behaviour as the Victorians had. Hospital staff
have the right to be concerned about their vulnerability to violence in
emergency departments and psychiatric facilities (Hansen, 1996), and they have
a legitimate interest in finding ways to reduce incidents of aggression. We
cannot properly evaluate the different options, however, unless we clearly
acknowledge that the purpose of the intervention is to control unwanted
behaviour, not to treat an illness.
Long-Term Behaviour Control
Although the claim that the forcible administration of
drugs in emergency situations is a therapeutic activity that is hard to
sustain, there is a more legitimate debate about the nature of antipsychotic
treatment when it is given to someone against their wishes on a continuing
basis. Psychiatric critics like Thomas Szasz have argued that all non-consensual drug ‘treatment’ should be considered a
form of social control and that it consists of the drug-induced modification of
behaviour that others find unacceptable. Mainstream opinion, however, regards
such activity as medical treatment that is given to improve the patient’s
‘health’, and this is the view that is enshrined in mental health law.
We saw in Chapter 7 how antipsychotic drugs can help to suppress
otherwise irresistible psychotic experiences and by doing so can sometimes
unlock people from the internal world that had engulfed them. Although some
people ultimately welcome these effects, many people find they do not
compensate for the state of demotivation and loss of interest the drugs produce.
Like Peter Wescott, people sometimes talk of undergoing a personality change
while taking the drugs, of becoming someone less interesting and less
distinctive than they were before. Moreover, people who are deemed to have
severe mental disorders often do not agree that there is anything wrong with
their actions, even when their psychotic symptoms have subsided. Where people
dislike the effects of the drug more than their symptoms, and where people do
not wish to change their behaviour, it is difficult to see how it can be argued
that ‘treatment’ is being imposed in their own interests.
Up until recent times, drugs could
only be forced on people against their will while they were in a psychiatric
institution or hospital. Once someone had recovered
sufficiently to be discharged, they were free agents again and could stop
taking their medication if they wished to do so, at least in theory. Research
led by Manchester sociologist Anne Rogers showed that even in these
circumstances, however, many people felt compelled to continue with their drug
treatment when they wished to stop it, even though they were under no legal
obligation to do so. The patients who were interviewed revealed that they were
cajoled and pestered to take medication by mental health staff, and that they
feared they would be taken back to hospital if they refused it. The researchers
concluded that some patients had internalised the control that can be exercised
through the Mental Health Act, and effectively policed their own medication
intake, no longer believing they had any real choice in the matter (Rogers et
al., 1998).
Many countries have now introduced
legislation that enables people with mental health problems to be legally
forced to continue treatment—usually drug treatment—after they are formally
discharged from hospital. Community treatment orders were introduced into
England and Wales in 2008, and, at first, the government anticipated they would
only be applied to only a small fraction of patients. The orders were intended
to be applied to the sort of people who had frequent admissions to hospital,
sometimes referred to as ‘revolving door’ patients, and it was estimated that
only around 450 orders would be applied in the first year. In reality 2134
orders were made in the first 5 months after the legislation came into force in
November 2008. As of the end of March 2011, 10,071 orders had been made, with
only 2210 of these being discharged. After taking account of patients who had
been recalled to hospital, as well as discharges, 4291 patients remained
subject to these powers in the community (NHS Information Centre for Health and
Social Care, 2011).
The increasing numbers of people
subject to enforced treatment in the community has not resulted in lower rates
of compulsory hospital admission, however, despite initial hopes. Numbers of
people being forcibly detained in psychiatric inpatient units also rose in the
period leading up to 2011, with almost 50,000 compulsory admissions in the
period 2010 to 2011 compared with only 46,500 in the 2006 to 2007 statistical
year (NHS Information Centre for Health and Social Care, 2011). It appears,
therefore, that compulsory community treatment is but one aspect of an
increasingly coercive approach to mental health problems. Far from becoming a
more voluntaristic enterprise, coercion still ‘runs deep and wide’ within
modern systems of mental health care ‘creating an unavoidable yet strangely
silent climate of intimidation and acquiescence’ (Kirk et al., 2013, p. 304).
The introduction of Community
Treatment Orders extends the reach of chemical control far beyond the walls of
institutions. The legislation enables mental health services, for the first
time in history, to enforce drug treatment on people who have recovered from
their mental breakdown, who manifest no further symptoms and who are able to
function perfectly well in their day-to-day lives. All that is needed to
justify the application of an order is the idea that there is a chance that the
individual will relapse at some point in the future. Although the threat of
being dragged back to hospital hung over patients in the past, they were
technically free to make their own choices about medication after they had been
properly discharged from hospital, unless they had committed a serious crime
and were subject to government supervision.4
Community treatment orders mean that many people who do not wish to take drugs
for the rest of their lives are no longer able to make that decision.
Yet, as we saw in Chapter 6, drug treatment does not eliminate the risk
of relapse, it only reduces it, and, in fact, we are not even certain that this
is the case owing to the confounding effects of antipsychotic withdrawal in
studies of long-term treatment. Even if we assume that antipsychotic treatment
does reduce the overall risk of having a relapse, however, this does not mean
that everyone benefits from, or requires, long-term treatment. Even after
several episodes the course of psychotic conditions is variable, and people may
recover, but there is, in any case, no requirement in the law to restrict
community treatment orders to people who have had many past episodes. They can
be and are, in my experience, sometimes applied to people who have had little
previous contact with psychiatric services. Enforcing drug treatment on people
who will derive little or no benefit from it produces substantial costs for the
individual who has to endure years of dangerous and unpleasant drug-induced
stultification, and for society, which has to pay for the consequences of
long-term antipsychotic treatment on people’s physical health. It is also not
clear why patients should not be able to make the choice to lead a drug-free
life, accepting the increased risk of occasional episodes of mental illness
which that decision might entail. This seems to be a rational and reasonable
course of action, and unless there is good reason to think that the individual
might commit a serious crime during an episode of mental disturbance, there can
be no justification for the enforcement of drug treatment based on
considerations of social order. It is only by misconstruing behaviour
modification as ‘treatment’ that denying people this choice can be justified.
The fact that society has endorsed
compulsory community psychiatric treatment may have little to do with
‘treating’ or helping the patient, however. There are economic and social
reasons why society does not want people to relapse. It is cheaper to maintain
patients in the community with chemical suppression
and disability payments than to have to admit them to hospital, and it is less
disturbing and more comfortable for the community for people to be subdued by
drug treatment than subject to vagaries of mental disorder. Since the final
closure of the old asylums in the 1980s and 1990s, there has been a continuing
drive to reduce the costly process of treating people in hospital. ‘Home
treatment’ teams were set up in the UK from the late 1990s in order to prevent
people being admitted to hospital, and their main function has become
persuading and cajoling people to take medication. There is also immense
pressure to discharge people who are admitted to inpatient units as soon as
possible, and community treatment orders are increasingly used to ensure that
people who have not yet recovered from an episode of psychosis can be
discharged early and continue to receive drug treatment. Although being allowed
to go home may be preferable to the patient, as well as the hospital, they are then
subject to on-going restrictions which may never be lifted, as it is
notoriously difficult to challenge a community treatment order. If the patient
remains well, this is taken as evidence that the order is working, but if the
patient is not doing well, this can also be used as an argument that continuing
restrictions are necessary.
A Conspiracy of Silence
Accounts of the drug-induced state produced by
antipsychotic drugs set out in Chapter 7,
and the one rare account of their use as a ‘chemical restraint’, suggest they
are the ultimate chemical straight-jacket. Not only do they decrease arousal,
like other sedatives, antipsychotics such as haloperidol restrict and inhibit
physical movement itself, and all antipsychotic drugs produce an emotional
state of indifference or placidity. Yet there is almost no reference to these
qualities in the psychiatric literature, and the use of antipsychotics for
rapid tranquillisation is justified instead by the idea that they are an
effective and specific treatment for psychosis or schizophrenia. Even where the
drastic alteration of behaviour produced by antipsychotics is undeniable, as in
their use for emergency sedation, the disease-centred model of drug action has
ensured that their psychoactive effects remain invisible.
In their book, Mad
Science, American academic David Cohen and colleagues described how
decreasing attention is paid to the mental and behavioural alterations produced
by drugs throughout their course from the laboratory to the clinic. Drug
companies test the effects of drugs on animal behaviour early on in their
development, but the results of such tests are rarely published. Following
this, studies on volunteers, known as phase 1
studies, are required to be performed as part of the licensing process, and
some of these involve basic psychological tests, such as reaction times. Again,
however, these studies are not frequently published and, when they are, only
minimal data on selected physiological measures and test scores are presented.
Phase 2 studies consist of randomised trials conducted to assess the efficacy
of a drug in reducing symptoms of a particular condition compared to placebo.
By focusing on the outcome of the diagnosed disorder, they provide no direct
evidence about the alterations produced by the drug or drugs involved. Phase 3
studies consist of long-term safety monitoring that takes place after a drug
has been licensed. The book concluded that ‘the determination of equivalent or
symmetrical psychoactive effects in human subjects as are definitely seen in
animals is unsystematic at best, and in most cases of drugs intended for
psychiatric use haphazard and possibly non existent’ (Kirk et al., 2013, p.
257).
The report by the Medicines and
Healthcare products Regulatory Agency, which formed the basis for the approval
of risperidone in the UK, illustrates the banishment of psychoactive effects
from serious consideration. The only statement about the subjective effects of
the drug reads: ‘Risperidone induced dose proportional CNS [central nervous
system] effects such as tiredness, sedation, lethargy, fatigue, headache,
dizziness, disorientation, impaired concentration, and migraine’ (MHRA, 1992).
No information on the drugs’ effects on mood, attention, memory, clarity of thought,
mental speed, emotional responsiveness, motivation, creativity or ‘any other
emotional or intellectual quality’ (Kirk et al., 2013, p. 258) was presented,
and no further details were provided about the effects described.
It seems extraordinary in the
twenty-first century that people should be forced to take drugs which
profoundly alter their bodily functions, their emotional life, their behaviour
and personality, and that the institutions that instigate and enforce this
‘treatment’ have no interest in the range of effects the drugs produce and how
they make people feel. The misrepresentation of the mental and behavioural
modifications produced by psychoactive substances as the targeted reversal of
underlying diseases has produced a scientific blind spot that means the full
pharmacological effects of psychiatric medications are not properly
investigated or appreciated. This ignorance means that the psychiatric
community has been historically slow to recognise the serious medical
complication that its drugs can produce, as we saw with the emergence of
tardive dyskinesia. In the next chapter we shall see how it has been equally
tardy in recognising other adverse effects, including those produced by the
latest miracle cures, the atypical antipsychotics.
Old and New Drug-Induced Problems
As well as understanding the immediate effects produced
by antipsychotic drugs and how these might impact on psychological symptoms and
challenging behaviour, a drug-centred understanding focuses the spotlight back
on the physical alterations that can result from taking these drugs, especially
over long periods. Looking at how evidence of the serious complications of
antipsychotic use emerged also reveals how modern psychiatry, sometimes, but
not always, guided by the pharmaceutical industry, has constructed an agenda
that enables it to avoid having to confront the harm its treatments can
produce. As we saw with the story of tardive dyskinesia, tactics include
blaming the underlying condition and minimising, obscuring or simply ignoring
the evidence.
Antipsychotics and Brain Size
A startling example of these strategies can be seen in
how research on brain volume has been handled. Despite the fact that evidence
implicating antipsychotic use in the smaller brain size observed in people
diagnosed with schizophrenia and other severe mental disorders has been
available for decades, only in recent years have these findings been given any
serious consideration. The significance of these effects is still barely
discussed, however, and there has been no discernible impact on the use of
these drugs in practice.
The occurrence of tardive dyskinesia
confirms that antipsychotics can irreversibly alter the way the brain
functions, and, as we saw in Chapter 6,
tardive dyskinesia is not simply an isolated abnormality of movement but is
associated with more generalised intellectual impairment. Further evidence for
the detrimental effects of antipsychotic drugs started to be revealed with the
introduction of sophisticated techniques for
visualising the brain, beginning with computed tomography (CT) scans, which
became available in the 1970s, followed by the technique called magnetic
resonance imaging (MRI). Most CT and MRI studies suggest that people diagnosed
with long-term schizophrenia have smaller brains and larger brain cavities, or
ventricles, than a comparison group, usually consisting of staff from the
hospital where the study was conducted. The majority of these studies involved
people who had received many years of antipsychotic treatment, but there was a
presumption that schizophrenia was the cause of any abnormal findings and a
prejudice against any evidence that pointed towards the effects of drugs.
Two studies illustrate this
tendency. The first is a well-known study conducted using CT technology in the
1980s by the research group at Northwick park hospital. The study revealed that
long-term hospital patients diagnosed with schizophrenia had smaller brains and
larger ventricles than patients with ‘neurotic’ conditions (depression,
anxiety, etc.). There was no difference between the brains of people with
schizophrenia and long-term patients diagnosed with manic depression (bipolar
disorder), however (Owens et al., 1985). As patients with severe manic
depression are also likely to be treated with antipsychotics, but those with
neurotic disorder are not, this finding itself points to the possible role of
drug treatment. In addition to this the strongest predictor of reduced brain
volume in this study was the presence of drug-induced movement abnormalities,
as measured by two separate scales developed for this purpose. The authors,
however, assumed the abnormal movements were a symptom of schizophrenia. Based
on a small analysis involving eight patients with schizophrenia, who had never
taken antipsychotic drugs and were found not to differ in brain volume from
eight fairly similar patients who had, they concluded that there was no
relationship between drug treatment and brain volume. The small numbers of
patients in this analysis meant only the grossest of differences would have
been detected, however.
A more recent study, using MRI,
found a similar overlap between patients diagnosed with schizophrenia and those
diagnosed with ‘bi polar disorder’. In people diagnosed with bipolar disorder,
who were the focus of the paper, brain volume reduction was more likely to
occur in people on higher doses of antipsychotic drugs (p
= 0.01), but, again, the authors did not consider the possibility that the
drugs directly affect brain size, suggesting instead that antipsychotic drug
use was only a ‘proxy for a more severe illness’ (Arnone et al., 2009, p. 197).
This bias is repeated in
longitudinal studies in which changes in brain size are tracked over time. One
of the first of these longitudinal studies was
conducted by psychiatrist Lynn DeLisi and colleagues based in SUNY University,
New York. The study involved 50 patients who had experienced their first
episode of a psychosis or schizophrenia-like condition, and a control group
consisting of people without any known mental health problems. After 4 years
the study revealed that the brain’s cerebral hemispheres shrank by an average
of 1.4% per year in the group with psychosis compared with 0.7% in the control
group. With little consideration of the possible effects of drug treatment, the
authors concluded that the study had demonstrated that a ‘continual active
abnormal process is occurring in the brain after the first episode of
psychosis’ (p. 136), and the paper was entitled ‘Schizophrenia as a chronic
active brain process: a study of progressive brain structural change subsequent
to the onset of schizophrenia’ (DeLisi et al., 1997).
The authors of a similar study,
conducted in the Netherlands, examined the role of drug treatment more directly.
The study involved 34 people with a first psychotic episode who were starting
drug treatment and 36 ‘carefully matched’ controls. The patients with psychosis
showed a decline in the total amount of grey matter (nerve cell bodies1)
in the brain of 2.9% over 1 year compared with the control group who showed a
slight increase in grey matter volume (1.1%), and the
difference was highly statistically significant (p
< 0.001). There was a strong correlation between the cumulative dose of
antipsychotic medication a patient had received over the follow-up year and the
amount of reduction of brain grey matter (r = 0.45, df 31, p
= 0.009) (Cahn et al., 2002). Despite finding this clear and strong association
between brain shrinkage and antipsychotic use in the 1-year follow-up of this
cohort of patients, reports of 5- and 10-year follow-ups have, surprisingly,
not analysed drug treatment. When I queried this with the lead researchers from
the group they did not provide an explanation nor did they indicate any
intention to publish this information. When I requested the data in order to do
it myself, they stopped responding to my enquiries.
Until recently, the effects of drug
treatment continued to be dismissed, with researchers still attributing brain
deficits to schizophrenia, citing as evidence Owens’ eight non-drug-exposed
patients, and the older air encephalography studies (Torrey, 2002). These
studies, conducted in the middle of the twentieth century, involved injecting
air into the brain cavities or ventricles to provide radiographic images of the
brain, and some of these studies reported that the brains of long-term mental
hospital patients were smaller than might be expected, and their ventricles
larger (Lemke, 1936; Huber, 1957). Most studies did not include a control or
comparison group, however, and many participants were
likely to have endured intensive ECT or insulin coma therapy, procedures which
were associated with enlarged ventricles in some studies (Storey, 1966). The
one study which involved a comparison between mental hospital patients and a
group of people with no known psychiatric disorder found no differences
(Storey, 1966) and nor did one which compared patients with different
psychiatric diagnoses (Peltonen, 1962).
In 2005 a large study was published
which started to fracture the preceding consensus. The study was funded by Eli
Lilly as a randomised comparison of olanzapine and haloperidol treatment in a
group of patients experiencing their first episode of psychosis, and it was set
up partly to examine whether the drugs reversed what was at this time assumed
to be an underlying, disease-related process of brain degeneration. As well as
161 patients, a group of 58 healthy controls was recruited, and all
participants had MRI scans at the beginning of the study, and then at 12 weeks
and 1 year later. The chief investigator was Jeffrey Lieberman, one of the
principle figures in academic psychiatry in the USA, and the results of the
study were published in the Archives of General Psychiatry,
the leading American psychiatric journal, in 2005. Considering that this is the
largest imaging study ever conducted with people with a first episode of
psychosis by a large margin, it received surprisingly little publicity,
however.
The study revealed that people
treated with haloperidol showed statistically significant shrinkage of the
brain’s grey matter after just 12 weeks compared with the control group, and at
1 year patients on both haloperidol and olanzapine showed reduced overall grey
matter volume, with reductions apparent in most brain areas. However, although
the reduction in brain volume in patients on olanzapine compared with controls
reached conventional levels of statistical significance (p
= 0.03), it did not reach the stricter criteria the study imposed to guard
against chance findings. Although controlling for random positive outcomes is a
worthy thing to do in other circumstances, when looking for potentially
important adverse effects of drugs it is preferable to be less, not more,
stringent. In this case, using the more restrictive criteria allowed the
authors to present the study as if it were only haloperidol that was associated
with brain volume reduction. They concluded that olanzapine, but not
haloperidol, can prevent an underlying process of brain shrinkage and only
briefly did they concede that the findings might indicate, alternatively, that
the drugs themselves reduce brain size, although only haloperidol was mentioned
in this respect (Lieberman et al., 2005).
Encouraged by the slight superiority
demonstrated by olanzapine, Eli Lilly then funded a study using macaque
monkeys, hoping that this would confirm that whereas the older drugs like
haloperidol might diminish brain size, olanzapine did not. Unfortunately for
Lilly the study provided the most incontrovertible evidence yet that both sorts
of drugs cause brain shrinkage. The animals were treated with doses of
olanzapine or haloperidol that were carefully tailored to be equivalent to the
doses used in human patients, and compared with monkeys who were treated with a
‘sham’ pellet containing no drug. After being treated for between 17 and 27
months the animals were sacrificed and their brains examined. The brains of the
monkeys that had been treated with haloperidol were 8.1% lighter than those who
had not had drug treatment, and the brains of olanzapine-treated monkeys were
9.6% lighter. The difference between the drug-treated monkeys and
non-drug-treated animals was statistically significant (p
= 0.04), and the differences were present in all parts of the brain, but were
most marked in the cerebral hemispheres—the seat of intelligence
(Dorph-Petersen et al., 2005).2
As a consequence of this study, some
researchers started to look at the evidence for a relationship between drug
treatment and structural brain changes in human subjects. At last the issue of
whether antipsychotics affected brain structure became a question that could be
asked, even if people remained hesitant about answering it clearly. Most
reviews of the area followed the lead of the Eli Lilly-funded study, suggesting
that although the older drugs were associated with brain shrinkage, ‘atypical
antipsychotics might ameliorate structural changes caused by the disease
process underlying schizophrenia’ (Scherk and Falkai, 2006, p. 145). Other
papers admitted that the drugs had effects on certain circumscribed brain
regions, but played down the idea that they might have global effects (Navari
and Dazzan, 2009; Smieskova et al., 2009). Much of the literature, however,
continued the previous tendency of ignoring evidence of drug-induced effects or
suggesting that drug treatment might reverse underlying changes (Hulshoff Pol and
Kahn, 2008).
In 2010 I published a paper with a
professor of anatomy, Jonathan Leo, which concluded, in typically hesitant
academic language, that ‘some evidence points towards the possibility that
antispsychotics reduce the volume of brain matter and increase the fluid or
ventricular space’. We even suggested that ‘antipsychotics may contribute to
the genesis of some of the abnormalities usually associated with schizophrenia’
(Moncrieff and Leo, 2010). It was possible to publish this review because the editor
of the journal, psychiatrist Robin Murray, had started to harbour suspicions
that antipsychotics diminish brain size, and he published
the paper despite opposition from most of the five referees it was sent to.
In 2011, the American group led by
Nancy Andreasen, a leading researcher in biological psychiatry and one-time
editor of the American Journal of Psychiatry,
published the latest results of its long-term brain imaging study. These
revealed a strong and statistically significant association between the dose of
antipsychotic that someone had received over their lifetime and the amount of
brain shrinkage detected. In contrast, the severity of symptoms and use of
illicit drugs were not strongly associated with brain changes. The authors did
not flinch from concluding that antipsychotics have a ‘subtle but measurable
influence on brain tissue loss over time’ (Ho et al., 2011, p. 128). In their
next paper, however, the researchers played down these findings, claiming that
the process of schizophrenia itself was responsible for brain shrinkage, and
barely mentioned the link with antipsychotic treatment demonstrated in the
previous paper. The second paper claimed to have parcelled off the effects of
drug treatment so that the remaining changes in brain volume could be
attributed to the underlying disease (Andreasen et al., 2011). However, the
analysis presented in the first paper consisted of a linear analysis of dose
levels, which only detects effects that occur in a neatly incremental fashion,
and it cannot be assumed to have captured the full effects of drugs. Only a
comparison with a non-drug-treated group could reliably discount the impact of
drug treatment.
A further animal study was published
in the same year that corroborated the earlier macaque monkey study. Rats
administered haloperidol or olanzapine in doses equivalent to those given to
human patients showed 6–8% greater reductions in brain volume than rats given
placebo, particularly in the cerebral cortex. The effects were seen after only
8 weeks, and they were apparent using brain scans and on post-mortem
examination (Vernon et al., 2011). It now seems virtually indisputable that
antipsychotics shrink the brain.
It is not necessarily the case,
however, that a subtle reduction in brain size will inevitably affect mental
functioning. The volume of the brain can vary considerably on a day-to-day
basis, according to levels of hydration, for example. Several longitudinal and
cross-sectional studies have found evidence of an association between impaired performance
on mental tests and brain volume changes, however, in people diagnosed with
schizophrenia (Sullivan et al., 1996; Gur et al., 1998, 1999; Ho et al., 2003).
A recent study of patients with bipolar disorder also found a significant
correlation between a reduction in intelligence quotient (IQ) and grey matter
density loss in the temporal lobe in patients and controls (Moorhead et al.,
2007). In contrast, an early study by Lynn DeLisi found no association between
tests of cognitive function and brain volume loss (DeLisi et al., 1991).
Although it continues to be asserted
that people with schizophrenia have abnormal brains irrespective of the effects
of drug treatment, direct evidence for this claim relies on a small number of
studies that have scanned patients with psychosis or schizophrenia prior to
them receiving antipsychotic drugs. Despite the fact that these studies have
failed to control for effects of intelligence, which is correlated with brain
volume (Deary et al., 2010), and likely to differ between patients and controls
(Woodberry et al., 2008), most have not reported the sort of global differences
in brain size observed between medicated patients and controls. Some have
detected differences in various local brain structures, but there is little
consistency across studies in the area identified. The largest study with
‘drug-naive’ patients, for example, which was conducted in China and involved
68 patients and 68 controls, did not report any differences in overall brain
matter, grey matter or ventricle volume, but detected some differences in areas
of the right temporal lobe of the brain (Lui et al., 2009). This area was not
found to be different from controls in three previous studies with
antipsychotic-naive subjects, however (Salgado-Pineda et al., 2003; Jayakumar
et al., 2005; Chua et al., 2007). The largest study to detect a difference in
global brain grey matter and cerebro-spinal fluid volume involved 51 patients
in its latest publication (Venkatasubramanian et al., 2008).
The most revealing of these studies
are the ones that involved people who had been thought to be suffering from
schizophrenia for some time. One of these involved 31 chronically ill,
untreated patients in India. Overall, there were no statistically significant
differences between patients and controls in the volume of both left and right
cerebral hemispheres (which were a little larger in
patients compared with controls), and left and right ventricular spaces
(McCreadie et al., 2002).3
The study was not reported as negative, however. Instead, the authors focused
on some differences between controls and subgroups of patients with and without
abnormal movements. Two other studies have been published involving patients who,
as a group, had been considered mentally unwell for an average of 4–5 years,
and neither reported any difference in global brain volumes (Buchsbaum et al.,
1996; Ichimiya et al., 2001). Hence, the only three studies of patients whose
duration of illness is comparable with patients who have taken antipsychotic
drug treatment for some time report no major differences between patients and
controls in the overall volume of the brain matter or brain cavities.
Tardive Dyskinesia and ‘Atypical’
Antipsychotics
Although the significance of tardive dyskinesia has
been minimised, as we saw in Chapter 5,
it is still regarded as an undesirable condition that should be avoided if
possible, and it was hoped and predicted that the new atypical antipsychotics
would dispense with the problem. Early studies of people taking atypicals, many
of which were conducted by the drug companies, suggested that overall the rate
at which people developed tardive dyskinesia was about one quarter of the rate
in people on the older drugs (Woods et al., 2010). Clozapine was thought to be
particularly safe in this respect, and switching people on the older drugs to
clozapine or other atypicals was recommended as a treatment for tardive
dyskinesia (Tamminga et al., 1994; Spivak et al., 1997a).
A systematic review published in
2008 summarised the results of studies of tardive dyskinesia in people taking
first- and second-generation antipsychotic drugs published since 2004, which
had involved more than 28,000 participants in total (Correll and Schenk, 2008).
The rate of new cases of tardive dyskinesia among people taking the older
antipsychotics was 5.5% per year compared with 4.0% for people taking the newer
drugs, but as people on the older drugs were older, and age is known to
increase vulnerability to tardive dyskinesia, the difference between the two
types of drugs may have been overstated in these data. Another study conducted
by researchers at Yale University followed up 352 patients who were confirmed
as being free from tardive dyskinesia. The incidence
of new cases over 4 years was around 20%, and there was little difference in
rates of onset between people taking the old generation antipsychotics and
those on atypicals. Moreover, people who were prescribed an old and a new
antipsychotic concurrently were almost twice as likely to develop tardive
dyskinesia as people taking the older drugs alone. When the authors compared
the results to an older study conducted at the same location using the same
methods, they found that the prevalence rate of tardive dyskinesia in the 1980s
was 33% compared with 32% in the 2000s (Woods et al., 2010).
Tardive Dementia and Psychosis
Equally worrying, but more difficult to pin down for
certain, is the idea that, as well as the movement disorder and accompanying
mental decline that constitute tardive dyskinesia, long-term treatment with
antipsychotics can lead to general intellectual impairment, behaviour and
personality changes, and worsening of psychotic symptoms, even in the absence
of tardive dyskinesia.
Evidence on the connection between
antipsychotics and intellectual impairment is complex and difficult to
interpret, and, again, little research has been dedicated to elucidating the
impact of the drugs in comparison to the mountains of studies concerning the
putative effects of schizophrenia. Often it is only when new drugs become the
centre of attention that the adverse effects of the older ones are
acknowledged.
The mental functioning of people who
are acutely psychotic improves as their symptoms improve. This may indicate
that drug treatment that suppresses psychotic symptoms improves people’s
ability to sit down and undertake a complex procedure like a test, but it may
also reflect what is called a ‘practice effect’. This is when subjects perform
better the second time they do a test because of having done it before. Claims
were made that atypicals were superior to the older antipsychotics in their
ability to improve the psychological performance of people diagnosed with
schizophrenia, but recent studies that have used more moderate doses of the
older drugs suggest there is little difference (Keefe et al., 2006, 2007).
However, as we saw in Chapter 8,
there is ample evidence that antipsychotics impair mental functioning in
animals and volunteers. Moreover, the mental capacity of older people with
long-term schizophrenia correlates negatively with the dose of antipsychotic
drugs they are taking (Torniainen et al., 2012), and although this may relate
to many factors, such as the severity of symptoms, it is consistent with the
other evidence that the drugs can impair mental
abilities. People with Alzheimer’s disease who are treated with an
antipsychotic for example—whether of the new or old variety—show greater
cognitive decline than those who are not (Schneider et al., 2005). In one study
the intellectual deterioration due to antipsychotic treatment was equivalent to
the 1 year’s worth of dementia-induced decline (Vigen et al., 2011).
Some research also suggests that
long-term antipsychotic use may provoke a characteristic change in personality
or behaviour, and that it may worsen the symptoms of psychosis. In the 1980s
and 1990s a behavioural syndrome was described called ‘tardive dysmentia’,
which was thought to occur with and without the presence of tardive dyskinesia.
A paper published in 1983 described the characteristic features as ‘unstable
mood, loud speech, and inappropriately close approach to the examiner’ (Wilson
et al., 1983, p. 18), and a later report summarised the features as consisting
of excessive emotional reactivity, enhanced responsiveness to environmental
stimuli and a reduced awareness of abnormal movements of tardive dyskinesia if
these are present (Myslobodsky, 1993). Features such as heightened tension,
aggression and a background mood of mild elation were also noted to occur. The
researchers suggested that the syndrome was a consequence of organic brain damage
induced by long-term antipsychotic treatment, and they pointed to similarities
between the characteristics of ‘tardive dysmentia’ and behaviours associated
with brain injury, especially injuries that affect the frontal lobe of the
brain. The reduced awareness of abnormal movements is well recognised in
tardive dyskinesia and reminiscent of the denial of disability that occurs in
other severe brain conditions such as stroke (when it is usually associated
with damage to a specific brain region—the parietal non-dominant lobe) and
generalised brain diseases, such as neurosyphilis and Korsakoff’s disease
(Breggin, 1997).
We have already come across evidence
that long-term antipsychotic treatment might provoke a psychotic episode either
after withdrawal or during the course of long-term treatment. This issue is
difficult to investigate because, without starting volunteers on years of
antipsychotic treatment, it is impossible to know for certain whether the
worsening of psychosis that can occur in later years in some patients who were
previously stable, is due to the drug treatment or merely the natural course of
their underlying condition. Unlike physical brain changes, it is difficult to
investigate in animals because they do not experience psychosis, although behavioural
changes in animals subjected to years of antipsychotic exposure might be
informative, given that this could not be done in healthy humans. Obviously, it
is of the utmost importance to know whether the drug
treatment of psychosis ultimately makes the problem worse in some people.
Evidence that long-term
antipsychotic treatment might provoke mental decline, personality change and
psychotic deterioration should be, but rarely is, a major consideration when
starting people on antipsychotic drugs in the first place, and in decisions
about whether to continue them or not. For people who recover from their
psychotic episodes, these prospects, even if not proven at present, must be a
factor in weighing up the pros and cons of continuing to take antipsychotic
treatment on a long-term basis. For people who suffer from enduring psychotic
symptoms that the drugs help to suppress, there may be no other option.
Metabolic Effects
All antipsychotics cause people and animals to put on
weight, although some have a stronger effect than others. In the 1990s it
became apparent that some of the newer antipsychotics cause people to put on
even more weight than usual, sometimes becoming massively and morbidly obese.
The effect was first apparent in relation to clozapine, with clozapine-treated
patients putting on weight at an average of 7.7 kg in 6 months in one study
(Lamberti et al., 1992) and 3 kg over 3 months in another (John et al., 1995).
Indications that patients on clozapine were vulnerable to developing diabetes also
started to accumulate, including case reports of people who had developed the
severe and life-threatening complication of this condition known as diabetic
keto-acidosis (Kamran et al., 1994; Koval et al., 1994). By the late 1990s, it
was apparent that other atypical antipsychotics had similar effects, especially
olanzapine. In one 6-month study patients on olanzapine gained 4 kg (McQuade et
al., 2004). Epidemiological data suggested that atypial antipsychotics in
general increased the risk of developing diabetes by a third (Sernyak et al.,
2002). There were reports of diabetic keto-acidosis occurring in people started
on olanzapine (Goldstein et al., 1999; Lindenmayer and Patel, 1999) and
laboratory studies suggesting olanzapine’s effects on the body’s regulation of
glucose were more marked than those of other antipsychotics (Newcomer et al.,
2002).
Eli Lilly’s attempts to play down
the metabolic effects of olanzapine were revealed in an article in the New York Times in 2006, based on the content of confidential
documents that were obtained in the course of legal proceedings brought by
patients who claimed that they had developed diabetes or other medical
complications as a consequence of taking olanzapine.
The article suggested that even as Eli Lilly continued to claim that scientific
evidence had not established that olanzapine causes diabetes, its scientific
employees had been concerned about the implications of ‘olanzapine-associated
weight gain and possible hyperglycaemia’ since 1999 (Berenson, 2006). In this
year Lilly established an ‘executive steering committee’ to manage the issues
associated with these adverse effects, and, in 2001, an ‘action team for quick
medical response to customers with Zyprexa safety questions’ was proposed (Eli
Lilly, 2001a, cited in Spielmans, 2009). The New York Times
article claimed that sales people were instructed not to introduce the subject
of weight gain and diabetes in presentations on Zyprexa, however, unless it was
raised by the audience (Berenson, 2006).
Eli Lilly employed another
time-honoured tactic that has not been fully exposed, however—blaming the
condition. The leaked Zyprexa documents referred to evidence that diabetes is
more common in people with mental disorders compared with the general
population, and suggested that psychiatric illness might itself be linked to
the condition (Eli Lilly, undated). In the early years of the twenty-first
century Lilly paid doctors to do ‘educational’ presentations on the link
between schizophrenia and diabetes, some of which I attended. While most
academics were writing about the metabolic effects produced by antipsychotic
drugs, Eli Lilly employees and consultants produced articles describing
schizophrenia as a ‘risk factor’ for diabetes (Dinan, 2004b; Holt et al., 2005).
The company also supported research that reported that there was abnormal
glucose metabolism in people with psychosis before starting drug treatment
(Ryan et al., 2003), although these findings were later refuted by a larger
study published in 2008 (Sengupta et al., 2008).
In October 2003 Eli Lilly sponsored
a ‘consensus meeting’ of academics led by Ted Dinan, professor of psychiatry in
Dublin, Ireland, and the meeting resulted in the publication of a supplement of
the British Journal of Psychiatry entitled
‘Schizophrenia and diabetes’. In his introduction to the issue, Dinan barely
mentioned the role of antipsychotic drugs except to say that two articles in
the supplement challenged the idea of a link between antipsychotics and
diabetes (Dinan, 2004a). One of the opening papers reviewed historical
evidence, which was claimed to demonstrate that ‘diabetes and disturbed
carbohydrate metabolism may be an integral part of schizophrenia’, although the
author admitted that the evidence was anecdotal and inconclusive (Kohen, 2004).
Three articles in the supplement, two of which were authored or co-authored by
Eli Lilly employees and the other by an academic with financial ties to Lilly, claimed to show that the data suggesting a
relationship between antipsychotic treatment and diabetes were flawed, and that
data from randomised controlled trials did not indicate a link (Bushe and Holt,
2004; Bushe and Leonard, 2004; Haddad, 2004). As the authors of one of the
papers admitted, however, clinical trials are far too short to detect a
condition like diabetes, which usually takes years to develop (Bushe and
Leonard, 2004).
The concluding statement of the
conference reveals its real aims. Entitled a ‘Consensus summary’, the statement
conceded that the ‘available evidence supports an association between
antipsychotics and impaired glucose metabolism’ (Expert Group, 2004, p. S112).
However, it continued, the evidence ‘does not establish causality’ (p. S113).
The statement suggested that clozapine might have a stronger relation than
other antipsychotic drugs with diabetes and incipient diabetes, but did not
mention olanzapine. It was concluded that severe mental illness itself, and the
associated unhealthy lifestyle, likely played a more significant role in the
high prevalence of diabetes in people with mental illness than antipsychotic
drugs (Expert Group, 2004).
Despite these efforts, by 2007 Eli
Lilly had paid out $1.2 billion to settle claims made by people who contended
that they had developed diabetes or other medical complications through taking
olanzapine (Berenson, 2007). The debate about diabetes and schizophrenia took
place largely within the academic literature and at professional gatherings,
and so this aspect of Eli Lilly’s strategy has not been fully appreciated.
Psychiatrists had set a precedent
for this tactic with tardive dyskinesia. Just as the gravity of this
neurological condition had been minimised, the metabolic effects of the
atypical antipsychotics were temporarily obscured by focusing on a possible
link with schizophrenia itself, thus minimising the potential backlash that may
have occurred as the impact of these drug-induced effects became increasingly
apparent. As evidence accumulated that the drugs induce metabolic disturbance
in volunteers (Sacher et al., 2008; Albaugh et al, 2011) and people with other
diagnoses (Chien et al., 2010; Andrade et al., 2011), it became increasingly
difficult to sustain the argument, and in 2008 David Healy and colleagues
reported that none of the people treated in hospital for a psychotic disorder
between 1894 and 1924 had diabetes on admission, and none were diagnosed with
the condition throughout 15 years of follow up. Moreover, no one hospitalised
with psychosis between 1994 and 2006 had diabetes at the time of admission, but
they developed diabetes at twice the rate of the general population over the
next few years (Le Noury et al., 2008). The idea of an intrinsic link between diabetes and schizophrenia faded out of the psychiatric
consciousness from around 2005, its plausibility exhausted. Its purposes were
already served by this time, however, as Zyprexa had become one of the world’s
biggest ever selling drugs.
Current data suggest that all
antipsychotics, except, perhaps, aripiprazole (Abilify) have a tendency to make
people put on weight, an effect that increases with dose, and that it is
greatest with olanzapine and clozapine (Rummel-Kluge et al., 2010; Correll,
2011). Most atypicals make people more vulnerable to developing diabetes, but
again clozapine, olanzapine and, to a lesser extent risperidone and quetiapine,
confer the greatest excess risk (Ramaswamy et al., 2006; Yood et al., 2009). It
also appears that interference with the body’s mechanisms for sugar and
carbohydrate regulation is part of a wider picture of metabolic disruption that
antipsychotic drugs induce. They affect fat metabolism as well, for example,
leading to increased levels of harmful fats like cholesterol (Rummel-Kluge et
al., 2010; Smith et al., 2010; Chaggar et al., 2011). Moreover, studies involving
healthy volunteers have demonstrated that the metabolic abnormalities develop
rapidly, after short periods of drug treatment and long before weight changes
appear (Albaugh et al., 2011).
Children appear to be particularly
susceptible to the metabolic complications of the new antipsychotics. They gain
more weight and are even more likely to develop diabetes in relation to the
norms for their age than adults taking these drugs. Again, clozapine and
olanzapine are the worst culprits (De Hert et al., 2011; Pringsheim et al.,
2011). A meta-analysis of data from randomised controlled trials found that
children started on olanzapine gained an average of 6–7 kg within 8 weeks of
starting treatment, and children on risperidone gained 1.7 kg in 12 weeks (Pringsheim
et al., 2011). An analysis of a large amount of data from children taking
atypical antipsychotics, mostly for behaviour problems and ‘mood disorders’
rather than schizophrenia or psychosis, found that rates of diabetes were more
than three times higher than in children who were not prescribed medication,
and more than twice as high as children who were taking antidepressant drugs
(Andrade et al., 2011).
Heart Disease and Death
The metabolic effects of antipsychotics are significant
not only for the direct discomfort they produce, but because they are
recognised risk factors for heart disease, stroke and premature death. People
who have what is sometimes called ‘metabolic syndrome’, for example, which is defined as increased weight and high blood pressure
combined with abnormalities in blood glucose and fat concentrations, have twice
the risk of developing coronary heart disease over 10 years compared with
people without this syndrome (Correll et al., 2006).
As well as disrupting metabolic
processes linked with atherosclerotic heart disease (the silting up of the
hearts’ blood vessels), antipsychotics are also known to interfere with the
electrical conductivity of heart muscle, causing prolongation of the ‘QT’
interval on the electrocardiogram (ECG). This disturbance is known to be
associated with irregular heart rhythms, which can lead to sudden death.
Studies of people who die suddenly owing to heart disease or malfunction show
that people taking antipsychotics have a 2–3-fold higher risk than people who
are not taking these drugs, taking into account other relevant factors (Straus
et al., 2004; Ray et al, 2001, 2009). The increased risk is the same for people
diagnosed with schizophrenia as it is for people who are prescribed the drugs
for other diagnoses like dementia (Straus et al., 2004). In one study the rate
of ‘sudden cardiac death’ was found to be similar in users of atypical
antipsychotics compared with users of the older antipsychotics, and for all
types of drug, except clozapine, there was a strong relationship with dose (Ray
et al., 2009) (Figure 9.1).
People on the highest doses of atypical antipsychotics, for example, were
almost three times more likely to die in this way than non-users, whereas those
on the lowest doses were only one and a half times more likely to die (Ray et
al., 2009). A dose-related trend of this sort is regarded as one of the
strongest indicators of a true causal link in medical research.
Further evidence of the detrimental
effects of antipsychotic drugs on the cardiovascular system comes from studies
of their use in people with dementia. In the late 1990s and early 2000s several
trials were conducted examining the effects of atypical antipsychotics in
controlling aggression and disturbed behaviour in people with dementia, many of
whom were residents in nursing homes. Most of these studies were never
published, but data provided by the manufacturers to the drug regulatory
agencies in Canada, the USA and Europe indicated that people in these trials
who were randomised to drug treatment rather than placebo had an increased risk
of having a stroke or a transient ischaemic attack (a TIA),4
and were more likely to die during treatment. The early data were derived from
trials of risperidone and then olanzapine, but by 2005 there were data from
trials of quetiapine and ariprirazole indicating the same trends (Mittal et
al., 2011).
Subsequent reviews have confirmed
these findings, although most of the data remain unpublished. An analysis of
data from 16 studies, only five of which had been
published in full in peer-reviewed journals, found an increased risk of stroke
in people taking atypical antipsychotics, in dementia compared with placebo, and
an increased risk of death. Moreover, the drugs produced only a slight
improvement in aggressive behaviour, with greater intellectual deterioration in
people taking the drugs compared with those on placebo (Schneider et al., 2005,
2006). Only one randomised study included patients who were prescribed the
older antipsychotics. This consisted of a withdrawal trial in which people who
had already been started on antipsychotics were randomised to two groups, one
of which continued on their anti psychotic treatment, and one of which had the
drugs gradually withdrawn and replaced by placebo. Patients who continued
taking antipsychotics of whatever variety showed increased mortality compared
with those who were withdrawn. The study also revealed that the excess mortality
in those taking antipsychotics widened with time, so that 12 months after the
study began the difference in survival between those taking antipsychotics and
those who were switched to placebo was 70% versus 77%, but 24 months after the
study began only 46% of those taking antipsychotics were still alive compared
with 71% of those who were not taking them. At 3 years the difference was 30%
versus 59% (Ballard et al., 2009).
Figure 9.1 Incidence rate of sudden death in people taking
antipsychotic drugs compared with people not taking themFrom New England Journal of Medicine, Ray et al.
(2009) Atypical antipsychotic drugs and the risk of sudden cardiac death. 260,
225–35. Copyright ©
2009 Massachusetts Medical Society, reprinted with permission from Massachusetts
Medical Society.
It has been known for a long time
that people with severe mental conditions like schizophrenia have a shorter
life-span than the general population. The majority of their excess mortality
is attributable to heart disease (Osby et al., 2000), and the role of drug treatment
in hastening death in this group of people has been the subject of much debate.
Undoubtedly, factors such as high rates of smoking and lack of exercise
contribute to the problem, but evidence also implicates antipsychotic drugs.
Authors of a recent review on the subject concluded that, despite the dearth of
research, there was enough evidence to suggest that long-term exposure to
antipsychotics is likely to increase the risk of dying prematurely (Weinmann et
al., 2009).
Several studies have found that the
death rate among people diagnosed with severe mental disorders is proportional
to the dose, or to the number, of antipsychotic drugs that patients take
(Waddington et al., 1998; Bralet et al., 2000; Joukamaa et al., 2006). A
Finnish study revealed that each additional antipsychotic drug taken increased
the risk of premature death by two and a quarter times compared with the
general population after taking account of some other risk factors, such as
smoking (Joukamaa et al., 2006). Another study from Finland, however, reported
that people with schizophrenia who had not taken
antipsychotics had a higher death rate than those who used this medication on a
long-term basis. The authors suggested that this surprising result might
reflect the ability of drug treatment to reduce the risk of suicide in people
diagnosed with schizophrenia (Tiihonen et al., 2009), but the paper has been
the focus of much debate. An extensive critique of the study argued that the
results were impossible to interpret because a large proportion of deaths were
excluded from the analysis because they had occurred in hospital, where data on
prescribing were incomplete (De Hert et al., 2010). Moreover, the analysis was
complex and opaque, with no figures provided for the actual numbers of deaths
in the different groups of patients. The critics also pointed out that although
the study reported that a large proportion of patients with schizophrenia had
never used antipsychotic drugs, findings from the same research group indicated
that data on medication use were highly unreliable. Between
49% and 96% of patients who were classified as not taking antipsychotics were,
in fact, taking them, for at least some of the time (Tiihonen et al., 2006;
Haukka et al., 2008).
There is no doubt, therefore, that
antipsychotic drugs have dangerous effects. There is substantial evidence that
both the old and the new generation of antipsychotics cause irreversible
neurological damage in the form of tardive dyskinesia, shrink the size of the
brain, cause people to put on weight, disrupt the body’s metabolic processes,
heighten the risk of heart disease and stroke, and cause premature death, at
least in some groups of people. Although the appropriate response to such toxic
substances would be to reserve them for the most extreme and irresolvable
circumstances, recent trends have been for antipsychotics to be prescribed to
increasing numbers of people for increasingly vague and varied problems. This
movement has been driven by claims that antipsychotics are good for the brain,
but, as we have seen, there is considerable evidence that they are bad for it,
and for the body. This is not to say that for someone trapped in the throes of
severe mental derangement the drugs might not be the lesser of two evils, but
an evil they are nonetheless.
The First Tentacles: The ‘Early
Intervention in Psychosis’ Movement
When the new atypical antipsychotics were brought to
the market in the 1990s, the first objective from a marketing perspective was
to replace the use of the older generation of antipsychotics drugs. Alongside
this takeover bid came the desire to expand the market for the drug treatment
of schizophrenia to its limits, and in this aspiration was nurtured the ‘Early
Intervention in Psychosis’ movement. The movement was so successful that it
ushered in a completely different ‘ethical paradigm’ in the treatment of people
with psychosis (McGlashan, 2005), overturning the previous consensus that
symptoms should be given a chance to resolve spontaneously before antipsychotic
treatment was started. Instead, it came to be accepted that young people who
were experiencing a psychotic episode, or just some psychotic symptoms, or
occasionally some vague problems that may or may not be psychotic symptoms,
should be started on antipsychotic medication as soon as possible. It was
widely believed that early treatment was needed to arrest the progress of a
degenerative brain disease, and it became increasingly difficult for patients
and their advocates to argue against the use of medication. The balance of
considerations was firmly tilted in favour of drug treatment, despite the
emerging evidence of its serious and life-threatening consequences.
Treating people early on in the
course of their mental condition has been a longstanding obsession of the
psychiatric profession and its sponsors. Historically, the idea of ‘early
intervention’ was strongly linked to arguments about the medical nature of
mental disturbance—the idea that ‘mental illness is a disease like any other’.
As insanity was increasingly claimed to arise from a disease of the body or
brain, medical intervention was presented as something that could modify the
underlying course of the disease, rather than acting as a band-aid that merely suppressed on-going symptoms. Early treatment was a
natural corollary of this view, as it is generally thought desirable to arrest
a disease process as early as possible. In more recent times, American
psychiatrist Jeffrey Lieberman, who became one of the most prominent advocates
of early intervention, proposed that the rapid initiation of antipsychotic
drugs in people with schizophrenia or psychosis could ‘ameliorate the
underlying pathophysiology, forestalling the progression of the disease and
preventing morbidity from increasing’ (Lieberman, 1999a, p. 732). The
enthusiasm for early intervention is thus another manifestation of the desire
to have specific treatments that target underlying diseases, in other words for
a disease-centred model of psychiatric treatment.
The last two decades have witnessed
fevered activity in support of the idea of early intervention in incipient
psychosis or schizophrenia. Dedicated services have emerged in many parts of
the world, publications have proliferated, an international association for
early intervention has been formed and a specialist journal was launched in
2007. In 2005, early intervention was declared to be an idea ‘whose time has
come’ that had captured the imagination of clinicians, researchers, families
and politicians (McGorry et al., 2005, p. S1). While the recent Early
Intervention movement has various drivers, including the commendable desire to
offer more support to families, it has been strongly associated with the rise
in popularity of the atypical antipsychotics, and the companies that developed
these drugs have provided financial support for discussions, conferences,
projects and academic organisations concerned with Early Intervention in
Psychosis. Critics have emerged, however, who have pointed to the dangers of
drawing more and more people into the net of long-term drug treatment (Warner,
2005; Bosanac et al., 2010).
The History of Early Intervention
According to historian Andrew Scull, ‘throughout the
19th century, it was an article of faith among those who dealt with lunatics
that the deranged were more readily restored in the early stages of the
disorder, so that delay in help could prove disastrous’ (Scull, 1993, p. 163).
One of the decisive arguments in bringing about the country-wide asylum
building programme in the UK in the mid-nineteenth century was the idea that
properly-run asylums would encourage people to seek help for themselves or
their disturbed relatives before they descended into a hopeless and
irremediable condition. Later on in the century, when it became apparent that the
asylums were silted up with people with chronic,
intractable difficulties, and more people died in the asylum than recovered,
psychiatrists continued to blame the fact that people did not come to them
early enough (Scull, 1993, p. 275).
In the early twentieth century there
was increasing interest in public health, and renewed optimism about the
possibility of preventing various physical diseases and social problems through
early treatment or intervention. The famous Maudsley hospital, set up in London
in 1907, was designed specifically to cater for early and acute cases of mental
disturbance, and had special exemption from the requirement of the 1890 Lunacy
Act for patients to be ‘certified’ insane prior to admission, in order to avoid
delays in treatment. The Macmillan Commission, which reviewed mental health
legislation in England in the early 1920s, memorably declared that ‘there is no
clear demarcation between mental and physical illness’ and emphasised the
importance of ‘prevention and treatment’. The Commission aspired to design a
new parliamentary Act that would make it possible to provide treatment for
mental illness ‘from the very earliest moment of the appearance of its
symptoms’ (Royal Commission, 1926; cited in Unsworth, 1987, p. 115). These concerns
continued to motivate changes in mental health legislation up until the 1959
English Mental Health Act, which, by finally abolishing the role of the
magistrate in admission proceedings, was designed to minimise legal bureaucracy
and provide more rapid access to treatment (Jones, 1972).
In the nineteenth century early
intervention formed one of the principle arguments for the erection of the
asylums. In the late twentieth century it was used, among other arguments, to
justify the policy of deinstitutionalisation and the replacement of the asylums
with community care. The asylums were regarded as outdated and stigmatising,
and general hospitals were proclaimed to be the best place to care for people
with mental health problems. ‘Community care’, as visualised by the government
of the UK, would provide early intervention and preventive work within the
community which would be possible because the looming fear of the asylum would
no longer discourage people from obtaining psychiatric help (Boardman, 2005).
The modern early intervention
movement has also been associated with an optimistic view of the possibilities
of psychiatric treatment. Proponents of the concept wanted to offer people who
suffered from psychotic episodes and their families ‘a more positive future’
(McGorry et al., 2005, p. S1). The services that started to be set up in the
1990s were designed to provide tailored support that would be more acceptable
and less stigmatising than intervention from generic mental health teams, with the hope that this would entice more young
people into mental health services, and relieve the burden on families
struggling to cope with a young person’s worrying behaviour. This motivation
was combined, however, with the questionable and contentious proposition that psychosis
is a ‘biologically toxic’ process that causes progressive damage to the brain
unless averted by selective drug therapy (Wyatt, 1991, p. 347).
In 1991 American psychiatrist Robert
Wyatt published a lengthy review of evidence for the impact of drug treatment
on the outcome of schizophrenia, concluding that ‘early intervention with neuro
leptics in first break schizophrenia patients increases the likelihood of an
improved long-term course’ (Wyatt, 1991, p. 325). None of the numerous studies
Wyatt described provided evidence to support this claim, however, and many
contradicted it. He cited the Chestnut Lodge study, for example, which showed
that in this specialist psychotherapeutic institution people with a short
duration of symptoms prior to admission (less than 1 year) had a good long-term
outcome despite not being treated with
antipsychotics, compared with those who had a longer duration of pre-admission
symptoms (more than 1 year), who had worse outcomes even though they did receive antipsychotics (Fenton and McGlashan, 1987).
The only study he cited on early drug treatment was small, excluded people with
a poor outcome and was never fully published (Anzia et al., 1988).
Nevertheless, Wyatt concluded that the evidence he had mustered suggested there
might be ‘something about being psychotic that is toxic to the individual
beyond the immediate psychotic episode’, which, he proposed, could be reversed
or prevented by the early initiation of drug treatment (Wyatt, 1991, p. 347).
Despite its deficiencies, Wyatt’s
paper had a seminal influence on the burgeoning early intervention movement and
was repeatedly referred to as a ‘landmark’ paper (McGorry et al., 2005, p. S2).
Wyatt himself became a major player in the International Early Psychosis
Association and after his death his colleagues demonstrated their respect by
dedicating the third conference of the Association to his memory.
In 1992 a group led by Jeffrey
Lieberman followed up 70 patients with a first psychotic episode and found like
the Chestnut Lodge study, that those whose symptoms had started a longer while
before admission had a worse outcome. They concluded that ‘duration of
psychosis before treatment could be an important predictor of outcome in first
episode schizophrenia. Acute psychotic symptoms could reflect an active morbid
process, which if not ameliorated by neuroleptic drug treatment, may result in
lasting morbidity’ (Loebel et al., 1992, p. 1183). Despite the fact that the
prevailing view of the time was that schizophrenia
was a ‘neurodevelopmental disorder’, which was present, although not manifest,
from birth, the importance of shortening the ‘duration of untreated psychosis’
soon became an article of faith, spawning an enormous amount of discussion and
research.
By the mid-late 1990s editorials and
reviews routinely emphasised the association between duration of untreated
psychosis and outcome, and the importance of starting drug treatment early
(Wyatt, 1995; Birchwood et al., 1997; Sheitman et al, 1997; Lieberman, 1999b).
Lieberman increasingly referred to psychosis itself as a ‘degenerative process’
that was operative when symptoms were present, but could be curtailed by drug
treatment (Lieberman, 1999a, 1999b). He also started to suggest that delaying
drug treatment could reduce its effectiveness, so that people who were not
treated early would be more likely to become ‘treatment resistant’ (Lieberman
et al., 1998). It was proposed that there might be a ‘critical period’ of
around 5 years when the course of the disorder is most amenable to intervention
(Birchwood et al., 1997). In 2005, reviews published in the top two American
psychiatric journals concluded that shortening the duration of untreated
psychosis by early initiation of drug treatment improved outcome and was an
important objective for clinical care (Marshall et al., 2005; Perkins et al.,
2005).
There is another simple explanation
for Lieberman’s original findings, however. It has long been recognised that
people who are subsequently diagnosed with schizophrenia, whose symptoms
develop slowly over the course of many months, have a worse outlook than those
in whom symptoms occur more rapidly. People in whom symptoms appear to be
precipitated by a stressful event usually have a particularly good outcome. It
used to be believed that people who had a long and gradual decline before their
first episode of frank symptoms had an intrinsically more severe and
chronically debilitating condition. The 1988 edition of the Companion
to Psychiatric Studies textbook, for example, stated that there was
‘firm agreement on the characteristics of the initial illness’ (Kendell and
Zealey, 1988, p. 327) that predict outcome, and that one of these was the
rapidity of onset of symptoms. Although the association between mode of onset
and the subsequent nature of the disorder was widely acknowledged in the early
1990s, it appeared to be forgotten as the concept of ‘duration of untreated
psychosis’ emerged. Moreover, studies that did not detect an association
between ‘duration of untreated psychosis’ and outcome, or found that the
association could be explained by other factors, were ignored (Ho et al.,
2000). The idea that the fundamental course of a severe mental condition could be modified by treatment appeared to be
irresistible, just as it had been in the past.
The ‘Neuroprotection’ Hypothesis
‘Duration of untreated psychosis’ was, at best,
however, only an indirect manifestation of the hypothesis that psychosis is a
toxic brain condition that can be arrested by drug treatment. The hypothesis
needed fleshing out and the early intervention enthusiasts were keen to
identify neuropathological evidence to support the theory. Findings that were
thought to indicate the underlying degenerative nature of psychosis and the
recuperative action of drug treatment were consequently drawn together to
construct a narrative about how antipsychotic drugs could exert
‘neuroprotective’ effects. Like other aspects of the anti psychotic story,
however, the evidence was more complex, and much of it pointed in the opposite direction,
suggesting that antipsychotics were actually neurotoxic.
Most post-mortem studies of brains
of people diagnosed with schizophrenia have failed to find any trace of the
characteristic changes that occur in people with well-accepted degenerative disorders
of the brain, such as Alzheimer’s disease (Harrison, 1999). In any case, the
studies have mostly included people exposed to years of drug treatment and
other potential brain insults like electro-convulsive therapy (ECT). The
principle evidence for the idea that schizophrenia is a neurodegenerative
process was therefore said to be the subtle diminution of brain matter that had
been demonstrated to occur in the magnetic resonance imaging (MRI) studies
described in Chapter 9. As we saw,
the possibility that the changes might be related to drug treatment was barely
considered for many years. By 2007, when researchers had to acknowledge that
antipsychotic treatment might account for some of the loss of brain tissue
observed in these studies, it was still being claimed that the atypical
antipsychotics, at least, ‘exert a potential neuroprotective effect’ (Jarskog
et al., 2007b, p. 57).
By this time a vast amount of
research had been conducted into the effects of various psychiatric drugs on
aspects of nerve cell survival, and antidepressants, lithium and antipsychotics
were all claimed to have neuroprotective properties (Duman et al., 1997; Manji
et al., 1999; Hunsberger et al., 2009). Atypical antipsychotics were said to
enhance the production of neurotrophic factors (chemicals responsible for
promoting nerve cell growth), prevent nerve cell death through various
mechanisms and increase the connections between nerve cells (Jarskog et al.,
2007a, p. 53). Once again, however, the evidence had been
selected and interpreted according to a set of assumptions that the effects of
drugs were protective and innocuous. It was possible, as it was with the
imaging studies, to tell quite a different story.
It is generally accepted that
lithium is the drug with the strongest claim to have neuroprotective properties
based on imaging studies where, in contrast to the situation with
antipsychotics, lithium treatment is sometimes associated with increased brain
volume. Acute lithium treatment enlarges animal brains, but this is thought to
reflect the water-retaining properties of lithium (Phatak et al., 2006) and
consequent effects on the imaging process (Cousins et al., 2013). A review of
45 studies of people suffering from bipolar disorder, or manic depression,
found that the majority of these did not detect an effect of lithium on brain
volume, and where such an effect was reported, it only occurred in certain
areas and was often marginal (Hafeman et al., 2012). Moreover, if lithium did
increase brain volume, it is not clear that this would be any more desirable
than the global reduction of brain volume associated with antipsychotics. The
older antipsychotics have been shown to enlarge the volume of the basal ganglia
in the brain, for example (Chakos et al., 1995), and some, though not all,
microscopic studies of post-mortem specimens have found evidence of nerve cell
damage and degeneration in this area (Christensen et al., 1970; Jellinger,
1977).
Other evidence cited to support the
idea that lithium has a neuroprotective action includes a number of studies
suggesting that lithium increases concentrations of a protein involved in
preventing nerve cell death, known as beta-cell lymphoma 2 protein, or Bcl-2
(Manji et al., 2000). A study that found that olanzapine and clozapine had
similar effects is commonly cited as evidence for the neuroprotective effects
of atypical antipsychotics (Bai et al., 2004). But an increase in
concentrations of Bcl-2 is characteristic of neurodegenerative disorders like
Alzheimer’s disease, where it is presumed to indicate a compensatory mechanism
employed by the brain to try and counterbalance the underlying disease-related
nerve cell loss and damage. So, if lithium and antipsychotics are associated
with increased concentrations of Bcl-2, this might just as well indicate that
they are causing damage to brain cells as protecting
them. In any case, a further study found that antipsychotic treatment had no
effect on Bcl-2 levels in rats, but it did, to the authors’ surprise, increase the
activity of a substance called caspase-3—one of the principle agents
responsible for nerve cell death (Jarskog et al., 2007a).
Many studies have demonstrated that
antipsychotics are toxic to brain cells (Dean, 2006). Numerous laboratory-based
investigations show that haloperidol kills and
damages nerve cell specimens (Behl et al., 1995; Post et al., 1998; Sagara,
1998). Indeed, some antipsychotics are so effective at killing nerve cells that
their use as anti-brain tumour agents has been explored (Gil-Ad et al., 2001).
There is less research on the effects of atypical antipsychotics, and some
studies suggest lower degrees of toxicity than are seen with haloperidol. One
study found that risperidone and sulpiride had no discernible effect on cell
death, for example, but clozapine produced even higher rates of cell death than
haloperidol (Gil-Ad et al., 2001). Another found that risperidone had weaker
effects than haloperidol, but could induce similar levels of nerve cell death
at higher doses (Ukai et al., 2004).
With a few exceptions, psychiatric
researchers have continued to presume that prescribed drugs are benign and
restorative, however, rather than potentially harmful. In the many studies and
reviews that cropped up in the first decade of the twenty-first century
unambiguous findings of the toxic effects of antipsychotics were swiftly passed
over, if they were mentioned at all, and other data were fitted into the
preconceived neuroprotective model, even where, like the research on Bcl-2,
this was inconsistent with research on other neurological diseases (Berger et
al., 2003; Jarskog and Lieberman, 2006; Buckley et al., 2007; Hunsberger et
al., 2009). The momentum behind the early intervention movement discouraged
critical scrutiny of the neuropathological evidence. Unsubstantiated, unlikely
and conflicting claims about the miraculous effects of the atypical
antipsychotics and other sorts of drugs continue to abound despite the fact
that there is no evidence that could justify the designation of these drugs as
‘neuroprotective’ agents, and indications that they are, in fact, substantially
toxic to brain cells.
Early Intervention in Psychosis Services
Starting in the 1990s, services specialising in the
care and treatment of people suffering their first psychotic breakdown started
to be developed in different parts of the world. One of these was the
pioneering centre in Melbourne, Australia, associated with the charismatic
psychiatrist Patrick McGorry. The Melbourne service consisted of a
community-based treatment programme known as the Early Psychosis Prevention and
Intervention Centre (EPPIC).
In 2001 the UK’s Department of
Health called for a network of Early Intervention in Psychosis services to be
formed across the country (Department of Health, 2001). Within a few years
there were more than 100 dedicated teams operating in England alone (Pinfold et
al., 2007). Staff in these teams had a smaller
caseload than those in standard community mental health teams and were meant to
offer, according to the Department of Health’s guidance, expertise in cognitive
behavioural therapy, family therapy and treatment of drug and alcohol problems,
as well as standard treatments for psychosis (Singh et al., 2003).
Despite the fact that Early
Intervention services have now been established throughout the world, only two
trials have compared these services with generic mental health care, and
neither of these examined the role of drug treatment independently from other
aspects of the intervention. The largest study was conducted in Denmark and
involved 547 patients with a first psychotic episode who were randomised to
specialist Early Intervention or routine care for a duration of 2 years. At the
end of this time patients in the specialist intervention group had lower rates
of psychotic and negative symptoms, slightly higher levels of functioning and
had spent fewer days in hospital. However, both groups received antipsychotic
treatment according to Danish government guidelines, with little difference in
medication use between the groups (Petersen et al., 2005; Thorup et al., 2005).
The patients were followed up again 3 years later, or 5 years after the start
of the study, and at this point there were no differences in any of the
principle outcomes (Bertelsen et al., 2008).
The Lambeth Early Onset (LEO) study
conducted in London enrolled 144 patients with a first or second episode of
psychosis. After adjusting for differences in the initial characteristics of
participants, the researchers found that people allocated to the Early Intervention
service were less likely to be readmitted to hospital than those receiving the
ordinary service, but there were no differences in rates of relapse, recovery
or the amount of time spent in hospital (Craig et al., 2004). No data on how
participants fared after they left the service have been published nor have any
details on levels of drug treatment received by each group.
These remain the only studies that
offer information about whether providing intensive treatment by specialist
teams in the initial phase of a psychotic disorder improves outcome. The Danish
study suggested such programmes improve symptoms only while they are running,
implying it is the intensive support that is effective, rather than a
fundamental modification of the underlying disease that might be attributable
to drug treatment. Neither of the two studies examined the role of drug
treatment specifically, however, and there remain no trials which assess
whether starting antipsychotic medication early on improves
outcome of its own accord, despite the fact that this idea was the embryo of
the Early Intervention movement.
Early Detection of Psychosis
Participants in the Danish- and London-based trials
were already involved with mental health services before taking part in the
studies, but other programmes have attempted to draw people into treatment
services through public education and mass media campaigns. The rationale for
these activities was, again, the unshakeable belief that shortening the
duration of untreated psychosis would improve the ultimate outcome of the
disorder of schizophrenia. The TIPS (Early Identification and Treatment of
Psychosis) programme in Norway was the most extensive of these programmes and
consisted of a mass media campaign that included newspaper, cinema and radio
advertisements, leaflets posted directly to households, face-to-face training
of general practitioners, school teachers and counsellors, and twice-termly
presentations in schools. In Canada, an early detection initiative consisted of
a public awareness campaign using leaflets, posters, television and cinema
advertisements, and training of general practitioners and school counsellors.
In Singapore, a similar campaign also involved a ‘docudrama’ screened on
primetime television, and the use of celebrities to endorse the campaign. In
Norway and Singapore, it was found that people who presented to services after
the early detection programme was instituted had a shorter ‘duration of
untreated psychosis’, than people who presented before, or in areas where it
had not yet been launched (Lloyd-Evans et al., 2011).
Only the TIPS programme provided any
data on whether early detection affects outcome per se. People who were
referred to treatment services in the area where the early detection programme
was initiated had milder conditions with lower levels of all types of symptoms
and higher rates of illicit drug use, suggesting that the psychotic episodes in
this group were more likely to be drug-induced than in the comparison group
(Melle et al., 2004; Larsen et al., 2006). Ten years later recovery rates were
higher in people who came from the early detection area, but no adjustment was
made for the severity of symptoms or differences in illicit drug use at the
start of the study. Few details of the characteristics of study participants
were presented in any of the study publications and the results of the study
are thus rendered quite meaningless. The fact that the authors could,
nevertheless, conclude that their findings support the benefits of early
intervention illustrates the strength of their underlying
assumptions (Hegelstad et al., 2012). The TIPS study merely reveals that people
who have less severe symptoms and impairments have a better outcome—a finding
that is hardly surprising and in no way demonstrates that earlier institution
of treatment has any benefits.
Prevention of Psychosis
In 1995 the Melbourne centre, under the leadership of
Patrick McGorry and his colleague Alison Yung, developed a service for
identifying young people who might be vulnerable to psychosis at some point in
the future. It was known as the Personal Assessment and Crisis Evaluation
clinic, or PACE. Motivated by the perceived need to start treatment as early as
possible, the aim of the programme was to identify people who might go on to
develop psychosis, but who had not yet experienced symptoms that would satisfy
diagnostic criteria for a psychotic condition.
In infectious diseases, the initial
stage is sometimes referred to as a ‘prodrome’, which is a state that can only
usually be identified retrospectively, as most early signs and symptoms are
non-specific. Yung and McGorry drew attention to the early stages of measles,
however, where an early sign of the disorder is the appearance of white patches
in the mouth known as Koplik spots. Koplik spots, if correctly identified, only
occur in measles, and are therefore 100% specific. When looking back at a small
group of patients who had experienced a psychotic episode, they noted that
although the most common early symptoms were anxiety, depression, irritability,
and social withdrawal, closer to the point at which a recognisable psychotic
state developed some patients exhibited psychotic-like features such as
‘perceptual disturbances’, ‘delusional mood’ and suspiciousness (Yung et al., 1996).
They hypothesised, therefore, that there was a pre-psychotic phase that
preceded the onset of frank psychosis, which it might be possible to identify
and that could be seen as analogous to the Koplik spots of measles. Based on
the characteristics of their clients, the PACE team set about constructing a
set of criteria which would define this state and help predict the onset of
psychosis. A research programme was set up that aimed to identify individuals
who were ‘at risk’ or at ‘high risk’ of developing psychosis in the near
future, in order to initiate antipsychotic treatment and prevent a full-blown
psychotic episode from developing.
Early attempts to predict whether an
individual would become psychotic were fairly impressive, even if they failed
to approach the specificity of Koplik spots. The Melbourne group reported that
41% of 49 young people identified using their
criteria for being in an ‘at risk’ mental state (Table 10.1)
developed a psychotic episode within a year, and they concluded that it was
‘possible to accurately identify people at imminent risk of psychosis’
(Phillips et al., 2000, p. S164).
Table 10.1 Melbourne criteria
for the ‘at risk mental state’
|
At risk
mental state identified if an individual satisfies one of the following three
criteria |
||
|
Experiences ‘attenuated’ (low
grade) psychotic symptoms, e.g. ‘magical thinking’, perceptual disturbance,
paranoid ideation, odd speech |
Experiences brief limited
intermittent psychotic symptoms (lasting less than 1 week) |
Has a family history of
psychosis, schizophrenia, or ‘schizotypal personality disorder’1
combined with a deterioration in the individual’s mental state or functioning
for at least a month |
The PACE group then proceeded to set
up a randomised controlled trial to assess whether instituting treatment in
people identified as being at ‘high risk’ could prevent the onset of psychosis.
The trial involved 59 young people who were randomised to two groups: one group
received supportive psychotherapy and help with individual problems, which
could, and did, include antidepressants and benzodiazepines in many cases, but
not antipsychotics; the other group received low-dose antipsychotic treatment
using risperidone plus a specially tailored programme of cognitive behaviour
therapy. No placebo was used and the study was not conducted blind so that
everyone was aware which group individuals had been assigned to. After 6 months
of treatment only 10% of people receiving risperidone plus cognitive behaviour
therapy had been diagnosed with a full-blown psychotic disorder compared with
36% of the comparison group, a statistically significant difference (p = 0.03). However, levels of symptoms, including both
positive and negative symptoms of schizophrenia, did not differ between the
groups at the end of the treatment period (McGorry et al., 2002). Nevertheless,
the trial provoked great excitement and was repeatedly cited as evidence for
the benefits of preventive treatment (McGlashan et al., 2006; Marshall and
Rathbone, 2011).
Three other trials have subsequently
been initiated involving the use of antipsychotic medication, and other studies
have tested the efficacy of cognitive behaviour therapy, without antipsychotic
medication, as a preventive measure. The PRIME study, conducted at Yale
University in the USA, and led by psychiatrist Thomas
McGlashan, consisted of a double blind comparison of low-dose olanzapine
against placebo in 60 people aged between 12 and 45 years. After a year of
treatment 16% of the olanzapine group had developed psychosis compared with 38%
of the placebo group, according to the authors’ own ‘presence of psychosis’
scale, a difference that did not quite reach conventional levels of statistical
significance. Again, there were no differences and only minimal changes on
conventional symptom measures like the Positive and Negative Symptom Scale
(PANSS), but people treated with olanzapine gained almost 9 kg during the year of
treatment (McGlashan et al., 2006). The researchers blamed the poor result on
the fact that recruitment had proved difficult, but McGlashan subsequently
distanced himself from this type of research, declaring he did not think that
drugs ‘could prevent full-blown psychosis, only delay it’ and pointing to the
fact that the drugs were more likely to induce weight gain than to produce any
measurable benefit (Carey, 2006).
Another study, conducted in Germany,
involved the use of a combination of amisulpride and cognitive behaviour
therapy in a similar design to the Melbourne study. With 124 people randomised
in total, it represents the largest trial so far, yet its results have never
been properly published. The treatment phase of the study was designed to last 12
months, but only preliminary data collected at 12 weeks have been published so
far, suggesting that the group treated with amisulpride and cognitive behaviour
therapy had improved levels of positive symptoms and general functioning
compared with the comparison group, but that negative symptoms were unaffected
(Ruhrmann et al., 2007; Marshall and Rathbone, 2011). To date, no details of
rates of onset of psychosis have been published, however, and, given the
excitement generated by the results of the Melbourne study, it seems probable
that no benefits of drug treatment were detected.
In 2012 results of a further trial
conducted by the Melbourne group were published. This trial utilised a placebo
and compared the effects of antipsychotic medication plus cognitive behaviour
therapy, placebo with behaviour cognitive therapy and placebo alongside
non-specific ‘supportive’ therapy. After a year of treatment only 13% of
participants had developed a diagnosable psychotic disorder, and there were no
statistically significant differences between the three groups. The authors
concluded the study failed ‘to provide support for the first-line use of
antipsychotic medications in patients at ultra-high risk of psychosis’ (McGorry
et al., 2013, p. 349). Findings from another US study of people being treated
for prodromal symptoms also found that the use of antipsychotic medication had no effect on whether people developed a
full-blown psychosis, although this was not a randomised trial (Walker et al.,
2009).
Other research groups have failed to
replicate the Australian group’s early predictive accuracy. In a multi-centre
trial, led from Manchester of cognitive behaviour therapy for prevention of
psychosis, which used the Melbourne criteria for identifying people at ‘high risk’,
only 8% of the participants went on to develop psychosis, with no difference
between those who received cognitive behaviour therapy and those who did not
(Morrison et al., 2012). Although a German study found a modest effect of a
psychological intervention for people with an ‘early initial prodromal state’,
the rate of onset of psychosis in the control group was still only 17% after a
year (Bechdolf et al., 2012). These figures suggest that 80–90% of people in a
trial of preventive treatment would be treated unnecessarily. As with so many
other miraculous interventions, the remarkable results proclaimed early on have
become increasingly marginal in successive studies, and the enterprise of
trying to prevent psychosis appears much less feasible than we were led to
believe a few years ago.
Criticism of Early Intervention
Despite the lack of evidence to suggest that early
intervention fundamentally changes the outlook for people diagnosed with
schizophrenia or psychosis, and the questionable effects of preventive
interventions, the bandwagon of Early Intervention in Psychosis roles on. The
general public continue to be told definitively that ‘the sooner a person gets
diagnosis and treatment, the better the outcome’ (schizophrenia.com,
2012) and that ‘early detection of psychosis greatly increases the chance of a
successful recovery’ (Fraser Health Authority, 2012). Emotive advertising is
designed to persuade clinicians that not starting antipsychotic treatment at
the earliest possible opportunity consigns people to a life of emptiness and
ruin. An advertisement for Risperdal Consta (injectable risperidone) produced
in 2007, for example, featured an image of a girl aged around 13 years walking
across a playground, dropping a doll and school books in her wake. The caption
read ‘Prescribe early, because what she loses, she could lose forever’, with
the obvious implication of a lost childhood without early drug treatment
(Risperdal Consta advertisement, 2007).
Despite the results of recent trials
of psychosis prevention, several services, especially in the USA, continue to
attempt to identify people with possible ‘prodromal’ symptoms. Maine Medical
Centre’s PIER (Portland Identification and Early Referral) programme, for example,
provides presentations on early warning signs for
school students and staff, which it lists as including social withdrawal,
decline in performance, difficulty concentrating, loss of motivation and other
difficulties that are common in teenagers in a variety of circumstances (Table 10.2).
People considered to be at ‘high
risk’ of going on to develop a full-blown psychotic episode are offered a
treatment package that includes medication (PIER, 2012). Columbia University’s
COPE (Centre of Prevention and Evaluation) programme also aims to attract
people with early ‘symptoms’, listing experiences and behaviour which, like
those of the PIER programme, are highly subjective and non-specific (COPE,
2012). The San Francisco-based PREP (Prevention and Recovery in Early
Psychosis) programme provides public information on early identification aimed
at young people, families, schools, churches and community groups, and
explicitly advises people that ‘caught very early, it is possible to prevent or
delay the onset of a psychotic illness’ (PREP, 2012).
The ethics of treating people
supposedly at ‘high risk’ of developing psychosis has now been challenged by
several leading researchers and clinicians, however (Bentall and Morrison,
2002; Warner, 2005; Verdoux and Cougnard, 2006; Bosanac et al., 2010). The most
accurate predictions of the Melbourne group fall far below the aspiration to
identify the Koplik spot of psychosis, but even if the most optimistic
predictions are correct, i.e. that about 40% of people identified progress to
develop a psychotic episode, so-called preventive treatment means that 60 out
of every 100 persons would be exposed to all the risks of antipsychotic
treatment without any hope of benefiting from it. It seems likely, however,
that the accuracy of prediction is much lower in the real world and that
treating people with so-called early signs of psychosis is likely to result in
80 or 90% of people receiving drug treatment unnecessarily.
Even without early detection or
prevention programmes, there has been a blurring of the boundaries between
full-blown psychosis and its early symptoms, however, which seems likely to
increase the rate at which people are diagnosed and treated for having a psychotic
episode. As American psychiatrist Richard Warner pointed out, community surveys
reveal that there is a large pool of people with psychotic-like symptoms who
never require medical or professional attention (Warner, 2005). One such study
found that two in every 1000 people fulfilled criteria for a diagnosis of
schizophrenia, whereas only a fraction of this number—around 0.24 per 1000—ever
come to the attention of traditional mental health services (Tien and Eaton,
1992). Another critic of early intervention services, psychiatrist David
Castle, showed that whereas the international World Health Organization studies
reported between seven and 14 new cases of psychosis per 100,000 people, the
early intervention service in Cambridge, UK, was finding an incidence rate of
50 per 100,000 people. He estimated that the Melbourne service was diagnosing
people at a rate of 100 per 100,000 people (Castle, 2012).
Table 10.2 PIER (Portland
Identification and Early Referral) programme (adapted from PIER, 2012)
|
‘Symptom’ |
Examples
provided |
|
Social withdrawal |
Spending more time alone |
|
Functional decline |
Dropping grades |
|
Behaviour changes |
Collecting objects or hoarding |
|
Concentration difficulty |
Having trouble focusing or
paying attention |
|
Loss of motivation or energy |
Quitting sports, groups or clubs |
|
Dramatic sleep and appetite
changes |
Eating more or less than usual |
|
Suspiciousness of others |
Worrying about what others are
thinking |
|
Unusual or exaggerated beliefs
about a person’s powers or influences |
Thinking you have special or
magical powers |
|
Heightened
sensitivity to sights, sounds, smells or touch |
Perceiving
that lights are brighter and sounds are louder |
As
we saw in Chapter 7, some people with full-blown
psychosis recover without drug treatment, and it seems likely that early, mild
and debateable signs of psychosis are even more likely to resolve
spontaneously. Early intervention services may be drawing in people who do not
need services, and although receiving general support may not be harmful, long
periods of unnecessary antipsychotic treatment certainly are. Ironically, one
of Yung and McGorry’s early papers documents the existence of transitory
psychotic experiences, describing in detail the histories of several young
patients who had developed psychotic symptoms, in some cases in response to
severely stressful situations, which resolved spontaneously without any
specific treatment (Yung et al., 1996).
The height of hubris of the early
intervention movement was the proposal for the inclusion of the ‘psychosis risk
syndrome’ as a new and distinct diagnosis in the fifth revision of the American
Psychiatric Association’s Diagnostic and Statistical Manual
(DSM) of mental disorders. Thankfully, the proposal
galvanised psychiatrists who were sceptical of the claims of the early
intervention enthusiasts, including such high profile figures as Allen Francis,
the head of the previous DSM revision taskforce. The
proposal was finally jettisoned, but only after considerable deliberation and
in the face of a mounting campaign against it (Maxman, 2012).
The Pharmaceutical Industry
The Early Intervention in Psychosis movement has
thrived because it fulfils the long-held ambition of the psychiatric profession
to have therapeutic interventions that confirm the medical nature of
psychiatric activity. It represents the ultimate horizon of the disease-centred
model of drug action; the idea that drugs do not just arrest an underlying
disease process, but can prevent its emergence in the first place. Early
intervention was also eagerly embraced by politicians looking for a quick and
simple solution to the costly problem of caring for people with severe mental
disorders. This political credulity has led to Patrick McGorry, an energetic
and persuasive publicist, becoming what has been described as ‘the most
powerful psychiatrist in the world’ (Francis, 2011). McGorry won over the
political establishment of Australia and became influential elsewhere through
his messianic approach to early intervention, which
enables him to ‘defend absolutely indefensible positions with the convincing
but inaccurate force of a true believer’ (Francis, 2011). Local campaigners,
worried about the ethical implications of his expansionist activities, have
fought back, however, accusing him of overstating the number of people
requiring mental health interventions (Medew, 2010). In return, McGorry has
countered his accusers by suggesting they are ‘irresponsible’ ‘merchants of
doubt’ (McGorry, 2011), whose views deserve ‘censure’ (McGorry et al., 2010, p.
402).
The success of early intervention is
not down to individual efforts, however, any more than it is justified by
scientific evidence. The hidden hand of the pharmaceutical industry has been
driving the movement since its early days. AstraZeneca, makers of quetiapine,
sponsored gatherings of academics that became known as the European First Episode
Schizophrenia network, starting in 1995. The Australian group received drug
company support through the ORYGEN research centre, and the Melbourne
prevention study was funded by Janssen, makers of risperidone. Eli Lilly
partially funded the US PRIME trial, and the TIPS early detection programme
received funding from Janssen-Cilag, Lundbeck Pharma and Eli Lilly. Conferences
organised by the International Early Psychosis Association have been supported
by the makers of atypical antipsychotics, and the 2012 conference courted
prospective sponsors with a glossy brochure outlining the opportunities for
product promotion (International Early Psychosis Association, 2012).
Papers presented at
company-sponsored conferences and in company-funded publications have repeatedly
stressed the benefits of the atypical antipsychotics, playing down their
adverse effects and underlining the ‘crude and iatrogenic’ effects of the older
drugs (McGorry et al., 2005, p. S1; Remington, 2005). In a company-sponsored
journal supplement, before the results of the PRIME study became apparent,
Thomas McGlashan justified treating people who might never develop psychosis by
the argument that the atypical antipsychotics were well-tolerated agents whose
harmful effects were ‘modest in frequency, and very modest in serious adverse
effects’ (McGlashan, 2005, p. S114). He did admit, however, that the long-term
consequences of treatment were not yet known.
Individual researchers can receive
considerable sums of personal income from drug companies for various services,
including ‘consultancy’ and delivering lectures, as well as funding for
research. The investigation into the Harvard-based child psychiatrist Joseph
Biederman and his colleagues revealed that millions of dollars can be accrued
from such activities (see Chapter 11).
Patrick McGorry commonly fails to declare any drug
company connections in his numerous publications, but when he was forced to by
the rigorous ‘conflict of interest’ policy of the British
Medical Journal it was revealed that he had ‘acted as a paid consultant
for, and received speaker fees and travel reimbursement from’ Janssen-Cilag,
Eli Lilly, Bristol Myers Squibb, AstraZeneca and Pfizer, and that all of these
companies, and not just Janssen who funded the risperidone trial, had donated
money towards his research activities (McGorry, 2008). The declaration of
interests by the authors of the non-randomised longitudinal prodrome study in
the USA ran to half a page of small text, with most authors having received
research funding, consultancy fees or ‘educational fees’ from a range of
pharmaceutical companies (Walker et al., 2009).
Allen Francis declared that ‘the
world is a safer place now that “Psychosis Risk” will not be in DSM 5. Its rejection saves our kids from the risk of
unnecessary exposure to antipsychotic drugs’ (Francis, 2012). In a dramatic
turnaround, McGorry also recently admitted that antipsychotics might not be
justified in people judged to be ‘high risk’ of developing psychosis, and abandoned
plans to launch a preventive trial using quetiapine amid mounting public and
professional criticism (Stark, 2011). In many ways, however, the DSM-5 committee, in considering the proposed diagnosis, was
reflecting what had already become normal practice. The concept of psychosis
has been profoundly altered by the early intervention movement, expanding to
encompass people with all sorts of unusual and troublesome behaviours. Many of
these people—who are mostly young—are being started on a course of lifelong
treatment with toxic drugs, whose benefit in such marginal situations has not
been proven, and whose toxic effects are well documented. Apart from
unnecessary exposure to drug treatment, these people will encounter all the
difficulties of being labelled a mentally ill person, including the
psychological vulnerability and helplessness this often produces. In addition,
overstretched services are concentrating resources on people who might have
recovered without their help, leaving less support for those with established
and severe mental health problems. And the drug companies are laughing all the
way to the bank!
The Antipsychotic Epidemic: Prescribing in
the Twenty-First Century
Having largely replaced the older antipsychotics, and
expanded drug treatment for people with schizophrenia or psychosis to its
limits through the Early Intervention movement, the makers of atypical
antipsychotics set about widening the market for their products beyond the
relatively small group of people who suffer from a serious, ‘psychotic’
disturbance. They achieved this end admirably, deftly combining legal and
illegal marketing strategies, and changing and shaping concepts of mental
disorder, as well as cleverly managing damaging data about the drugs’ adverse
effects in ways revealed in Chapter 9.
The symbol of the chemical imbalance and the corresponding notion that the
drugs restored biochemical harmony, was pivotal to this programme because it
allowed these toxic substances to be portrayed, misleadingly, as essentially
harmless.
The increasing use of antipsychotic
drugs in a whole variety of countries since the late 1990s is a clear testament
to the success of these activities (Verdoux et al., 2010). In cases where data
are available, it appears that this rising use is driven principally by
‘off-label’ prescribing for people diagnosed with a variety of common
psychological complaints, rather than more severe mental disorders. In the USA,
for example, data on medical consultations showed that those involving a
prescription of antipsychotics nearly tripled between 1995 and 2006, with the
bulk of this increase occurring from 2001 onwards (Alexander et al., 2011). In
2008 only 51% of consultations in which older antipsychotics were prescribed
involved people diagnosed with schizophrenia, and less than a quarter (24%) of
consultations which resulted in prescriptions of new or atypical
antipsychotics. Thirty-four per cent of atypical antipsychotics were prescribed
to people diagnosed with some sort of ‘bipolar disorder’, and most of the rest
were prescribed to people with depression, anxiety,
dementia and other conditions for which the drugs have not been licenced.
Moreover, the rising use of antipsychotics has been paralleled by an increasing
tendency for people to be prescribed numerous different psychiatric medications
concurrently. Between 1996 and 2003, 87% of consultations involving
antipsychotic prescriptions also involved prescriptions of other psychiatric
drugs, most commonly antidepressants, ‘mood stabilisers’ or another sedative
(Sankaranarayanan and Puumala, 2007).
The situation in the UK is similar.
Between 1991 and 2000 only 10% of newly initiated prescriptions of
antipsychotics in general practice were issued to people with a diagnosis of
psychosis or schizophrenia. Fifty per cent were prescribed to people with
anxiety and depression, and 15% to people with dementia (Kaye et al., 2003).
More recent data on prescriptions showed that most of the commonly used
antipsychotic drugs, both of the older and newer variety, are prescribed
predominantly in low-dose preparations, well below the doses that would be used
for people diagnosed with schizophrenia or psychosis (Ilyas and Moncrieff,
2012). Moreover, figures from the USA suggest that antipsychotics are
increasingly prescribed by general physicians and family doctors, rather than
psychiatrists. In 2002 almost a third of consultations (32.2%) resulting in a
prescription of antipsychotics involved physicians who were not mental health
specialists, which was more than double the proportion in 1998 (Aparasu et al.,
2005).
Data from the USA also show that the
rate of antipsychotic prescribing to children and young people increased almost
five times between 1995 and 2002. In the year 1995–96 there were 8.6 prescriptions
of antipsychotics issued for every 1000 people aged under 18 years in the USA,
whereas in 2001–02 this had increased to 39.4 per 1000. The majority of
antipsychotic prescriptions issued to this age group were for ‘behaviour
problems’ and mood disorders, and only 14% were given for psychotic conditions
(Olfson et al., 2006). Again, almost a third (32.4%) of prescriptions to
children were not issued by psychiatrists or mental health specialists (Cooper
et al., 2006).
Both legal and illegal strategies
have been employed to achieve this expansion in the market for the atypical
antipsychotics. Illegal marketing targeted general practitioners and staff of
mental health nursing homes in order to increase the use of these drugs in
people with dementia, depression and anxiety (Spielmans, 2009). More sinister
than the illegal tactics, however, has been the mostly legal manipulation of
public and professional understanding of what has come to be called ‘bipolar
disorder,’ the condition previously, and more expressively, known as manic depression. The manufacturers of atypical
antipsychotics have set about changing the meaning of this once rare and
distinctive condition, expanding its boundaries beyond recognition so that
‘bipolar disorder’ has become a label that can be attached to a whole myriad of
common personal difficulties, which thereby become legitimate targets for
antipsychotic treatment.
The New Bipolar Disorder
An article in the British publication The Psychiatrist entitled ‘I want to be bipolar’ describes
the relatively recent phenomenon of people actively seeking to be diagnosed
with ‘bipolar disorder’ (Chan and Sireling, 2010). Journalist Patrick Strudwick
was one of these people, and he described his story in The
Times in 2012. After the breakdown of a difficult relationship in 2003,
he threw himself into his work, found that he was sleeping less, and had
periods when he felt his mind was racing, he was full of energy and
over-talkative. He researched his problems on the Internet and decided he had
bipolar disorder. Although a friend advised him he most probably did not have
the condition, he described how he convinced himself and his doctor that he
did. ‘I want a label for how I’m feeling and drugs to make it stop’. He
recalled ‘I read reams about bipolar disorder. Every sensation of the past few
months morphs into these descriptions of symptoms. I ignore the ones I don’t
have’.
When he saw his general
practitioner, he described ‘only the apex of the hyper moods, the edited
highlights. The more complicated reality – that these episodes undulate,
subside and sometimes last only an hour or two – I do not describe in case he
doesn’t take me seriously’ (Strudwick, 2012).
Patrick’s general practitioner
referred him to a psychiatrist who was happy to confirm the diagnosis of
bipolar disorder, and Patrick was started on a drug called Depakote (see p.
193). He took this for several years until another psychiatrist questioned the
diagnosis, and eventually Patrick started to doubt it himself. Finally tiring of
the sedating effects of the drug, he weaned himself off. When he confessed to
this episode some years later, two of his friends described how they too had
been labelled as having ‘bipolar disorder’ in the same sort of circumstances. A
few days after The Times article was published, an
old friend of mine contacted me with a similar story. Like the author of the
article, my friend had been diagnosed with bipolar disorder and treated for
several years with the antipsychotic drug Seroquel (quetiapine) after a life
crisis. She had belatedly come to realise that she had been labelled as having a serious, life-long mental condition, which
could have untold consequences for her future.
Bipolar disorder was ripe for
exploitation. Longstanding associations between manic depression and creativity
gave the condition a glamorous image, and it was not linked with the
intellectual and social deterioration associated with the concept of
schizophrenia. Moreover, experience with the marketing of depression in the
1990s proved that many people were willing to reconceive various social and
personal difficulties as arising from a brain-based condition. As Strudwick
illustrates, the idea that one’s feelings and behaviour constitute an illness
or disease can provide a reassuringly concrete explanation for emotional
turmoil. Moreover, by locating the problem in defective brain functioning,
depression and other illness labels separate the individual’s actual, true self
from the difficulties they are experiencing, which can therefore be shrugged
off and disowned (Stepnisky, 2007). By the late 1990s, however, the label of
depression was becoming commonplace, and thereby losing its ability to signal
something exceptional. A diagnosis of bipolar disorder was the next step up the
ladder, enabling people to retain the feeling that their problems were distinct
from ordinary experience, extrinsic to themselves and worthy of regarding as a
brain disease.
The ‘bipolar’ epidemic started in
the USA in the 1990s when some academics started to suggest that the disorder
was under-recognised (Ghaemi et al., 1999). The condition that had originally
been called ‘manic depression’ is a rare disorder in which the sufferer becomes
aroused and over-active over a sustained period lasting weeks at least, and frequently
many months. It is easily recognisable because the individual’s behaviour is
out of character and often out of control, and it usually leads to admission to
a psychiatric unit. Most inpatient facilities in the UK see only a handful of
such cases a year.
The term ‘bipolar disorder’ started
to be employed in the 1970s, proving attractive to psychiatrists perhaps
through its association with electricity and thus with physical science. There
were suggestions from this time that there might be a milder form of the
condition, which was named ‘bipolar II disorder’ to distinguish it from the
classical form of manic depression, which was referred to as ‘bipolar I.’
Bipolar II disorder was essentially a variant of depression, in which people
were said to suffer principally from episodes of depression with occasional
periods of mildly elevated mood. There was little interest in this milder form
of the disorder, however, until the mid-1990s, when bipolar disorder became the
focus of renewed academic attention, and a whole range of situations and
behaviours were swept under its umbrella. The concept of ‘bipolar spectrum disorder’, which was formulated in 1996,
suggested that a tendency for moodiness, or ‘lifelong temperamental
dysregulation’, could be seen as arising from the same biological processes
that were thought to give rise to classical manic depression, although, of
course, it had to be admitted that these processes were not yet identified
(Akiskal, 1996).
The prevalence of bipolar disorder
has increased in line with its expanding boundaries. Although classical manic
depression was commonly said to affect about 1% of the population, research
suggests that fewer than 1 in a 1000 people were hospitalised for a typical
episode of mania during the twentieth century (Healy, 2008). An American
house-to-house survey conducted in the early 1990s, however, reported that 1.3%
of the population suffered from bipolar I disorder (Kessler et al., 1994). By
1998 it was claimed that the prevalence of classical bipolar disorder with
full-blown mania was 5% (Angst, 1998). In 2003, an additional 11% of the
population was said to suffer from bipolar II disorder, and a total of 24% was
thought to show some form of disturbance on the ‘bipolar spectrum’ (Angst et
al., 2003).
Bipolar disorder has been
transformed from a readily discernible pattern of behaviour to a highly
flexible concept that can be applied to almost any individual in some sort of
difficulty. Although all forms of the disorder are proposed to consist of some
sort of abnormal variation of mood, there is a world of difference between the
sustained periods of heightened arousal, disinhibited behaviour and
over-activity characteristic of classical mania, and the periods of increased
energy that most people experience from time to time. There is no research
evidence that can confirm that these situations are the same phenomena or that
they have the same origins. As Patrick Strudwick noticed when he attended the
local bipolar support group: ‘The others in the group share stories of
kaleidoscopic hallucinations, distinctly inappropriate public nudity and
policemen fishing them out of reservoirs. My stories do not compare’
(Strudwick, 2012).
The Concept of a ‘Mood Stabiliser’
Increasing academic interest in bipolar disorder, or
the bipolar ‘disorders’ as they were often referred to, coincided with the
first wave of interest from the pharmaceutical industry, which came not from
the makers of antipsychotics but from the manufacturer of the drug Depakote
(Healy, 2006b). Depakote is the brand name for a newly configured form of the
old anti-epileptic drug sodium valproate, and it was released onto the market
as a treatment for mania in 1995. Drugs used in
epilepsy had been suggested to be useful in manic depression back in the 1980s,
based on a misleading analogy between epilepsy and manic depression. As
anti-epileptic drugs prevented fits by reducing the brain’s nervous
excitability, it was proposed that they might quell whatever processes lay
behind repeated episodes of manic depression.
Following the release of Depakote
the concept of the ‘mood stabiliser’ started to enter the psychiatric lexicon.
Its precise meaning was never clear and psychiatrists could not agree on what
the concept referred to (Bowden, 1998; Ghaemi, 2001), but it had popular
resonance and people came to believe that drugs referred to as ‘mood
stabilisers’ rectified something awry in the biological basis of emotional
regulation. Mood stabilisation became the vague counterpart of the new and
equally vague notion of bipolar disorder.
The only research that provided any
evidence of the therapeutic potential of Depakote simply consisted of a
placebo-controlled trial conducted with people with severe mania. Not
surprisingly, in view of Depakote’s sedative properties, it performed somewhat
better than placebo (Bowden et al., 1994). No research was ever conducted, or
at least published, which showed that the drug reduced mood variability, and
there remains no evidence that it modifies the biological basis of mood or mood
regulation—whatever complex interaction of numerous neurotransmitters that
might involve. Moreover, the only published study to have examined the use of
Depakote for the long-term prevention of relapse in people with a diagnosis of
bipolar I disorder found that neither Depakote nor lithium was superior to
placebo (Bowden et al., 2000).
Notwithstanding the evidence, sales
of Depakote soared as the concept of mood instability, and the idea that there
was a specific treatment for it, infiltrated mental health services (Ilyas and
Moncrieff, 2012). Other anti-epileptic drugs were also targeted at the mood
disorder market, based on the same rationale, and gabapentin and lamotrigine
became widely prescribed in this area, the former through illegal promotion as
it was never licenced for this indication (Van Voris and Lawrence, 2010). The
manufacturers of the atypical antipsychotics witnessed this development, and in
the late 1990s, Eli Lilly set up trials designed to obtain a licence for
olanzapine for the treatment of bipolar disorder. Studies were conducted with
people with acute mania and showed, again not surprisingly in view of the
strong sedation olanzapine induces, that it was superior to placebo and
comparable to Depakote and haloperidol in this situation (Tohen et al., 1999,
2002, 2003). In March 2000 olanzapine was granted a licence for use in an
episode of mania in people diagnosed with type I bipolar disorder or manic
depression.
As well as revealing the strategies drug companies use
to obscure the nature and severity of adverse events, the opening up of the
Zyprexa papers provided an unprecedented insight into Eli Lilly’s marketing
strategy. It was clear that the company saw Zyprexa (olanzapine) as the natural
successor to Prozac, and as the patent on Prozac was about to expire, the
company set about devising a strategy to make Zyprexa into the ‘most successful
pharmaceutical product ever’. The future of the company was seen as riding on
the success of this strategy: ‘The company is betting the family farm on
Zyprexa’ the ‘Zyprexa Product Team’ declared in an internal presentation in
2001. ‘The ability of Eli Lilly to remain independent and to emerge as the
fastest growing pharma company of the decade depends solely on our ability to
achieve world class commercialisation of Zyprexa’
(Eli Lilly, 2001, cited in Spielmans, 2009, original emphasis). This strategy
hinged on the ability of the company to reposition Zyprexa as a treatment for
mood disorders that could be marketed to the millions of people who currently
thought of themselves as depressed, and could be prescribed not just by
psychiatrists but by general practitioners or primary care physicians. The
newly flexible concept of bipolar disorder was the link that would enable this to
happen. In 1997, for example, the Zyprexa product team predicted that sales
projections would increase more than fourfold if olanzapine could be viewed as
a ‘Depakote like...MOOD STABILISER’ rather than a ‘Risperdal
like...Antipsychotic’ (Tollefson, 1997, cited in Spielmans and Parry, 2010,
original emphasis).
The repositioning of Zyprexa as a
‘mood stabiliser’ was achieved through a disease-awareness campaign, similar in
nature to previous campaigns that had publicised other vague and expandable
mental conditions during the 1990s; conditions like ‘social anxiety disorder’
and ‘premenstrual dysphoric disorder’ (Koerner, 2002). In 2002, Eli Lilly ran
an advertisement on US television which began, according to David Healy’s
description,
...with a vibrant woman dancing late into the night. A
background voice says, ‘your doctor never sees you like this’. The
advertisement cuts to a shrunken and glum figure, and the voice-over now says
‘this is who your doctor sees.’ Cutting again to the woman, in active shopping
mode, clutching bags with the latest brand names, we hear: ‘That is why so many
people with bipolar disorder are being treated for depression and aren’t
getting any better – because depression is only half
the story.’ We see the woman depressed, looking at bills that have arrived in
the post before switching again to see her energetically painting her
apartment, ‘That fast talking, energetic, quick tempered, up-all-night you,’
says the voice-over, ‘probably never shows up in the doctor’s office’ (Healy, 2008,
p. 190)
The advertisement did not mention Zyprexa, or any other
drug, but encouraged people to log onto the website of the ‘Bipolar Help
Centre’, sponsored by Eli Lilly, and to take a ‘bipolar test’. It concluded by
showing the heroine filling in the questionnaire, and recommended viewers take
the test to their doctor to obtain a ‘correct diagnosis’.
Material aimed at general
practitioners again intended to change perceptions about people who might
previously have been diagnosed with depression. Eli Lilly formulated the idea
of ‘complicated mood’ to delineate a group of people with common symptoms like
irritability, anxiety, disturbed sleep and mood swings, suggesting these were
indications of incipient and previously unrecognised bipolar disorder. The
concept of ‘complicated mood’ helped to bridge the gap between the serious
mental conditions that were normally associated with the use of antipsychotics,
and the sort of mental distress that general practitioners saw on an everyday
basis (Spielmans, 2009). To underline this reorientation, sales representatives
were instructed to focus on ‘symptoms and behaviours’ (Eli Lilly, 2000, cited
in Spielmans, 2009), rather than diagnoses, to emphasise the broad action of
olanzapine, and to encourage general practitioners to identify and prescribe to
‘higher functioning’ people at ‘the low to middle end’ of bipolar severity
(Porat, 2002, cited in Spielmans and Parry, 2010). Eli Lilly provided a number
of patient profiles for use by its sales representatives, ten of which were
revealed in the Zyprexa papers. The majority of these described people with
common and subjective problems such as those included under the rubric of
‘complicated mood,’ as well as others like distractibility, ‘a tendency to be
over-talkative’ and ‘erratic behaviour’ (Eli Lilly, undated, 2001, both cited
in Spielmans, 2009).
Wider experience with direct to
consumer advertising in the USA and New Zealand proved that patients themselves
could provide a useful marketing tool. In 2002, for example, it was estimated
that one out of every five medical consultations was instigated by a patient
who had seen an advertisement for a product or condition (Mintzes et al.,
2002). Associations between drug companies and patient support groups have also
provided a vehicle for changing opinions about the nature and frequency of
bipolar disorder and the role of drug treatment. In the UK the Manic Depression Fellowship promoted the use of ‘mood
diaries’ constructed by Eli Lilly, which encourage people to focus on their
mood in minute detail by rating it hour-to-hour. Measurement techniques of this
sort, which are available on numerous websites, uncover normal emotional
variations that occur in everyone. Once translated into numerical and visual
form, however, the fluctuations can appear unusual and worrying, and can easily
be construed as incipient bipolar disorder (Healy and Le Noury, 2007).
Eli Lilly and the Manic Depression
Fellowship also teamed up to produce leaflets and booklets whose message was
‘bipolar disorder is a lifelong illness needing lifelong treatment...people
feel better because the medication is working’. Anyone who might consider
stopping their medication was warned that ‘almost everyone who stops taking
medication will get ill again’ and that ‘the more episodes you have the more
difficult they are to treat’ (cited in Healy and Le Noury, 2007, p. 211).
Information produced by drug
companies, patient groups and professional organisations also emphasises the
idea that the disorder is caused by ‘chemical imbalances in the brain’
(AstraZeneca, 2012) that can be rectified with drugs. In 2011, for example, the
Geodon website (an atypical antipsychotic made by Pfizer) stated that ‘current
medicines are designed to help correct these imbalances’, accompanied by a
picture of a young woman sitting cross-legged, with her hands carefully
positioned on her knees, in a perfectly symmetrical and ‘balanced’ position
(Pfizer, 2011). The Manic Depression Fellowship, now renamed the Bipolar
Organisation, describes on its website how antipsychotics work by altering the
‘balance of a brain chemical called dopamine which is known to be abnormal in
mania and psychosis’ (Bipolar UK, 2012).
In the early years of the
twenty-first century, the media was flooded with stories about bipolar
disorder. In 2006 the BBC (British Broadcasting Company) screened a documentary
in which the well-known comedian Stephen Fry explored bipolar disorder and
‘owned up’ to having been diagnosed with the condition himself. The programme
won a prestigious Emmy award and did more to glamorise and popularise the
condition than any advertising campaign could wish to accomplish. Fry
interviewed a number of celebrities diagnosed with the condition, including
Hollywood actors, British comedians and television personalities, and many
other successful and enthralling characters. ‘Manic types do well in Hollywood,
in all of show business’ he mused. Describing his own problems, Fry admitted to
feeling ambivalent, hating the feelings of depression, but also describing the
‘huge buzz’ and ‘sense of adventure’ he experienced during his ‘manic’ periods.
‘I love my condition too’ he stated at one point,
continuing, ‘it has tormented me all my life with the deepest of depressions,
while giving me the energy and creativity that perhaps has made my career’. One
of his interviewees, a former businessman and imprisoned fraudster, wrote on
the bipolar support website he had set up: ‘still suffering in bliss and agony’
(BBC, 2006).
Despite these alluring aspects of
the so-called disorder, Fry stressed that the condition is a ‘serious’ ‘disease
of the brain’ and claimed that four million people in the UK have the
disorder—a staggering 8% of the adult population. He explored a number of forms
of treatment, including drugs, electro-convulsive therapy (ECT) and cognitive
behavioural therapy, and although he was unsure about the necessity or benefits
of receiving treatment himself, he seemed delighted with the diagnosis. ‘I
wouldn’t live a normal life’ he declared, ‘not for all the tea in China’. The
programme repeatedly emphasised the importance of early detection, claiming
that the condition was often unrecognised, and Fry saw his mission as
de-stigmatising the disorder so that more people would be willing to identify
themselves or those around them as ‘being bipolar’ (BBC, 2006). In this manner,
ordinary people were encouraged to aspire to this emblem of celebrity culture:
the exciting, stylish and tragic condition of the gifted and troubled soul.
Further Expansion
Following studies involving people with an acute
episode of mania, Eli Lilly set up a trial to examine the effects of long-term
treatment with olanzapine. It found that olanzapine was superior to placebo in
preventing a relapse of mania or depression in people who had recovered from an
episode of acute mania, but it has been criticised because all the participants
were taking olanzapine prior to entering the study, and the results suggest
that a discontinuation effect occurred. Half of the placebo group relapsed
within 22 days of randomisation, for example, and almost all of them had
relapsed within 3 months of the trial commencing, suggesting relapse was
constituted or precipitated by the effects of medication withdrawal (Tohen et
al., 2006). Even among the olanzapine-treated group, 47% of participants
relapsed within a year. Research that has examined the natural history of
bipolar I, or manic depression, in the era before supposedly specific drugs
like lithium were introduced has found that around 50% of people recently recovered
from an episode suffered a relapse over the following 2–3 years (Winokur, 1975;
Harris et al., 2005). In other words, people treated with olanzapine in the Eli
Lilly study relapsed in under half the time of the natural history of the
condition. Although a partial explanation may lie in
the loose definitions of relapse employed in modern clinical trials, the
evidence provides little reassurance that long-term olanzapine therapy is
better than no treatment at all.
Nevertheless, on the basis of this
one trial olanzapine received a licence for the prophylactic treatment of
bipolar I disorder and the National Institute for Health and Clinical
Exellence’s (NICE) guideline on the treatment of bipolar disorder published in
2006 recommended olanzapine alongside lithium and sodium valproate as the first
choice of medication for the long-term management of people with the condition
(National Institute for Health and Clinical Excellence, 2006). The guideline
also recommended quetiapine for the management of people with recurrent
depressive symptoms, and depression has since become a major market for this
drug. Although the process of instituting prolonged drug treatment for people
under the increasingly expandable bipolar umbrella was already well underway by
this time, official approval of atypical antipsychotics as the principle agents
of treatment provided further momentum to commercial efforts to ensure the
migration of these drugs out of the arena of severe mental disorder into the
much larger market of people with everyday ups and downs.
The case of quetiapine, or Seroquel,
also illustrates the on-going transformation of the market for antipsychotics.
Although initially launched as a treatment for schizophrenia and psychosis on
the basis of trials revealing mostly modest differences between the drug and
placebo (Leucht et al., 2008), it has since been promoted for use in mania and,
more recently, as a treatment for depressive symptoms, both in people diagnosed
with bipolar disorder and with simple depression. In 2009 AstraZeneca applied
to the United States Food and Drug Administration (FDA) for a licence to treat
depression and anxiety, which, if obtained, would have opened up a market
estimated to consist of more than 20 million Americans (USA Today, 2009). Following
advice from a panel of experts, the FDA rejected the application because of
concerns about the adverse effects of the drug, particularly its metabolic
effects and cardiac toxicity. It endorsed the use of Seroquel as an adjunctive
treatment for depression in people who have not responded to other drugs,
however, and, as the majority of people treated with antidepressants continue
to experience chronic or recurrent symptoms—85% of participants in the large
STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, for
example (Rush et al., 2012), this still represents an immense opportunity for
extending the drug’s reach.
Although some randomised controlled
trials have found quetiapine to have superior effects to a placebo for people
diagnosed with depression, scrutinising depression
trials reveals that the majority of the response to drug treatment is
attributable to the placebo effect (Kirsch et al., 2002). Moreover, any drug
with psychoactive properties, including many other antipsychotics, appears to
demonstrate an effect on depression in one clinical trial or another,
suggesting the portion of the response attributable to drug treatment is the
non-specific result of being in an altered, drug-induced state (Moncrieff,
2001). As with antidepressants, however, the effects of quetiapine are trivial.
Trials involving people diagnosed with depression or with a depressive bipolar
episode have typically found differences between the drug and placebo of only
2–3 points on the Montgomery–Åsberg Depresson Rating Scale (MADRS), which has a
maximum score of 60 (Bauer et al., 2009; Weisler et al., 2009; McElroy et al.,
2010; Bortnick et al., 2011). The large size of the studies, which mostly
involved several hundred people, has ensured that these small differences are
statistically significant, even though they do not represent a clinically
significant effect. Meanwhile, AstraZeneca is busy reaping the rewards of the
depression market, while propagating the adverse effects that the FDA panel
expressed concern about.
Paediatric Bipolar Disorder
Although it is the adult market that accounts for the
bulk of sales of atypical antipsychotics, it is the use of these drugs in
children alongside the emergence of the diagnosis of paediatric bipolar
disorder that best illustrates the way in which a severe mental disorder can be
morphed into a label for common or garden difficulties, as well as the role
that money plays in this process. As with adults who seek a bipolar diagnosis
to avoid confronting various personal or social difficulties, the concept of
paediatric bipolar disorder can appeal to parents because, like attention
deficit disorder (ADHD), autism, Asperger’s and numerous other diagnoses, it
provides a seemingly concrete label for difficult and challenging behaviour.
Moreover, by locating the problem in the brain of the child, it seemingly
detaches it from the situation within the family. The story of Rebecca Riley,
who died aged 4 after being diagnosed with bipolar disorder and ‘ADHD’, and
whose parents were convicted of her murder, illustrates the potentially tragic
consequences of this medicalisation of young children’s behaviour.
Rebecca Riley was found dead on her
parents’ bedroom floor in the town of Hull, Massachusetts, in the USA in 2006.
At the time of her death she had been prescribed quetiapine along with
Depakote, and another sedative drug, clonidine. On
the night she died her parents admitted to giving her extra doses of clonidine,
along with an over-the-counter cold remedy. The District Attorney’s medical
examination determined that she died from the combined effects of her
prescription medicine and the drugs contained in the cold remedy, and that her
heart and lungs were damaged by previous prolonged use of the prescribed
medication. Rebecca’s preschool reported that prior to her death she was so
drugged she had to be helped up the stairs and propped up in her chair (Able,
2007).
Prosecutors alleged that Rebecca’s
parents used prescription drugs to keep their three children quiet and in order
to obtain disability benefits, and they were noted to be applying for benefits
for Rebecca at the time of her death. A year before Rebecca’s death, her mother
had been found by the local social services department to have neglected her
children and her father had been accused of sexually abusing his 13-year-old
step-daughter (Able, 2007).
In 2010, both parents were convicted
of Rebecca’s murder by ‘intentional overdose’, and received long prison
sentences. Rebecca’s psychiatrist, Kayoko Kifuji, was defended by her employer,
Tufts Medical Centre, for practising appropriately and ‘within responsible
professional standards’ (Carey, 2007). The judge at the trial of Rebecca’s
father disagreed: ‘If what Dr Kifuji did in this case is the acceptable
standard of care for children in Massachusetts’ he concluded, ‘then there is
something very wrong in this State’ (Wen, 2010).
Before the tragic death of Rebecca
Riley, the American media had been reporting the increase in the diagnosis of
bipolar disorder among children as a positive development, whereby an
unrecognised, but real, condition was being uncovered. In an article entitled
‘Young and bipolar’ Time Magazine
reported on how manic depression or bipolar disorder was not as rare as
previously thought and that ‘Doctors ...are coming to the unsettling conclusion
that large numbers of teens and children are suffering from it as well’. The
article stressed the need for prompt diagnosis and treatment, and expressed
concern that without it ‘plenty of kids are suffering needlessly’ (Kluger and
Song, 2002).
David Healy and colleagues have
convincingly deconstructed the diagnosis of bipolar disorder in children. Prior
to the turn of the last century, as they point out, true bipolar disorder, or
manic depression, was thought to be vanishingly rare in children. From 2000
onwards, however, a variety of popular books and publications on the ‘bipolar
child’ started to appear, which described children with a variety of common
behaviour problems, including temper tantrums, irritability and poor sleep, finally being ‘recognised’ as displaying
signs of childhood bipolar disorder. Academic psychiatry fuelled this craze,
with added financial incentive from the pharmaceutical industry, but, in 2007,
when Healy’s paper was published, the scale of this liaison had not been
revealed (Healy et al., 2007).
In the 1990s, a group led by child
psychiatrist Joseph Biederman, who was based at Massachussets General Hospital
and the prestigious Harvard Medical School, started to suggest that children
could manifest ‘mania’ or bipolar disorder, but that it was frequently missed
because it was often co-existent with other childhood problems like ADHD and
‘antisocial’ behaviour (Faraone et al., 1998). In a paper published in 1996 the
group suggested that 21% of children attending their clinics with ADHD also
exhibited ‘mania’, which was diagnosed on the basis of symptoms such as
over-activity, irritability and sleep difficulties (Biederman et al., 1996). A
year later the group were referring to bipolar disorder in children as if it
were a regular, undisputed condition, and emphasised the need for ‘an
aggressive medication regime’ for children with the diagnosis (Bostic et al.,
1997).
As Healy observed, the more bipolar
disorder in children was written and spoken about, the more it appeared to be a
legitimate condition (Healy, 2008). In 2003 another group of academics
formulated official ‘treatment guidelines’, which were published in the leading
American journal of child psychiatry. Like Biederman’s group, the authors of
the guidelines stressed the importance of ‘early diagnosis and aggressive
treatment’ (Kowatch et al., 2005, p. 214). They acknowledged that children with
bipolar disorder did not meet official diagnostic criteria because they did not
have clearly defined episodes and their ‘symptoms’ were not prolonged and
severe. In fact, the discussion makes it plain that the condition being
considered was quite different from bipolar disorder or manic depression as it
presents in adults. Children with bipolar disorder do not have discrete periods
of mania, the guidelines stated, but rather have ‘frequent daily mood swings
that have been occurring for months to years’ (p. 214). Moreover, the ‘mood
swings’ are most commonly characterised, not by elation and excitement, as in a
classical manic episode, but by ‘intense mood lability and irritability’ (p.
14). Instead of drawing the obvious conclusion that the behaviours being
diagnosed as ‘bipolar’ in children have no relation to the protracted episodes
of over-arousal and euphoria characteristic of typical adult mania, the
guideline authors suggested that different or adapted criteria were necessary.
They recommended treatment with antipsychotics, lithium and other ‘mood
stabilisers’, and regimes involving combinations of
two or more drugs were suggested to be needed in the frequent cases where a
single drug produced only a ‘partial’ response. Moreover, additional medication
was said to be required for the frequently occurring concurrent disorders like
attention deficit disorder and anxiety.
The guidelines were the product of a
two-day meeting held under the auspices of the Child and Adolescent Bipolar
Foundation, which was sponsored by Abbott Laboratories, AstraZeneca, Eli Lilly,
Forest Pharmaceuticals, Janssen, Novartis and Pfizer. In the same year that the
guidelines were published, several companies sponsored a symposium at the
American Psychiatric Association’s annual meeting in San Francisco on ‘juvenile
bipolar disorder’, which featured four talks by Biederman’s group (Healy,
2008). By this time, the group had started to run trials of various
antipsychotics for the treatment of bipolar disorder in children, sponsored by
the manufacturers of the drugs involved. By 2012, risperidone, olanzapine,
ariprirazole and zisprasidone had been investigated, mostly in small-scale
studies that were not conducted double blind. The drugs were said to have
beneficial effects on symptoms of ‘mania’, which is most likely attributable to
their sedative properties, and the researchers concluded that larger double
blind studies were justified. One of these studies was aimed at pre-school
children aged between 4 and 6 years (Biederman et al., 2005), and children were
recruited to these trials through advertisements that told parents that challenging
behaviour and aggression in young children might stem from bipolar disorder
(Healy, 2008). The trials revealed high rates of adverse effects, including
substantial weight gain, especially with olanzapine. In one study children
gained 5 kg after only 8 weeks of olanzapine treatment (Frazier et al., 2001),
but instead of stopping the research in its tracks, the researchers added more
drugs to the mix in an attempt to combat the metabolic effects of the
antipsychotic (Wozniak et al., 2009).
These trials were run from the
Johnson & Johnson Centre for Paediatric Psychopathology Research, which was
set up with money from Janssen Pharmaceuticals, the makers of risperidone, at
the request of Joseph Biederman. Documents relating to the centre’s objectives
were released during litigation brought by parents who alleged their children
had been harmed by antipsychotic drugs. The centre’s annual report of 2002
stated that the centre’s research should satisfy three criteria: it should
improve psychiatric care for children, have high standards and ‘move forward
the commercial goals of J&J’. The report went on to state that the
activities of the centre would lead to ‘safer, more appropriate and more widespread use of medications in children’ (my
emphasis) and that without the data the centre could
produce ‘many clinicians question the wisdom of aggressively treating children
with medications, especially those like neuroleptics, which expose children to
potentially serious adverse events’. An e-mail from a Johnson & Johnson
executive stated that the rationale of the centre was to ‘generate and
disseminate data supporting the use of risperidone’ in children and adolescents
(Harris and Carey, 2008).
In 2008, just before these reports
were made public, an investigation by the Republican senator Charles Grassley
revealed that Biederman and some of his colleagues had failed to declare
millions of dollars of personal income they had received in consultancy fees
from drug companies. When pressed by Senator Grassley, Biederman belatedly
admitted to receiving $1.6 million from drug companies between 2000 and 2007,
and his Harvard colleagues, psychiatrists Timothey Wilens and Thomas Spencer,
admitted to receiving $1.6 and $1 million respectively. Even these figures may
be an underestimate, however, as information provided to Senator Grassley by
the drug companies indicated even higher payments (Harris and Carey, 2008). The
fact that the researchers had failed to declare the extent of their income
violated the conditions of the substantial federal funds they had received to
conduct research and their programme was temporarily suspended.
Before the scandal erupted, the head
of psychiatry at Harvard assured reporters that Biederman would not be
influenced by his association with drug companies: ‘For Joe, it is his ideas
and mission that drive him, not the fees’ (Allen, 2007). This was before the
extent of these ‘fees’ became public, but even afterwards it seems that Harvard
did not see the incident as meriting serious punishment. The only sanctions
levied against the three offenders were that they had to refrain from
conducting company-sponsored research for 1 year, and subsequently submit
proposals to conduct such research for approval for a further 2 years. They
were also told that they might face a delay in consideration for promotion, but
as all three were already at professorial level, it is not clear that this
would affect their prestige or income in any way (Yu, 2011).
Biederman continues to publish
numerous papers on the drug treatment of childhood conditions, including
so-called paediatric bipolar disorder. In 2011 his group published a major
review of drug treatments for the condition, in which they declared that
‘pediatric bipolar disorder is a chronic, severe, and often disabling psychiatric
condition’, with no reference to any criticism of the concept (Liu et al.,
2011, p. 749). In 2012 the group published a study of the antipsychotic
quetiapine for ‘bipolar spectrum disorder’ in preschool children aged 4–6 (Joshi et al., 2012). The restrictions imposed by
Harvard seem hardly to have dented Biederman’s research activities, which
currently receive support from the drug companies Janssen, Shire and Next Wave
pharmaceuticals (Joshi et al., 2012).
Neither Harvard nor Massachusetts
General Hospital, nor any other psychiatric or medical institution has
commented on the fact that prominent academics were found to be enriching
themselves to the tune of millions of dollars through researching and promoting
the use of dangerous and unlicensed drugs in children and young people.
Although some individual psychiatrists have expressed misgivings (Able, 2007),
academic papers continue to discuss the diagnosis, treatment and outcome of
bipolar disorder in children as if no controversy existed, with more than 100
papers on the subject published in Medline-listed journals between 2010 and
2012. Notwithstanding the death of Rebecca Riley and the disgrace of Joseph
Biederman, the practice of diagnosing children with bipolar disorder and
treating them with antipsychotics remains alive and kicking.
Off-Label Prescribing
Papers released during recent court actions have
revealed that several drug companies deliberately engaged in illegal strategies
to market atypical antipsychotics in situations in which their use was not
licenced, particularly in nursing homes for use in elderly people with
dementia. According to the Zyprexa papers, people with dementia were one of the
principle targets for the promotion of olanzapine (Spielmans, 2009). At first
it appears that Eli Lilly and some other companies intended to obtain a licence
for the use of atypical antipsychotics in dementia to manage psychotic symptoms
along with agitation and behaviour problems. Unfortunately, although trials of
risperidone and ariprirazole showed small reductions in the occurrence of
challenging behaviours, olanzapine did not perform any better than placebo, and
it soon became apparent that the use of any of these drugs hastened death in
this group of vulnerable elderly people whose nervous systems were already
compromised (Schneider et al., 2005, 2006). Moreover, as we saw in Chapter 9, the studies revealed that antipsychotics
worsen rather than improve cognitive function in people with Alzheimer’s
disease or dementia (Schneider et al., 2005). A study involving people with
learning disability and behavioural problems also found that neither
haloperidol nor risperidone improved aggression more than a placebo over a
4-week period (Tyrer et al., 2008). So although antipsychotics are undoubtedly effective for the immediate containment of
challenging and aggressive behaviour (see Chapter
8), the evidence suggests that they are not particularly useful when
used continuously over longer periods.
In 2008 the British government
commissioned a report into the use of antipsychotic drugs in people with
dementia. The report concluded that while 180,000 people with dementia received
these drugs, less than a fifth of them derived any benefit, and that around 1800
excess deaths were caused by their use in England alone each year (Banergee,
2009).
Eli Lilly appeared to abandon its
attempts to obtain a licence for the use of Zyprexa in dementia by 2003, but,
like other atypical manufacturers, the company was not deterred from continuing
to promote the drug illegally, as the Zyprexa papers suggest it had been doing
since the 1990s (Spielmans, 2009). In 2009 Eli Lilly was fined $1.4 billion for
these activities, the largest corporate fine in US legal history at the time.
The United States Justice Department stated that the drug had been marketed for
behavioural problems in people with dementia, as well as for ‘generalised sleep
disorder’ and depression in the general population (United States Department of
Justice, 2009). Later that year an even bigger fine of $2.3 billion was levied
against Pfizer for illegal marketing of several drugs, including its
antipsychotic Geodon (zisprasidone), which was the fourth time Pfizer had been
fined for such practices in 5 years (Harris, 2009). In 2010 AstraZeneca was
fined $520 million for promoting Seroquel for unapproved uses, including
aggression, dementia, anger management, anxiety, attention deficit disorder,
post-traumatic stress disorder and sleeplessness (United States Department of
Justice, 2010). Johnson & Johnson agreed to pay the US government $2.2
billion in 2012 as a penalty for allegations of illegal marketing of Risperdal
and other drugs, including the claim that it had provided financial inducements
to the nursing home pharmacy company, Omnicare Inc., to recommend Risperdal
(Fisk et al., 2012). Later in the year it was ordered to pay a further $1.2
billion by the state of Texas for illegal promotion of Risperdal (Thomas,
2012).
When a company seeks a licence for a
product it has to demonstrate that, for a particular problem in a particular
group of people, giving the drug concerned is better than doing nothing.
Although the placebo-controlled trials that are thought to provide this
evidence have many drawbacks, as we saw in Chapter
6, the licensing process at least involves an attempt to evaluate
the pros and cons of drug treatment. When drugs are used for situations in
which approval has not been obtained, there may be no evidence that the drug is
of any use at all, let alone safe.
All is not as it Seems
The conventional history of antipsychotics presents
them as the miracle drugs that finally banished the dark days of
straight-jackets and lobotomies, and allowed psychiatry to rise out of its
ambivalent position straddling medicine, social work and criminal justice to
become a fully-fledged member of the medical sciences. Antipsychotics were
proclaimed to be the first intervention that worked in a truly medical manner,
not just suppressing symptoms but targeting an underlying disease, and this
belief seemingly confirmed the psychiatric profession’s longstanding contention
that mental disorders arise from distinct, biological anomalies just like other
medical conditions. The fact that now-discredited interventions, such as
insulin coma therapy, had also been regarded as acting in a disease-specific
manner was soon forgotten, and antipsychotics, along with other drugs developed
since the 1950s, came to be seen as a completely new and unique sort of
treatment, quite different from anything that went before.
The early antipsychotics ushered in
the age we now inhabit, in which drugs have come to be seen as ‘magic bullets’
that can eradicate all sorts of unwanted experiences and behaviours. The
‘antidepressants’, which followed close on their heels, were claimed to remedy
the ancient state of melancholy or despair, ‘anxiolytics’ apparently abolished
the tendency for worry and fear, and stimulants could rectify children’s unruly
behaviour. More recently it has been claimed that drugs can make us happier
(Kramer, 1993), cleverer (Greely et al., 2008) and will finally prevent us from
aging (Cooper, 2011).
From the beginning, however, the
story of the antipsychotics is not as it seems. From the ‘creation myth’, where
it transpires that the heroic surgeon Laborit was a quack with ‘screwy ideas about
the treatment of shock’ (Swazey, 1974, p. 272), to the clinical trial evidence
that shows that the drugs do not reduce psychotic
disturbance much more than a placebo, most of the cherished beliefs about these
drugs do not stand up to scrutiny. Most traditional accounts give no hint that
Laborit’s idea that shock should be treated by counteracting the body’s
physiological reactions had long been rejected by the majority of his
profession, and that his anaesthetic cocktails designed to produce a state of total
bodily shut-down were unusual and highly dangerous. With a track record of such
hazardous procedures as insulin coma therapy, ‘deep sleep therapy’ and
lobotomy, safety was, in any case, no impediment to psychiatry’s acceptance of
a new intervention at that time. The conventional account presents the pioneers
of modern drug treatments as fighting a heroic battle against the entrenched
forces of psychoanalysis (Swazey, 1974; Healy, 1996), but in reality it appears
little resistance was offered, and psychiatry, which was already adept at
interfering with the body, was ripe for the introduction of a new physical
technique, especially one that could be administered as easily as a drug.
By the 1970s if not before, the idea
that antipsychotics target the basis of an underlying brain disease or
abnormality was widely accepted, although there was no evidence that could
confirm such a notion. Even now, there remains almost no research which could,
or does establish that antipsychotics have a disease-centred mechanism of
action in schizophrenia, psychosis or any other disorder. The desire to have
disease-specific treatments was so overwhelming, however, that the mere
suggestion that antipsychotics could act in this way was embraced
enthusiastically and more or less without debate. The aspirations of the
psychiatric profession united with political ambitions to reduce the bill for
the care of the mentally disabled, to make the myth of a disease-specific
therapy into a seeming and unquestioned reality. Once adopted, the psychiatric
community chose to forget that there was any other way to understand the action
of its drugs. By the 1990s the disease-centred model was so entrenched that no
one even thought it necessary to describe or explore the psychoactive and
physical state induced by the new, ‘atypical’ antipsychotics introduced at the
time.
The psychiatric establishment has
had to make strenuous efforts to suppress alternative ways of thinking about
the action of its drug treatments, however, and although the usual response to
any countervailing view is to ignore it, when critics gain publicity the
reaction can be harsh. The American Psychiatric Association (APA) and the
pro-drug National Alliance for the Mentally Ill (NAMI) combined forces against
Peter Breggin, for example, after he appeared on the Oprah Winfrey show in 1987. Acting on transcripts handed over by the
APA, NAMI lodged an official complaint about Breggin’s medical licence with the
Maryland State licencing authority, alleging his appearance on the programme
had encouraged patients to stop taking their psychiatric medication. The
complaint referred to some final, informal remarks Breggin had made to Oprah on
the subject of how to obtain help, when he suggested that people in distress
should seek a psychotherapist instead of a psychiatrist, and should not take
drugs if they were offered them. At no point did he recommend that anyone
should stop taking a medicine they were already prescribed. Breggin was
completely vindicated by the licencing board, which agreed with him that his
accusers had attempted to curtail his right to free speech (Anonymous, 1987;
International Center for the Study of Psychiatry and Psychology, 2009).
British-based psychiatrist David
Healy was the victim of a similar attack during his long-standing campaign to
draw attention to the drug-induced effects of the selective serotonin reuptake
inhibitor antidepressants (SSRIs) and their ability to drive some people to
think of, or attempt, suicide (Healy, 2006a). More common than malicious attempts
to discredit individuals and deprive them of their livelihoods, however, is the
elimination of dissent through silence. Breggin has been making his argument
about the nature of psychiatric drugs since the 1980s, based on a detailed
analysis of the scientific evidence, but there has been no debate about his
views in the mainstream literature and no attempt to refute them. The refusal
to acknowledge that there are other ways of conceptualising how psychiatric
medications produce their effects means that many mental health professionals,
and much of the wider public, have the impression that the disease-centred
model of psychiatric drug action is the only credible, or even possible, way of
thinking about what these drugs do.
Although not all psychiatrists
subscribe to a disease-centred view of their drug treatments, nevertheless, the
drug-centred model presents a fundamental threat to the beliefs that underpin
the biologically oriented psychiatry that has been on the ascendance since the
1970s. Although the drug-centred model does not in itself involve any
supposition about the nature of mental disorders, challenging the
disease-centred model of drug action can be perceived as undermining the very
basis of modern psychiatry because the idea that present-day drugs target
underlying biological abnormalities is believed to represent the strongest
evidence that mental disorders are diseases ‘like any other’. As part of an
intellectual debate the drug-centred view is tolerated because it can be
ignored, but when it is taken to the people the argument has to be silenced in case the weakness of the medical model
of mental disturbance is exposed.
The Effects of Antipsychotics
The adoption of the disease-centred model of
antipsychotic action in the 1950s and 1960s led research to focus increasingly
on the effects of the drugs on the proposed disorder or disease. The result was
an abundance of clinical trials, which created the impression that we know a
great deal about these drugs. The message that emerged was that antipsychotics
make people better in the short-term, and prevent relapse in the longer term.
People in general fare better when treated with antipsychotics than they would
do without them. It turns out that these studies can throw little light on the
question of whether it is better to take antipsychotics than not to, however,
nor on whether taking antipsychotics improves the long-term outlook for people
diagnosed with schizophrenia or psychosis. Looking at these studies in detail
reveals that the vast majority were conducted with people who were already
established on antipsychotic drugs. In fact, most studies involved people who
had been taking medication for many years—including the initial studies of the
atypical antipsychotics.
These studies only tell us what
happens when someone stops taking antipsychotics, not what effects the drugs
have when they are first started. Astoundingly, no proper clinical trials have ever been conducted involving only people who had not
previously been exposed to anti psychotic medication. There is reasonable
evidence from early trials that antipsychotics reduce the symptoms of an acute
psychotic disturbance for a short period, but other than this fairly
predictable observation, the thousands of studies that have been conducted since
the 1950s and 1960s tell us almost nothing about the ultimate value of
antipsychotic treatment.
Moreover, randomised clinical trials
provide little information about what the drugs are actually doing when they
reduce symptoms, and the rich descriptions provided by people who have taken
the drugs themselves and the careful clinical observations made by early
researchers, have been lost from the scientific literature because the
presumption that the drugs work in a disease-specific manner renders them uninteresting
and unimportant. In modern textbooks and journal articles we can only glimpse
the nature of these drugs through sterile lists of ‘side effects’. Yet,
first-person accounts indicate how antipsychotics can dampen down psychotic
thoughts and experiences along with most other
aspects of mental and physical functioning. It is a state that is usually found
to be unpleasant, but may be judged as preferable to being assailed by intense
psychotic phenomena.
What is politically useful and at
the same time most dangerous about the disease-centred view of drug action is
the way it obscures the pharma cological nature of antipsychotics and other
psychiatric drugs. By focusing attention on the disease the drugs are thought
to treat, rather than the drugs themselves, the model diverts attention away
from the dangerous and debilitating effects the drugs induce. Because
antipsychotics are construed not as toxins, like recreational drugs, but as
medicines, it is assumed that their effects are necessarily benign, and there
is a corresponding tendency to dismiss or ignore their adverse effects,
especially if these are linked to their desired, therapeutic actions. The saga
of tardive dyskinesia—the minimisation of its prevalence, attempts to blame the
condition and the almost complete eclipse of research suggesting it involves
general mental impairment as well as involuntary movements—was repeated in many
of its elements in subsequent decades. Drug companies mirrored the psychiatric
profession’s approach to tardive dyskinesia by seeding the idea that the
metabolic toxicity caused by some of the atypical antipsychotics might be
attributable instead to the condition of schizophrenia. This strategy helped to
delay the backlash against these drugs long enough to establish their position
as market leaders, even though the pronounced obesity they cause is plain for
everyone to see.
In a similar way, the fact that
people diagnosed with schizophrenia are often found to have smaller brains than
other people was, for many years, presented as incontrovertible evidence that
schizophrenia is rightly thought of as a brain disease. A small number of
researchers now quietly admit that the evidence suggests that long-term
antipsychotic treatment is what shrinks brains, although the idea that
‘schizophrenic’ brains are somehow different appears to be hard to relinquish
completely. But evidence on the effects of antipsychotics has been available
for decades now, and for decades Peter Breggin has been pointing it out.
The lack of interest in clarifying
the long-term effects of antipsychotics is perhaps most striking given that
long-term treatment is the norm for almost all situations in which
antipsychotics are used. We do not know the extent to which people and animals
become ‘tolerant’1
to the immediate effects of antipsychotics, despite research that demonstrates
that the body starts to increase the sensitivity of dopamine receptors within
days of starting on a drug like haloperidol (Samaha et al., 2007). We have
little information on the nature and range of withdrawal effects,
and we know almost nothing about the impact of long-term antipsychotic use on
intellectual function, even though it has been well demonstrated that
short-term use impairs the mental abilities of human volunteers and animals.
Although some evidence suggests that long-term antipsychotic treatment may, in
itself, increase an individual’s vulnerability to having a psychotic episode or
relapse (including what is sometimes referred to as ‘supersensitivity
psychosis’), we are no nearer confirming whether this effect exists and, if so,
how frequently it occurs and by what mechanism. In fact, we remain ignorant of
the mechanism behind many of the drugs’ most common and profound effects,
including the sedation they produce, the metabolic disturbance and tardive
dyskinesia.
An almost religious commitment to
the disease-centred view of psychiatric drug action has created a blind spot to
the serious physical consequences that long-term ingestion of toxic substances
is likely to produce, and drug companies are still able to present
antipsychotic drugs as innocuous and restorative agents that work by balancing
the brain’s ‘natural chemicals’ (Eli Lilly, 2011). The history of antipsychotics
illustrates how far the Hippocratic oath, ‘first do no harm’, is from being
followed, and how strong is the opposite inclination to view interventions
visited on ‘patients’ by ‘doctors’ as an inevitable and undiluted blessing.
Antipsychotics and Diagnosis
The rise of the disease-centred model of drug action
has gone hand-in-hand with the application of medical-type systems of diagnosis
to the troubles of the mind. Starting in the 1970s, as a response to challenges
to mainstream psychiatry from the antipsychiatry movement and economic
competition from non-medically-qualified therapists, the conception of mental
illness was thoroughly ‘remedicalised’ (Wilson, 1993). The new orientation was
expressed in the third edition of the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM)
published in 1980, which expunged the psychoanalytic influence of previous
editions and adopted a seemingly objective and explicit approach to assigning
labels to disordered behaviour (American Psychiatric Association, 1980a). The
new approach was intended to parallel medical taxonomy and numerous distinct
disorders were devised, each defined by lists of characteristic behaviours and
experiences. Subsequent editions of the manual have grown, with more and more
disorders being added and some being taken out, just as homosexuality was famously removed in the 1970s. The latest version, DSM-5, came close to including a diagnosis for a situation
in which someone might develop a disorder in the
future. Even without the proposed ‘psychosis risk syndrome’, however, the new
edition expands the net of medicalisation further over ordinary experience,
with critics claiming that it will pathologise ‘mild eccentricity, loneliness,
shyness, sadness and much else’ (P. Kinderman cited in Watts, 2012)).
The credibility of the modern DSM and similar systems (the International
Classification of Diseases version 10, for
example) lies in the implication that the various labels they propose indicate
the presence of an underlying disease, which particular treatments can target
and rectify. In fact, faith in the specificity of drug treatment formed one of
the foundations of the new approach to psychiatric classification. The
architect of DSM-3, psychiatrist Robert Spitzer,
defended the validity and utility of psychiatric diagnosis against its critics
in the 1970s by citing the ‘superiority of major tranquilisers [antipsychotics]
in schizophrenia, of electro-convulsive therapy in depression, and more
recently of lithium carbonate for the treatment of mania’ (Spitzer, 1975, p.
450).2
Indeed, as Spitzer recognised, if the process of diagnosis cannot direct the
choice of treatment, then it has no practical or convincing purpose. The idea that
the new drugs worked by attacking the underlying disease process provided the
new diagnostic systems with the legitimacy they needed. In turn, these new
systems helped to construct the use of mind-altering drugs as medical
treatments rather than chemical suppressants. Psychiatric theory became a
self-perpetuating cycle, with the illness model of mental disturbance justified
by the disease-centred model of drug action, which was itself bolstered by the
idea that mental disorders are properly thought of as discrete,
biologically-based ‘diseases’.
The concept of schizophrenia
illustrates this interaction and the way that a drug-centred approach threatens
the biological conception of psychiatry and its activities. The idea that the
drugs used to treat people with schizophrenia and psychosis act by targeting an
underlying, brain-based abnormality is considered as evidence that these
conditions are manifestations of a discrete disease. Following from this belief
in the disease-centred nature of drug action, the biochemical effects of the
drugs, such as their ability to reduce dopamine activity, were presumed to
point to the basis of the proposed disease. Because the assumption of
disease-specific drug action was not perceived to be an assumption, it came to
be believed that abnormal dopamine function lay at the root of schizophrenic or
psychotic symptoms, and this dopamine ‘hypothesis’ then appeared to constitute
evidence that antipsychotic drugs work by targeting
the underlying disease. Challenging the disease-centred model of drug action
therefore removes one of the foundations for the current case that
schizophrenia and psychosis should be regarded as bona fide brain diseases in
the same sense as conditions like epilepsy or encephalitis. Of course, other
evidence might still be found to support the idea that these disorders
originate from identifiable brain lesions, and disease-centred treatments might
eventually be discovered. The fact that current treatments do not work by
targeting a disease process does not mean that there is no disease to be
uncovered. But it does reveal that we have not found it yet.
Antipsychotics and Psychiatric Care
Examining the history of antipsychotics from a
drug-centred perspective helps to resolve the debate between those who claim
that the introduction of antipsychotic drugs was responsible for emptying the
asylums, and those who maintain that community care was driven by political
imperatives. It would be surprising, from what we have learnt, if the use of
antipsychotics did not reduce levels of disturbed behaviour such that people
could more easily be accommodated outside the confines of a large institution,
and in that sense the drugs can be credited with having hastened the decline in
the mental hospital population, even if they did not initiate it. It is
doubtful that more people are living independently now than in the era before
the introduction of modern drugs, however, and people diagnosed with
schizophrenia still occupy more hospital beds, for longer periods, than people with
any other medical or psychiatric condition (Pillay and Moncrieff, 2011). David
Healy and colleagues found that people with severe psychiatric disorders, such
as those diagnosed with schizophrenia, currently spend several more years in an
institution of some sort (including supported accommodation like residential
homes) than they did 100 years ago (Healy et al., 2005). A process referred to
as the ‘re-institutionalisation’ of mental health care has been documented
across Europe since the 1990s, with reductions in ordinary psychiatric hospital
beds compensated for by an increase in places in residential and nursing homes,
alongside a rise in the provision of privately-run, secure facilities (Priebe
et al., 2005). The head of the National Institute of Mental Health, American
psychiatrist Thomas Insel, even admitted that ‘despite five decades of
antipsychotic medication and deinstitutionalisation, there is little evidence
that the prospects for recovery have changed substantially in the past century’
(Insel, 2009, p. 130).
In a similar way, an uncritical
faith in the benefits of drug treatment facilitated the introduction of laws
that allow people to be forced to continue psychiatric medication after they
have been discharged from hospital. Dressed up as a process of enabling people
to receive a necessary medical intervention, compulsory community treatment
enforces drug-induced suppression beyond the bounds of a ‘bricks and mortar’
institution, creating a virtual net of control and containment. Although a
randomised controlled trial of the use of Community Treatment Orders found that
they did not reduce hospital admissions (Burns et al., 2013), they appear to be
increasingly employed to enable people to be discharged from hospital earlier
than they would have been otherwise. In this way compulsory community treatment
reduces the financial costs of providing for the mentally distressed, while
helping to maintain the peace of mind of the community at large. The price is
borne by those who lose their liberty and autonomy maybe for ever, but perhaps
also by all of us, as the principle of self-determination is gradually whittled
away.
The Patients’ Predicament
Understanding antipsychotic drugs through a
drug-centred lens also helps to explain how they can be both the scourge of
modern psychiatry—the ‘drug prison’ described by some
of those who have been forced to take them (Breggin, 1993a, p. 57)—and a useful
intervention that can reduce unwelcome thoughts and emotions, particularly in
people suffering from what is currently labelled as psychosis or schizophrenia.
As we saw in Chapter 7, the mental
suppression and emotional restriction the drugs produce can help drive
intrusive and preoccupying psychotic experiences into the background, and
dissipate their intensity and significance, at the same time allowing ‘sane’
modes of thinking and behaving to re-emerge from psychotic turmoil. Severe
mental disturbance can blight a person’s whole existence and in this situation antipsychotic
treatment, despite its many drawbacks, may be able to provide a quality of life
that might not otherwise have been possible. The drugs do not always work,
however. People can continue to be preoccupied with internal phenomena, and
some prefer to remain in a psychotic world that is vibrant and intense than be
transported back into a muted and stifled version of reality. For many people,
as illustrated by the stories in Appendix 2, the drugs may reduce the intensity of
psychotic experiences and lessen the distress they produce, but symptoms and
difficulties persist, often compounded by the noxious effects of the drugs.
What we are to make of the near
universal practice of prescribing these drugs for years upon end is the most
pressing question we face. Are the experts who made up the Schizophrenia
Commission right that antipsychotic drugs are the ‘cornerstone of treatment for
schizophrenia and psychosis’, and the ‘foundation upon which personal recovery
is based’, or should we heed Robert Whitaker’s warning that long-term drug
treatment has created an iatrogenic epidemic of adverse effects and increased
dependency (Whitaker, 2010; Schizophrenia Commission, 2012, p. 29)? Is the
treatment worse than the cure, as even some high-profile psychiatrists now seem
to be suggesting (McGlashan, 2006; Tyrer, 2012)? There are indications that
some people diagnosed with an episode of psychosis, and even with full blown
schizophrenia, might function better in the long run by not taking
antipsychotics, at least not continuously over long periods. We certainly know
from historical data that not everyone who experiences a psychotic breakdown
requires long-term medication. We also know that people who develop tardive
dyskinesia undergo a decline in their mental abilities. What is less certain is
whether long-term antipsychotic use leads to other types of deterioration,
including behavioural changes, worsening psychosis and more generalised
intellectual impairment, all of which might cancel out any beneficial effects
the drugs might have in terms of reducing symptoms or
risk of recurrence. We urgently need to clarify how antipsychotics impact on
the ultimate course of psychotic conditions such as ‘schizophrenia’, and whether
their long-term use contributes to the poor outcome of people given this
diagnosis in the Western world.
While accepting the necessity of
using antipsychotics in some circumstances, the data presented in this book
suggest they are dangerous substances that should be avoided where possible.
Current mental health services provide little opportunity for severe mental
disorders to be managed without recourse to prolonged drug treatment, yet
experiments like the Soteria project and the Finnish study demonstrate that
this is possible within a supportive environment or network. A minority of
people can endure a psychotic episode without any antipsychotic treatment and
many others require only small amounts of medication on a temporary basis.
Helping people in this way is likely to be more labour intensive, costly and
protracted than the short, sharp solution that antipsychotics offer, however,
and as bed numbers shrink and funds are squeezed, mental health services are
more reliant than ever on drugs. There needs to be a radical change of attitude
and practice before alternative approaches could be countenanced and
implemented effectively within mainstream services, and the political
commitment would need to be in place to provide the resources and the assurance
to underpin the necessary changes. Many patients and carers want to see
alternative approaches to the treatment of severe mental disturbance, however,
in which antipsychotic medication is avoided or minimised.2
Where antipsychotics are used to
treat an acute and severe psychotic episode, a policy of discontinuing
antipsychotic medication after someone has recovered from their symptoms—and
not many months or years afterwards—may offer the best chance of avoiding all
the dangers associated with long-term treatment. In this way, people who would
never have had another breakdown are not consigned to a lifetime of unnecessary
exposure to harmful substances. Although people may need support to withdraw from
antipsychotics safely, the costs of allowing people to continue on these toxic
drugs may greatly outweigh the expenses incurred in enabling people to stop
them. Not everyone will succeed, but every person that does reduces the
considerable burden of drug-related disease and death, and for the individual
there is also relief from sexual impairment, mental slowing, emotional
suppression and agitation to name just a few of the unpleasant and debilitating
effects that antipsychotics produce.
Without recognising that
discontinuation may itself provoke unwanted effects, however, the process of
medication withdrawal may simply entrench the view
that long-term treatment is indispensable. People need to be given the chance
to see if post withdrawal difficulties resolve with time or with other
temporary measures, rather than being told, as many now are, that their attempt
to stop medication has failed and that they were foolish to want to try it in
the first place. People inevitably make different choices and some may opt to
accept on-going drug treatment, especially if their symptoms are severe or
disruptive. Yet others may decide to accept the risk of future relapses rather
than embarking on a lifetime of chemical subjection. The important point is
that people should be free to make their own choices about antipsychotic
medication unless there are good legal reasons why they should not.
It should be acknowledged that in
many circumstances antipsychotic drugs are not used because the individual
finds them helpful, in fact, but because other people, or society in general,
cannot tolerate the person’s behaviour. Framing this situation as the treatment
of a medical condition confuses and obscures the reality of what is
involved—the forcible modification of behaviour using drugs. The
disease-centred theory of antipsychotic action has played a major part in the
obfuscation of the social control function that has always been embedded at the
heart of psychiatric practice. The idea that antipsychotics target an
underlying disease means that even when people are pinned down to the ground to
be forcibly injected, they can be said to be receiving a therapeutic
intervention administered for their own benefit. When the practice of forced
drugging is portrayed honestly, it is clear that it requires open, transparent
and democratic debate and scrutiny, none of which can occur properly while it
is dressed up as a medical treatment. It is also apparent that physical
measures might be preferable from the point of view of the individual on the
receiving end of pacification techniques. It may be less frightening to be
restrained or placed in a seclusion room than to have your mind and body
invaded by a foreign chemical substance. Physical methods also brook no denial
about the nature of the situation. It is not necessarily wrong to make people
change their behaviour if it is seriously antisocial, threatening or dangerous.
It is imperative, however, that as a society we should feel a sense of guilt
and responsibility about trying to do so, and be prepared to think honestly
about the methods we use to do it.
The Creeping Expansion
Although antipsychotics have a place, in my opinion, in
the treatment of people with serious mental disorders like psychosis or
schizophrenia, the same balance of considerations
does not apply in people with other, less devastating conditions. We should be
particularly concerned about the recent epidemic of antipsychotic prescribing
that has been encouraged by the pharmaceutical industry. Not only have the
boundaries of psychosis been stretched so far that any teenager with unusual
behaviour might qualify as having early signs of psychosis or schizophrenia,
antipsychotics have spread their tentacles out into the realm of what David
Healy once called ‘everyday nerves’ (Healy, 2004). Antipsychotics are now
frequently prescribed for depression and anxiety, and packaged under the less
frightening name of ‘mood stabilisers’ they are promoted for the vague, new
version of bipolar disorder—a diagnosis that can now be applied to almost
anyone.
In many of these situations the
drugs have not been properly tested and, where trials have been conducted, it
is impossible to tell whether they have any real benefit over and above the
sedative effects they are known to produce. What is certain is that the
metabolic impairment, cardiac toxicity and neurological damage they induce can
occur in anyone, regardless of the individual’s diagnosis or the nature of
their problems. It is highly unlikely therefore that the benefits of
antipsychotics outweigh the risks in people who do not suffer from the most
severe forms of mental disturbance. The increasingly indiscriminate prescribing
of these noxious substances represents a substantial public health problem
waiting to happen. The vision of a population incapacitated by prolonged
chemical toxicity may yet be realised if we don’t wake up to the real nature of
antipsychotic drugs.
1 Cure or Curse: What Are Antipsychotics?
1. Receptors are
chemicals on the outside of brain cells to which neurotransmitters attach and
through which they effect their actions.
2. Laing’s precise
phrasing was ‘a perfectly rational adjustment to an insane world’.
3 Magic Bullets: The Development of Ideas on Drug
Action
1. I am indebted to
other accounts that have noted how a disease-centred view of antipsychotic
action emerged during the 1950s and 1960s, especially those of David Healy,
Robert Whitaker and Sheldon Gelman (Gelman, 1999; Healy, 2002; Whitaker, 2002).
2. The
‘extrapyramidal’ system denotes the brain centres responsible for the involuntary control and regulation of movement, and is so
named to contrast with the ‘pyramidal’ system, which is a pyramid-shaped tract
of nerves that is directly involved in voluntary
movement.
4 Building a House of Cards: The Dopamine Theory of
Schizophrenia and Drug Action
1. The technique
involves the injection of a radioactively-labelled chemical called a ‘ligand’
that binds to the receptor site; the positrons emitted by the ligand are
detected by the radioactivity scanner.
5 The Phoenix Rises: From Tardive Dyskinesia to the
Introduction of the ‘Atypicals’
1. I am indebted to
other accounts of the emergence of tardive dyskinesia (Tarsy, 1983; Breggin,
1993; Gelman, 1999).
2. The term ‘tardive
dyskinesia’ literally means late-onset (tardive) abnormal movement
(dyskinesia).
3. The basal ganglia
is a group of nerve cell nuclei located below the cerebral hemispheres, which
form part of the extrapyramidal system. They include the striatum (the name for
the caudate nucleus and the putamen), and are sometimes referred to as the
striatum or striatal system.
8 Chemical Cosh: Antipsychotics and Chemical Restraint
1. The Mindfreedom
and Psychrights organisations have organised demonstrations against forced
drugging in the USA; the Kissit campaign and Beyond Bedlam have been active in
the UK, Mad Pride in Eire and We Shall Overcome in Norway.
2. I am grateful to
Dr Laura Allison who undertook some of the research for this chapter during the
course of her studies for an MSc in Psychiatric Research at University College
London.
3. Hydrotherapy
involved prolonged immersion in cold or hot baths and was practised in asylums
from the late nineteenth century.
4. Under Section 41
of the Mental Health Act of England and Wales people who have committed serious
offences are made subject to government supervision after discharge from
hospital.
9 Old and New Drug-Induced Problems
1. The brain
consists of grey matter, which comprises the nerve cell bodies, and white
matter, which consists of the projecting and connecting fibres.
2. The cerebral
hemispheres (also known as the cerebral cortex) are the largest part of the
brain and responsible for higher intellectual abilities.
3. These overall
differences between patients and controls were not provided in the paper, but
could be calculated from other data provided.
4. A transient
ischaemic attack (TIA) occurs when there is a temporary loss of blood supply to
part of the brain causing a temporary neurological deficit.
10 The First Tentacles: The ‘Early Intervention in
Psychosis’ Movement
1. Schizotypal
personality disorder is defined as ‘a pervasive pattern of social and
interpersonal deficits marked by acute discomfort with, and reduced capacity
for, close relationships, as well as by cognitive and perceptual distortions or
eccentricities of behaviour beginning in early adulthood and present in a
variety of contexts’ (American Psychiatric Association, 1980a).
12 All is not as it Seems
1. ‘Tolerance’ is a
pharmacological term referring to the phenomena in which the body produces
alterations that help to combat the effects of a drug when it is taken on an
on-going basis.
2. The quotation
cited is from one of two articles that Spitzer wrote in response to the famous
Rosenhan experiment, in which psychology students posed as potential patients
by presenting at accident and emergency departments saying they heard a voice
saying ‘thud’. All were admitted as psychiatric inpatients and discharged with
a diagnosis of schizophrenia or schizophrenia ‘in remission’. The experiment
sparked accusations that psychiatrists could not distinguish the mad from the
sane, and added to other criticisms of the reliability and validity of
psychiatric diagnosis (Rosenhan, 1973).
3. The Soteria
Network, for example, is a group of professionals, patients and carers
interested in developing alternative services for those with severe mental
disorders in the UK. The network supports small independent initiatives, as
well as working with mainstream services (http://www.soterianetwork.org.uk/).
Appendix 1: Common Antipsychotic Drugs
Appendix 2: Accounts of Schizophrenia and
Psychosis
The following three accounts are abridged
versions of stories found in the National Institute for Health and Clinical
Excellence’s (NICE) guideline on the treatment of schizophrenia (National
Institute for Health and Clinical Excellence, 2002).
Story 1
Mr
A described how he started to develop symptoms while he was at University. He
was hearing voices and ‘reading strange meanings into what was going on’. He
was referred to a psychiatrist, but managed to persuade the psychiatrist that
there was nothing wrong, and he recovered without any intervention and went on
to finish his degree. Later, in his mid-20s, while he was working as a research
scientist, he started to hear voices and also to see things, and he was
hospitalised after he took an overdose triggered by his distress at what was
happening. He was started on an antipsychotic drug in hospital, which he describes
as the start of a ‘vicious cycle’. He would be put on drugs, find it difficult
to function at work, stop taking them and end up being readmitted to hospital.
Eventually, he had to give up work, and after 20 years, and despite being on
antipsychotic treatment, he describes how the ‘voices are still awful when they
are really loud. They discuss me, put me down, shout obscenities, comment on
what is happening to me and tell me to do things that put me in danger. It is
very difficult to remain communicating in the real world, and doing this leaves
me exhausted. In addition, I often end up seeing the world in a very different
and frightening way and at the time I’m having these delusions I really believe
them. I can still get very distressed by it all but these days living with
schizophrenia is easier than it was when I was first ill’.
Story 2
Mr
B developed symptoms at the age of 33 years. He felt ‘wonderfully excited as
though I was the only person in the country to be let in on a great secret’ and
recounted how he spent the summer travelling around in search of more
‘delusional excitement’, and thought he had ‘become involved in the peace
process in Northern Ireland’. At the end of the summer he was admitted to
hospital after an outburst in which he caused a considerable amount of damage
to property. In hospital he was prescribed an antipsychotic, which made him
‘suicidally depressed’ and he stopped taking it as soon as he was discharged.
He spent the next 10 years in a cycle of ‘gradually getting ill’, which he
usually enjoyed, ‘getting arrested, being sectioned, and feeling suicidal
because of the side effects of the drugs’. At the time he said his ‘benchmark
for happiness’ was ‘not being medicated’ and when he was psychotic he felt
‘positive and purposeful’. Eventually, he accepted drug treatment, encouraged
by a supportive relationship with a community psychiatric nurse who was willing
to listen to his point of view and he had not had an admission for 4 years at
the time of writing.
Story 3
Mrs
C was diagnosed with schizophrenia a few years after she was married. Her
husband described how, during her psychotic episodes, she would wonder the
streets in a disturbed state, frequently being picked up by the police and
ending up in hospital, sometimes for many months. He felt that drug treatment
pacified her, but at the cost of destroying her personality and curtailing her
enjoyment of life: ‘My wife is naturally a very lively and stimulating person
to be with and seeing her pacified by the side effects of medication was
heartbreaking’. Eventually, his wife was prescribed a low dose of medication,
which appeared to control her symptoms without too many adverse effects, and
allowed her and her husband to lead ‘as normal a life as possible’ despite her
condition.
The fourth story is taken from Bert
Kaplan’s book The Inner World of Mental Illness, a
collection of first-person accounts of episodes of mental disturbance published
in 1964 (Anonymous, 1964).
Story 4
A
middle-class, professional woman who had worked as a social worker before
having children described having three attacks of psychotic experiences in her
late 30s. At the age of 36 years she started having an intense affair, and, in
order to deal with the strength of her emotions, she started to write poetry and
prose. Her writing became increasingly compulsive, and she lost interest in and
neglected her children and the ‘practical details of living’. She became
convinced that she had discovered the secrets of the universe and that she
could prove the existence of God. She also thought there had been a world
catastrophe, and she thought her children had died; she had a general sense of
fear and dread, as well as some unusual religious and sexual ideas. She was
taken to hospital in 1948 in a ‘rigid catatonic condition’ where she was given
a barbiturate and discharged after 5 months. Her second episode occurred 1 year
later, and she was admitted in much the same state for 3 months and recovered
spontaneously. The third episode started in 1951, and she was in hospital on
this occasion for over a year. During this episode she developed the idea that
she should kill her youngest son and some other people, although she did not
act on these thoughts. She was treated with ECT twice during this admission,
and up until the time that the book was compiled in the early 1960s, she had
had no further episodes. Looking back at the time the account was written she
felt that the experience had reduced her anxiety, helped her gain confidence,
freed up her intellectual capacities and enabled her to change ‘from a
non-religious to a religious orientation’.
Able, D. (2007) ‘Hull parents
arrested in girl’s poisoning death’, Boston Globe, 6
Feb.
Ackner, B., Harris, A. and Oldham,
A. J. (1957) ‘Insulin treatment of schizophrenia: controlled study’, Lancet, 2, 607–11.
Adler, C. M., Elman, I., Weisenfeld,
N., Kestler, L., Pickar, D. and Breier, A. (2000) ‘Effects of acute metabolic
stress on striatal dopamine release in healthy volunteers’, Neuropsychopharmacology,
22, 545–50.
Agid, O., Kapur, S., Arenovich, T.
and Zipursky, R. B. (2003) ‘Delayed-onset hypothesis of antipsychotic action: a
hypothesis tested and rejected’, Arch Gen Psychiatry,
60, 1228–35.
Akiskal, H. S. (1996) ‘The prevalent
clinical spectrum of bipolar disorders: beyond DSM-IV’, J
Clin Psychopharmacol, 16, 4S–14S.
Albaugh, V. L., Singareddy, R.,
Mauger, D. and Lynch, C. J. (2011) ‘A double blind, placebo-controlled,
randomized crossover study of the acute metabolic effects of olanzapine in
healthy volunteers’, PLoS One, 6, e22662.
Alexander, J., Tharyan, P., Adams,
C., John, T., Mol, C. and Philip, J. (2004) ‘Rapid tranquillisation of violent
or agitated patients in a psychiatric emergency setting. Pragmatic randomised
trial of intramuscular lorazepam v. haloperidol plus promethazine’, Br J Psychiatry, 185, 63–9.
Alexander, G. C., Gallagher, S. A.,
Mascola, A., Moloney, R. M. and Stafford, R. S. (2011) ‘Increasing off-label
use of antipsychotic medications in the United States, 1995–2008’, Pharmacoepidemiol Drug Saf, 20, 177–84.
Allen, S. (2007) ‘Backlash on
bipolar diagnoses in children’, Boston Globe, 17 Jun.
Allen, M. H., Currier, G. W.,
Hughes, D. H., Reyes-Harde, M. and Docherty, J. P. (2001) ‘The expert consensus
guideline series: Treatment of behavioural emergencies’, Postgrad
Med, 1–88.
Alty, A. and Mason, T. (1994) Seclusion in Mental Health (London: Chapman & Hall).
American Psychiatric Association
(1980a) Diagnostic and Statistical Manual of Mental
Disorders, 3rd edn. (Washington, DC: American Psychiatric Association).
American Psychiatric Association
(1980b) Task Force Report: Tardive Dyskinesia
(Washington, DC: American Psychiatric Association).
American Psychiatric Association
(1996) Schizophrenia (Washington, DC: American
Psychiatric Association).
American Psychiatric Association
(2005) Lets Talk Facts About Depression (Washington,
DC: American Psychiatric Association).
Andrade, S. E., Lo, J. C., Roblin,
D., Fouayzi, H., Connor, D. F., Penfold, R. B., et al. (2011) ‘Antipsychotic
medication use among children and risk of diabetes mellitus’, Pediatrics, 128, 1135–41.
Andreasen, N. C., Nopoulos, P.,
Magnotta, V., Pierson, R., Ziebell, S. and Ho, B. C. (2011) ‘Progressive brain
change in schizophrenia: a prospective longitudinal study of first-episode
schizophrenia’, Biol Psychiatry, 70, 672–9.
Angermeyer, M. C., Loffler, W.,
Muller, P., Schulze, B. and Priebe, S. (2001) ‘Patients’ and relatives’
assessment of clozapine treatment’, Psychol Med, 31,
509–17.
Angst, J. (1998) ‘The emerging
epidemiology of hypomania and bipolar II disorder’, J Affect
Disord, 50, 143–51.
Angst, J., Gamma, A., Benazzi, F.,
Ajdacic, V., Eich, D. and Rossler, W. (2003) ‘Toward a re-definition of
subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II,
minor bipolar disorders and hypomania’, J Affect Disord,
73, 133–46.
Anonymous (1964) ‘An autobiography
of a schizophrenic experience’, in Kaplan, B. (ed.) The
Inner World of Mental Illness, pp. 89–115 (New York: Harper & Row).
Anonymous (1965) ‘Irreversible side
effects of phenothiazines’, JAMA, 191, 333–4.
Anonymous (1987) ‘Psychiatrist is
cleared in ethics case’, New York Times, 13 Oct.
Anonymous
(1990) Warley
Hospital Brentwood. the First Hundred Years 1853–1953 Incorporating Into the
Second Century 1953–1963 (Brentwood: Warley Hospital).
Anonymous (2009a) ‘Comment on
olanzapine’, available at: www.askapatient.com (accessed 14 April 2013).
Anonymous (2009b) ‘Comment on
Riserpdal’, available at: www.askapatient.com (accessed 14 April 2013).
Anton-Stephens, D. (1954)
‘Preliminary observations on the psychiatric uses of chlorpromazine
(largactil)’, J Ment Sci, 100, 543–57.
Anzia, N., Okazaki, Y., Miyauchi,
M., Harada, S.-I., Kanou, Y., Sasaki, T., et al. (1988) ‘Early neuroleptic
medication within one year after onset can reduce risk of later relapses in
schizophrenia patients’, Annu Rep Pharmacopsychiatry Res
Found, 19, 258–65.
Aparasu, R. R., Bhatara, V. and
Gupta, S. (2005) ‘U.S. national trends in the use of antipsychotics during
office visits, 1998–2002’, Ann Clin Psychiatry, 17,
147–52.
Apud, J. A., Egan, M. F. and Wyatt,
R. J. (2003) ‘Neuroleptic withdrawal in treatment-resistant patients with
schizophrenia: tardive dyskinesia is not associated with supersensitive
psychosis’, Schizophr Res, 63, 151–60.
Arnone, D., Cavanagh, J., Gerber,
D., Lawrie, S. M., Ebmeier, K. P. and McIntosh, A. M. (2009) ‘Magnetic
resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis’,
Br J Psychiatry, 195, 194–201.
AstraZeneca (2011) ‘Seroquel XR for
schizophrenia’, available at: www.seroquelxr.com/schizophrenia/index.aspx?ux=t
(accessed 14 April 2013).
AstraZeneca (2012) ‘Bipolar
disorder’, available at: http://www.seroquelxr.com/bipolar-disorder/index.aspx?ux=t
(accessed 14 April 2013).
Austin, S. C., Stolley, P. D. and
Lasky, T. (1992) ‘The history of malariotherapy for neurosyphilis. Modern
parallels’, JAMA, 268, 516–19.
Azcarate, C. L. (1975) ‘Minor
tranquilizers in the treatment of aggression’, J Nerv Ment
Dis, 160, 100–7.
Bai, O., Zhang, H. and Li, X. M.
(2004) ‘Antipsychotic drugs clozapine and olanzapine upregulate bcl-2 mRNA and
protein in rat frontal cortex and hippocampus’, Brain Res,
1010, 81–6.
Baldessarini, R. J. and Viguera, A.
C. (1995) ‘Neuroleptic withdrawal in schizophrenic patients’, Arch Gen Psychiatry, 52, 189–92.
Baldessarini, R. J., Tondo, L. and
Viguera, A. C. (1999) ‘Discontinuing lithium maintenance treatment in bipolar
disorders: risks and implications’, Bipolar Disord,
1, 17–24.
Ballard, C., Hanney, M. L.,
Theodoulou, M., Douglas, S., McShane, R., Kossakowski, K., et al. (2009) ‘The
dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a
randomised placebo-controlled trial’, Lancet Neurol,
8, 151–7.
Banergee,
S. (2009) The
Use of Antipsychotic Medication for People With Dementia: Time for Action (London: Department of Health).
Barany, S., Ingvast, A. and Gunne,
L. M. (1979) ‘Development of acute dystonia and tardive dyskinesia in cebus
monkeys’, Res Commun Chem Pathol Pharmacol, 25,
269–79.
Bartholini, G., Haefely, W., Jalfre,
M., Keller, H. H. and Pletscher, A. (1972) ‘Effects of clozapine on cerebral
catecholaminergic neurone systems’, Br J Pharmacol,
46, 736–40.
Batki, S. L. and Harris, D. S.
(2004) ‘Quantitative drug levels in stimulant psychosis: relationship to
symptom severity, catecholamines and hyperkinesia’, Am J
Addict, 13, 461–70.
Bauer, M., Pretorius, H. W.,
Constant, E. L., Earley, W. R., Szamosi, J. and Brecher, M. (2009)
‘Extended-release quetiapine as adjunct to an antidepressant in patients with
major depressive disorder: results of a randomized, placebo-controlled,
double-blind stud’, J Clin Psychiatry, 70, 540–9.
Baumeister, A. A. and Francis, J. L.
(2002) ‘Historical development of the dopamine hypothesis of schizophrenia’, J Hist Neurosci, 11, 265–77.
BBC (2006) ‘Stephen Fry: the secret
life of the manic depressive’, Broadcast 19 and 26 September (London: British
Broadcasting Corporation).
Beasley, C. M., Jr, Sanger, T.,
Satterlee, W., Tollefson, G., Tran, P. and Hamilton, S. (1996a) ‘Olanzapine
versus placebo: results of a double-blind, fixed-dose olanzapine trial’, Psychopharmacology (Berl), 124, 159–67.
Beasley, C. M., Jr, Tollefson, G.,
Tran, P., Satterlee, W., Sanger, T. and Hamilton, S. (1996b) ‘Olanzapine versus
placebo and haloperidol: acute phase results of the North American double-blind
olanzapine trial’, Neuropsychopharmacology, 14,
111–23.
Bechdolf, A., Wagner, M., Ruhrmann,
S., Harrigan, S., Putzfeld, V., Pukrop, R., et al. (2012) ‘Preventing
progression to first-episode psychosis in early initial prodromal states’, Br J Psychiatry, 200, 22–9.
Behl, C., Rupprecht, R., Skutella,
T. and Holsboer, F. (1995) ‘Haloperidol-induced cell death—mechanism and
protection with vitamin E in vitro’, Neuroreport, 7,
360–4.
Bentall, R. and Morrison, A. P.
(2002) ‘More harm than good: The case against using antipsychotic drugs to
prevent severe mental illness’, J Mental Health, 11,
351–6.
Berenson, A. (2006) ‘Eli Lilly said
to play down risks of top pill’, New York Times,
available at: http://www.nytimes.com/2006/12/17/business/17drug.html?pagewanted=all
(accessed 14 April 2013).
Berenson, A. (2007) ‘Lilly settles
with 18,000 over Zyprexa’, New York Times, available
at: http://query.nytimes.com/gst/fullpage.html?res=9F00E5DB1430F936A35752C0A9619C8B63
(accessed 14 April 2013).
Beresford, V., Jenkins, D.,
Marshall, S. B., Montgomery, V., Swan, H. and Wilson, J. N. (1956)
‘Experimental hemorrhage: the deleterious effect of hypothermia on survival and
a comparative evaluation of plasma volume changes’, Ann Surg,
144, 696–714.
Berger, G. E., Wood, S. and McGorry,
P. D. (2003) ‘Incipient neurovulnerability and neuroprotection in early
psychosis’, Psychopharmacol Bull, 37, 79–101.
Berridge, C. W. (2006) ‘Neural
substrates of psychostimulant-induced arousal’, Neuropsychopharmacology,
31, 2332–40.
Bertelsen, M., Jeppesen, P.,
Petersen, L., Thorup, A., Ohlenschlaeger, J., Le Quach, P., et al. (2008)
‘Five-year follow-up of a randomized multicenter trial of intensive early
intervention vs standard treatment for patients with a first episode of
psychotic illness: the OPUS trial’, Arch Gen Psychiatry,
65, 762–71.
Biederman, J., Faraone, S., Mick,
E., Wozniak, J., Chen, L., Ouellette, C., et al. (1996) ‘Attention-deficit
hyperactivity disorder and juvenile mania: an overlooked comorbidity?’, J Am Acad Child Adolesc Psychiatry, 35, 997–1008.
Biederman, J., Mick, E., Hammerness,
P., Harpold, T., Aleardi, M., Dougherty, M., et al. (2005) ‘Open-label, 8-week
trial of olanzapine and risperidone for the treatment of bipolar disorder in
preschool-age children’, Biol Psychiatry, 58, 589–94.
Bipolar UK (2012) ‘Medications for
bipolar: a short description and resource guide’, available at: http://www.bipolaruk.org.uk/assets/uploads/documents/information_leaflets/bipolar_uk_introduction_to_medical_treatment.pdf
(accessed 14 April 2013).
Birchwood, M., McGorry, P. and
Jackson, H. (1997) ‘Early intervention in schizophrenia’, Br
J Psychiatry, 170, 2–5.
Bishop, Y. (2005) The Vetinary Formulary, 6th edn. (London: Pharmaceutical
Press).
Bleuler, E. (1911) ‘Dementia praecox
oder gruppe der schizophrenien’, in Aschaffenburg, G. (ed.) Handbuch
der Psychiatrie (Leipzig: Franz Deuticke).
Bleuler, E. (1951) ‘Autistic
thinking’, in Rapoport, D. (ed.) Organisation and Pathology
of Thought. Selected Sources, pp. 397–437 (New York: Columbia University
Press).
Bleuler, M. (1974) ‘The long-term
course of the schizophrenic psychose’, Psychol Med,
4, 244–55.
Bloch, H. S. (1970) ‘Brief sleep
treatment with chlorpromazine’, Compr Psychiatry, 11,
346–55.
Boardman, J. (2005) New Services for Old – An Overview of
Mental Health Policy (London: Sainsbury Centre for Mental Health).
Bola, J. R. and Mosher, L. R. (2003)
‘Treatment of acute psychosis without neuroleptics: two-year outcomes from the
Soteria project’, J Nerv Ment Dis, 191, 219–29.
Borison, R. L. and Diamond, B. I.
(1978) ‘A new animal model for schizophrenia: interactions with adrenergic
mechanisms’, Biol Psychiatry, 13, 217–25.
Borison, R. L. and Diamond, B. I.
(1983) ‘Regional selectivity of neuroleptic drugs: an argument for site
specificity’, Brain Res Bull, 11, 215–18.
Borison, R. L., Diamond, B. I.,
Sinha, D., Gupta, R. P. and Ajiboye, P. A. (1988) ‘Clozapine withdrawal rebound
psychosis’, Psychopharmacol Bull, 24, 260–3.
Bortnick, B., El Khalili, N., Banov,
M., Adson, D., Datto, C., Raines, S., et al. (2011) ‘Efficacy and tolerability
of extended release quetiapine fumarate (quetiapine XR) monotherapy in major
depressive disorder: a placebo-controlled, randomized study’, J Affect Disord, 128, 83–94.
Bosanac, P., Patton, G. C. and
Castle, D. J. (2010) ‘Early intervention in psychotic disorders: faith before
facts?’, Psychol Med, 40, 353–8.
Bostic, J. Q., Wilens, T., Spencer,
T. and Biederman, J. (1997) ‘Juvenile mood disorders and office
psychopharmacology’, Pediatr Clin North Am, 44,
1487–503.
Bowden, C. L. (1998) ‘New concepts
in mood stabilization: evidence for the effectiveness of valproate and
lamotrigine’, Neuropsychopharmacology, 19, 194–9.
Bowden, C. L., Brugger, A. M.,
Swann, A. C., Calabrese, J. R., Janicak, P. G., Petty, F., et al. (1994)
‘Efficacy of divalproex vs lithium and placebo in the treatment of mania. The
Depakote Mania Study Group’, JAMA, 271, 918–24.
Bowden, C. L., Calabrese, J. R.,
McElroy, S. L., Gyulai, L., Wassef, A., Petty, F., et al. (2000) ‘A randomized,
placebo-controlled 12-month trial of divalproex and lithium in treatment of
outpatients with bipolar I disorder. Divalproex Maintenance Study Group’, Arch Gen Psychiatry, 57, 481–9.
Braden, W., Fink, E. B., Qualls, C.
B., Ho, C. K. and Samuels, W. O. (1982) ‘Lithium and chlorpromazine in
psychotic inpatients’, Psychiatry Res, 7, 69–81.
Bralet, M. C., Yon, V., Loas, G. and
Noisette, C. (2000) [‘Cause of mortality in schizophrenic patients: prospective
study of years of a cohort of 150 chronic schizophrenic patients’], Encephale, 26, 32–41 [in French].
Braslow, J. (1997) Mental Ills and Bodily Cures (Berkely, CA: University of
California Press).
Breggin, P. (1983) Hazards to the Brain (New York: Springer).
Breggin, P. (2008) Brain-Disabling Treatments in Psychiatry, 2nd edn. (New
York: Springer).
Breggin, P. R. (1990) ‘Brain damage,
dementia and persistent cognitive dysfunction associated with neuroleptic
drugs. Evidence, etiology, implications’, J Mind Behav,
11, 425–64.
Breggin, P. R. (1993a) Toxic Psychiatry (London: Fontana).
Breggin, P. R. (1993b) ‘Parallels
between neuroleptic effects and lethargic encephalitis: the production of
dyskinesias and cognitive disorders’, Brain Cogn, 23,
8–27.
Breggin,
P. R. (1997) Brain Disabling Treatments in Psychiatry: Drugs
Electroshock and the Role of the FDA
(New York: Springer).
Breggin, P. R. (2006) ‘Intoxicatrion
anosognosia: the spellbinding effect of psychiatric drugs’, Ethical
Human Psychol Psychiatry, 8, 201–15.
Breier, A. (1989) ‘A.E. Bennett
award paper. Experimental approaches to human stress research: assessment of
neurobiological mechanisms of stress in volunteers and psychiatric patients’, Biol Psychiatry, 26, 438–62.
Breier, A. (1995) ‘Serotonin,
schizophrenia and antipsychotic drug action’, Schizophr Res,
14, 187–202.
Brill,
H. (1956) The
First Years’ Experience With Large-scale Use of Chlorpormazine and Reserpine in
the Mental Hygiene Institutions of New York State: A Preliminary Report (Rochester: New York State Hospital).
Brill, H. and Patton, R. E. (1957)
‘Analysis of 1955–1956 population fall in New York State mental hospitals in
first year of large-scale use of tranquilizing drugs’, Am J
Psychiatry, 114, 509–17.
Brindle, D. (2011) ‘Abuse at leading
care home leads to police inspections of private hospitals’, Guardian, 1 Jun.
Brodie, B. B., Spector, S. and
Shore, P. A. (1959) ‘Interaction of drugs with norepinephrine in the brain’, Pharmacol Rev, 11, 548–64.
Brooks, G. W. (1959) ‘Withdrawal
from neuroleptic drugs’, Am J Psychiatry, 115, 931–2.
Brown, S., Chhina, N. and Dye, S.
(2010) ‘Use of psychotropic medication in seven English psychiatric intensive
care units’, Psychiatrist, 34, 130–5.
Brunello, N., Masotto, C., Steardo,
L., Markstein, R. and Racagni, G. (1995) ‘New insights into the biology of
schizophrenia through the mechanism of action of clozapine’, Neuropsychopharmacology, 13, 177–213.
Buchsbaum, M. S., Someya, T., Teng,
C. Y., Abel, L., Chin, S., Najafi, A., et al. (1996) ‘PET and MRI of the
thalamus in never-medicated patients with schizophrenia’, Am
J Psychiatry, 153, 191–9.
Buckley, P. F., Mahadik, S., Pillai,
A. and Terry, A., Jr (2007) ‘Neurotrophins and schizophrenia’, Schizophr Res, 94, 1–11.
Bunney, B. S., Walters, J. R.,
Kuhar, M. J., Roth, R. H. and Aghajanian, G. K. (1975) ‘D & L amphetamine
stereoisomers: comparative potencies in affecting the firing of central
dopaminergic and noradrenergic neurons’, Psychopharmacol
Commun, 1, 177–90.
Burns, T., Rugkasa, J., Molodynski,
A., Dawson, J., Yeeles, K., Vazquez-Montes, M., et al. (2013) ‘Community
treatment orders for patients with psychosis (OCTET): a randomised controlled
trial’, Lancet, 25 March, doi:
10.1016/S0140-6736(13)60107-05 (Epub ahead of print).
Burt, D. R., Creese, I. and Snyder,
S. H. (1977) ‘Antischizophrenic drugs: chronic treatment elevates dopamine
receptor binding in brain’, Science, 196, 326–8.
Bushe, C. and Holt, R. (2004)
‘Prevalence of diabetes and impaired glucose tolerance in patients with
schizophrenia’, Br J Psychiatry Suppl, 47, S67–S71.
Bushe, C. and Leonard, B. (2004)
‘Association between atypical antipsychotic agents and type 2 diabetes: review
of prospective clinical data’, Br J Psychiatry Suppl,
47, S87–S93.
Byne, W., White, L., Parella, M.,
Adams, R., Harvey, P. D. and Davis, K. L. (1998) ‘Tardive dyskinesia in a
chronically institutionalized population of elderly schizophrenic patients:
prevalence and association with cognitive impairment’, Int J
Geriatr Psychiatry, 13, 473–9.
Cahn, W., Hulshoff Pol, H. E., Lems,
E. B., van Haren, N. E., Schnack, H. G., van der Linden, J. A., et al. (2002)
‘Brain volume changes in first-episode schizophrenia: a 1-year follow-up
study’, Arch Gen Psychiatry, 59, 1002–10.
Carey, B. (2006) ‘A career that has
mirrored psychiatry’s twisting path’, New York Times,
23 May.
Carey, B. (2007) ‘Debate over
children and psychiatric drugs’, New York Times, 15
Feb.
Carlsson, A. (2006) ‘The
neurochemical circuitry of schizophrenia’, Pharmacopsychiatry,
39(Suppl. 1), S10–S14.
Carlsson, A., Lindqvist, M. and
Magnusson, T. (1957) ‘3, 4-Dihydroxyphenylalanine and 5-hydroxytryptophan as
reserpine antagonists’, Nature, 180, 1200.
Carlsson, A., Rasmussen, E. B. and
Krist, J. P. (1959) ‘The urinary excretion of adrenaline and noradrenaline by
schizophrenic patients during reserpine treatment’, J
Neurochem, 4, 318–20.
Carpenter, W. T., Jr (1995)
‘Serotonin-dopamine antagonists and treatment of negative symptoms’, J Clin Psychopharmacol, 15, 30S–35S.
Carpenter, W. T., Jr, Buchanan, R.
W., Kirkpatrick, B. and Breier, A. F. (1999) ‘Diazepam treatment of early signs
of exacerbation in schizophrenia’, Am J Psychiatry,
156, 299–303.
Casey, J. F., Lasky, J. J., Klett,
C. J. and Hollister, L. E. (1960a) ‘Treatment of schizophrenic reactions with
phenothiazine derivatives. A comparative study of chlorpromazine,
triflupromazine, mepazine, prochlorperazine, perphenazine, and phenobarbital’, Am J Psychiatry, 117, 97–105.
Casey, J. F., Bennett, I. F.,
Lindley, C. J., Hollister, L. E., Gordon, M. H. and Springer, N. N. (1960b)
‘Drug therapy in schizophrenia. A controlled study of the relative
effectiveness of chlorpromazine, promazine, phenobarbital, and placebo’, Arch Gen Psychiatry, 2, 210–20.
Castle, D. J. (2012) ‘The truth, and
nothing but the truth, about early intervention in psychosis’, Aust N Z J Psychiatry, 46, 10–13.
Cazzullo, C. L. and Guareschi, A.
(1954) [‘Effect of a phenothiazine derivative, largactil, on the electric
activity of the brain, in dogs’], Riv Neurol, 24,
602–32 [in Italian].
Chaggar, P. S., Shaw, S. M. and
Williams, S. G. (2011) ‘Effect of antipsychotic medications on glucose and
lipid levels’, J Clin Pharmacol, 51, 631–8.
Chakos, M. H., Lieberman, J. A.,
Alvir, J., Bilder, R. and Ashtari, M. (1995) ‘Caudate nuclei volumes in
schizophrenic patients treated with typical antipsychotics or clozapine’, Lancet, 345, 456–7.
Chan, D. and Sireling, L. (2010) ‘“I
want to be bipolar”...a new phenomenon’, Psychiatrist,
34, 103–5.
Chen, E. Y., Hui, C. L., Lam, M. M.,
Chiu, C. P., Law, C. W., Chung, D. W., et al. (2010) ‘Maintenance treatment
with quetiapine versus discontinuation after one year of treatment in patients
with remitted first episode psychosis: randomised controlled trial’, BMJ, 341, c4024.
Chertok, L. (1982) [‘30 years later.
The story of the discovery of neuroleptics’], Ann Med
Psychol (Paris), 140, 971–6 [in French].
Chien, I. C., Chang, K. C., Lin, C.
H., Chou, Y. J. and Chou, P. (2010) ‘Prevalence of diabetes in patients with
bipolar disorder in Taiwan: a population-based national health insurance
study’, Gen Hosp Psychiatry, 32, 577–82.
Chouinard, G. and Jones, B. D.
(1980) ‘Neuroleptic-induced supersensitivity psychosis: clinical and
pharmacologic characteristics’, Am J Psychiatry, 137,
16–21.
Chouinard, G., Jones, B., Remington,
G., Bloom, D., Addington, D., MacEwan, G. W., et al. (1993) ‘A Canadian
multicenter placebo-controlled study of fixed doses of risperidone and
haloperidol in the treatment of chronic schizophrenic patients’, J Clin Psychopharmacol, 13, 25–40.
Christensen, E., Moller, J. E. and
Faurbye, A. (1970) ‘Neuropathological investigation of 28 brains from patients
with dyskinesia’, Acta Psychiatr Scand, 46, 14–23.
Chua, S. E., Cheung, C., Cheung, V.,
Tsang, J. T., Chen, E. Y., Wong, J. C., et al. (2007) ‘Cerebral grey, white
matter and csf in never-medicated, first-episode schizophrenia’, Schizophr Res, 89, 12–21.
Clopixol Acuphase advertisement
(1990) Advertisement, Br J Psychiatry, July, backcover.
Clow, A., Theodorou, A., Jenner, P.
and Marsden, C. D. (1980) ‘Changes in rat striatal dopamine turnover and
receptor activity during one years neuroleptic administration’, Eur J Pharmacol, 63, 135–44.
Cole, J. O. (1959) ‘The evaluation
of the effectiveness of treatment in psychiatry’, in Cole, J. O. and Gerard, R.
W. (eds) Psychopharmacology Problems in Evaluation:
Proceedings, pp. 92–107 (Washington, DC: National Academy of Sciences).
Cole, J. (1996) ‘The evaluation of
psychotropic drugs’, in Healy, D. (ed.) The
Psychopharmacologists Volume I, pp. 239–64 (London: Chapman & Hall).
Comité Lyonnais de Recherches
Therapeutiques en Psychiatrie (2000) ‘The birth of psychopharmacotherapy:
explorations in a new world – 1952–1968’, in Healy, D. (ed.) The Psychopharmacologists III, pp. 1–53 (London: Arnold).
Cooper, R. (2011) ‘“We can live to
150 and stay healthy”: Professor says first “wonder drugs” could be ready this
decade’, Daily Mail, 19 Oct.
Cooper, W. O., Arbogast, P. G.,
Ding, H., Hickson, G. B., Fuchs, D. C. and Ray, W. A. (2006) ‘Trends in
prescribing of antipsychotic medications for US children’, Ambul
Pediatr, 6, 79–83.
COPE (2012) ‘The Centre of
Prevention and Evaluation’, available at: http://www.copeclinic.org/The_COPE_Clinic_at_Columbia_Psychiatry.html
(accessed 14 April 2013).
Correll, C. U. (2011) ‘Safety and
tolerability of antipsychotic treatment in young patients with schizophrenia’, J Clin Psychiatry, 72, e26.
Correll, C. U. and Schenk, E. M.
(2008) ‘Tardive dyskinesia and new antipsychotics’, Curr
Opin Psychiatry, 21, 151–6.
Correll, C. U., Frederickson, A. M.,
Kane, J. M. and Manu, P. (2006) ‘Metabolic syndrome and the risk of coronary
heart disease in 367 patients treated with second-generation antipsychotic
drugs’, J Clin Psychiatry, 67, 575–83.
Costall, B. and Naylor, R. J. (1975)
‘Detection of the nueroleptic properties of clozapine, sulpiride and
thioridazine’, Psychopharmacologia, 43, 69–74.
Cousins, D. A., Aribisala, B., Nicol
Ferrier, I. and Blamire, A. M. (2013) ‘Lithium, gray matter, and magnetic
resonance imaging signal’, Biol Psychiatry, 73,
652–7.
Craig, T. K., Garety, P., Power, P.,
Rahaman, N., Colbert, S., Fornells-Ambrojo, M., et al. (2004) ‘The Lambeth
Early Onset (LEO) Team: randomised controlled trial of the effectiveness of
specialised care for early psychosis.’, BMJ, 329,
1067.
Crane, G. E. (1956) ‘Further studies
on iproniazid phosphate’, J Nerv Ment Dis, 124,
322–31.
Crane, G. E. (1967) ‘Tardive
dyskinesia in schizophrenic patients treated with neuroleptic drugs’, Aggressologie, 9, 209–18.
Crane, G. E. (1968) ‘Dyskinesia and
neuroleptics’, Arch Gen Psychiatry, 19, 700–3.
Crane, G. E. (1973) ‘Clinical
psychopharmacology in its 20th year. Late, unanticipated effects of
neuroleptics may limit their use in psychiatry’, Science,
181, 124–8.
Crilley, J. (2007) ‘The history of
clozapine and its emergence in the US market’, Hist
Psychiatry, 18, 39–60.
Crow, T. J. (1987) ‘The dopamine
hypothesis survives, but there must be a way ahead’, Br J
Psychiatry, 151, 460–5.
Crow, T. J. and Gillbe, C. (1974)
‘Brain dopamine and behaviour. A critical analysis of the relationship between
dopamine antagonism and therapeutic efficacy of neuroleptic drugs’, J Psychiatr Res, 11, 163–72.
Crow, T. J., Owens, D. G.,
Johnstone, E. C., Cross, A. J. and Owen, F. (1983) ‘Does tardive dyskinesia
exist?’, Mod Probl Pharmacopsychiatry, 21, 206–19.
Crow, T. J., MacMillan, J. F.,
Johnson, A. L. and Johnstone, E. C. (1986) ‘A randomised controlled trial of
prophylactic neuroleptic treatment’, Br J Psychiatry,
148, 120–7.
Cullberg, J., Levander, S.,
Holmqvist, R., Mattsson, M. and Wieselgren, I. M. (2002) ‘One-year outcome in
first episode psychosis patients in the Swedish Parachute project’, Acta Psychiatr Scand, 106, 276–285.
Cundall, R. L., Brooks, P. W. and
Murray, L. G. (1972) ‘A controlled evaluation of lithium prophylaxis in
affective disorders’, Psychol Med, 2, 308–11.
Dale, H. H. and Laidlaw, P. P.
(1910) ‘The physiological action of beta-iminazolylethylamine’, J Physiol, 41, 318–44.
Dale, H. H. and Richards, A. N.
(1918) ‘The vasodilator action of histamine and of some other substances’, J Physiol, 52, 110–65.
Dale, H. H. and Laidlaw, P. P.
(1919) ‘Histamine shock’, J Physiol, 52, 355–90.
Dartalan advertisement (1960) Journal of Mental Science, 106, July, xviii.
Davis, J. M. (1980) ‘Antipsychotic
drugs’, in Kaplan, H. I., Freedman, A. M. and Sadock, B. J. (eds) Comprehensive Textbook of Psychiatry, 3rd edn, pp. 2257–89
(Baltimore, MD: Williams & Wilkins).
Davis, J. M. and Cole, J. (1975)
‘Antipsychotic drugs’, in Freedman, D. X. and Dyrud, J. E. (eds) American Handbook of Psychiatry, Volume 5, Treatment, 2nd
edn, pp. 441–75 (New York: Basic Books).
Davis, K. L., Kahn, R. S., Ko, G.
and Davidson, M. (1991) ‘Dopamine in schizophrenia: a review and
reconceptualization’, Am J Psychiatry, 148, 1474–86.
De Hert, M., Correll, C. U. and
Cohen, D. (2010) ‘Do antipsychotic medications reduce or increase mortality in
schizophrenia? A critical appraisal of the FIN-11 study’, Schizophr
Res, 117, 68–74.
De Hert, M., Detraux, J., van
Winkel, R., Yu, W. and Correll, C. U. (2011) ‘Metabolic and cardiovascular
adverse effects associated with antipsychotic drugs’, Nat
Rev Endocrinol, 8, 114–26.
Dean, C. E. (2006)
‘Antipsychotic-associated neuronal changes in the brain: toxic, therapeutic, or
irrelevant to the long-term outcome of schizophrenia?’, Prog
Neuropsychopharmacol Biol Psychiatry, 30, 174–89.
Deary, I. J., Penke, L. and Johnson,
W. (2010) ‘The neuroscience of human intelligence differences’, Nat Rev Neurosci, 11, 201–11.
DeGrandpre,
R. (2006) The
Cult of Pharmcology. How America became the world’s most troubled drug culture (Durham, NC: Duke University Press).
Delay, J. and Deniker, P. (1952) ‘38
cas de psychoses traites par la cure prolongee et continue de 4560 R.P.’, C R Congres Med Alien Neurol France, 50, 503–13.
Delay, J. and Deniker, P. (1953)
[‘Neuroplegics in psychiatric therapy’], Therapie, 8,
347–64.
Delay, J. and Deniker, P. (1955)
‘Neuroleptic effects of chlorpromazine in therapeutics of neuropsychiatry’, Int Rec Med Gen Pract Clin, 168, 318–26.
Delay, J. and Deniker, P. (1956)
‘Chlorpromazine and neuroleptic treatments in psychiatry’, J
Clin Exp Psychopathol, 17, 19–24.
Delay, J., Deniker, P. and Harl, J.
M. (1952) [‘Therapeutic use in psychiatry of phenothiazine of central elective
action (4560 RP)’], Ann Med Psychol (Paris), 110,
112–17.
Delay, J., Deniker, P., Green, A.,
and Mordret, M. (1957) [‘Excito-motor syndrome provoked by neuroleptic drugs’],
Presse Med, 65, 1771–4 [in French].
DeLisi, L. E., Hoff, A. L.,
Schwartz, J. E., Shields, G. W., Halthore, S. N., Gupta, S. M., et al. (1991)
‘Brain morphology in first-episode schizophrenic-like psychotic patients: a
quantitative magnetic resonance imaging study’, Biol
Psychiatry, 29, 159–75.
DeLisi, L. E., Sakuma, M., Tew, W.,
Kushner, M., Hoff, A. L. and Grimson, R. (1997) ‘Schizophrenia as a chronic
active brain process: a study of progressive brain structural change subsequent
to the onset of schizophrenia’, Psychiatry Res, 74,
129–40.
Denham, J. (1965) ‘Clinical use of
the phenothiazines’, in Marks, J. and Pare, C. M. B. (eds) The
Scientific Basis of Drug Therapy in Psychiatry. Proceedings of a Symposium Held
at St Bartholomew’s Hospital, London, pp. 56–61 (London: Pergamon Press).
Denham, J. and Carrick, D. J. (1960)
‘Therapeutic importance of extrapyramidal phenomena evoked by a new
phenothiazine’, Am J Psychiatry, 116, 927–8.
Deniker, P. (1956)
‘Psychophysiologic aspects of the new chemotherapeutic drugs in psychiatry;
some practical features of neuroleptics in order to screen new drugs’, J Nerv Ment Dis, 124, 371–6.
Deniker, P. (1960) ‘Experimental
neurological syndromes and the new drug therapies in psychiatry’, Compr Psychiatry, 1, 92–102.
Deniker, P. (1970) ‘Introduction of
neuroleptic chemotherapy into psychiatry’, in Ayd, F. and Blackwell, B. (eds) Discoveries in Biological Psychiatry, pp. 155–64
(Philadelphia: J B Lippincott Company).
Deniker, P. (1983) ‘Discovery of the
clinical use of neuroleptics’, in Parnham, M. J. and Bruinvels, J. (eds) Discoveries in Pharmcology, pp. 163–80 (Amsterdam:
Elsevier).
Deniker, P. (1989) ‘From
chlorpromazine to tardive dyskinesia (brief history of the neuroleptics)’, Psychiatr J Univ Ott, 14, 253–9.
Department of Health (2001) The Mental Health Policy Implementation Guide (London:
Department of Health).
Depatie, L. and Lal, S. (2001)
‘Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?’, J Psychiatry Neurosci, 26, 203–20.
DeWolfe, A. S., Ryan, J. J. and
Wolf, M. E. (1988) ‘Cognitive sequelae of tardive dyskinesia’, J Nerv Ment Dis, 176, 270–4.
Diamond, B. I. and Borison, R. L.
(1986) ‘Basic and clinical studies of neuroleptic-induced supersensitivity
psychosis and dyskinesia’, Psychopharmacol Bull, 22,
900–5.
Dinan, T. G. (2004a) ‘Schizophrenia
and diabetes 2003: an expert consensus meeting. Introduction’, Br J Psychiatry Suppl, 47, S53–S54.
Dinan, T. G. (2004b) ‘Stress and the
genesis of diabetes mellitus in schizophrenia’, Br J
Psychiatry Suppl, 47, S72–S75.
Divry, P., Bobon, J. and Collard, J.
(1958) [‘R-1625: a new drug for the symptomatic treatment of psychomotor
excitation’], Acta Neurol Psychiatr Belg, 58, 878–88
[in French].
Divry, P., Bobon, J., Collard, J.,
Pinchard, A. and Nols, E. (1959) [‘Study & clinical trial of R 1625 or
haloperidol, a new neuroleptic & so-called neurodysleptic agent’], Acta Neurol Psychiatr Belg, 59, 337–66 [in French].
Domino, E. F. (1985) ‘Induction of
tardive dyskinesia in Cebus apella and Macaca speciosa monkeys: a review’, Psychopharmacology
Suppl, 2, 217–23.
Donlon, P. T. and Tupin, J. P.
(1974) ‘Rapid “digitalization” of decompensated schizophrenic patients with
antipsychotic agents’, Am J Psychiatry, 131, 310–12.
Dorph-Petersen, K. A., Pierri, J.
N., Perel, J. M., Sun, Z., Sampson, A. R. and Lewis, D. A. (2005) ‘The
influence of chronic exposure to antipsychotic medications on brain size before
and after tissue fixation: a comparison of haloperidol and olanzapine in
macaque monkeys’, Neuropsychopharmacology, 30,
1649–61.
Dreifus, C. (2008) ‘A conversation
with Nancy Andreasen: Using imaging to look at changes in the brain’, New York Times, 15 Sep.
Druckman, R., Seelinger, D. and
Thulin, B. (1962) ‘Chronic involuntary movements induced by phenothiazines’, J Nerv Ment Dis, 135, 69–76.
Dubovsky, S. L., Davies, R. and
Dubovsky, A. N. (2001) ‘Mood disorders’, in Hales, R. E. and Yudofsky, S. C.
(eds) Textbook of Clinical Psychiatry (Washington,
DC: American Psychiatric Association).
Duman, R. S., Heninger, G. R. and
Nestler, E. J. (1997) ‘A molecular and cellular theory of depression’, Arch Gen Psychiatry, 54, 597–606.
Ebaugh, F. G. (1943) ‘A review of
the drastic shock therapies in the treatment of the psychoses’, Ann Int Med, 18, 294–5.
Ehrhardt, H. (1966) ‘Present status
of insulin coma and electric convulsive treatment in Germany’, in Rinkel, M.
(ed.) Biological Treatment of Mental Illness, p. 838
(New York: Farrar, Straus & Giroux).
Ehringer, H. and Hornykiewicz, O.
(1960) [‘Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the
human brain and their behavior in diseases of the extrapyramidal system’], Klin Wochenschr, 38, 1236–9 [in German].
Eli Lilly (2011) ‘How Zyprexa
works’, available at: www.zyprexa.com/schizophrenia/pages/howzyprexaworks.aspx
(accessed 25 March 2011).
Eli Lilly (undated) ‘Zyprexa
papers’, available at: www.furiousseasons.com/zyprexa%20documents/
(accessed 31 January 2011).
Elkes, J. and Elkes, C. (1954)
‘Effects of chlorpormazine on the behaviour of chronically overactive psychotic
patients’, Br Med J, ii, 560–5.
Ellis, R. (2006) ‘The asylum, the
Poor Law, and a reassessment of the four-shilling grant: admissions to the
county asylums of Yorkshire in the nineteenth century’, Soc
Hist Med, 19, 55–71.
Emanuel, M. B. (1999) ‘Histamine and
the antiallergic antihistamines: a history of their discoveries’, Clin Exp Allergy, 29(Suppl. 3), 1–11.
Evans, J. H. (1965) ‘Persistent oral
dyskinesia in treatment with phenothiazine derivatives’, Lancet,
1, 458–60.
Expert Group (2004) ‘“Schizophrenia
and Diabetes 2003” Expert Consensus Meeting, Dublin, 3–4 October 2003:
consensus summary’, Br J Psychiatry Suppl, 47, S112–14.
Fagan, D., Scott, D. B., Mitchell,
M. and Tiplady, B. (1991) ‘Effects of remoxipride on measures of psychological
performance in healthy volunteers’, Psychopharmacology
(Berl), 105, 225–9.
Fann, W. E. and Linton, P. H. (1972)
‘Use of perphenazine in psychiatric emergencies: the concept of chemical
restraint’, Curr Ther Res Clin Exp, 14, 478–82.
Faraone, S. V., Biederman, J.,
Mennin, D. and Russell, R. (1998) ‘Bipolar and antisocial disorders among
relatives of ADHD children: parsing familial subtypes of illness’, Am J Med Genet, 81, 108–16.
Farde, L., Wiesel, F. A., Hall, H.,
Halldin, C., Stone-Elander, S. and Sedvall, G. (1987) ‘No D2 receptor increase
in PET study of schizophrenia’, Arch Gen Psychiatry,
44, 671–2.
Farde, L., Nordstrom, A. L., Wiesel,
F. A., Pauli, S., Halldin, C. and Sedvall, G. (1992) ‘Positron emission
tomographic analysis of central D1 and D2 dopamine receptor occupancy in
patients treated with classical neuroleptics and clozapine. Relation to
extrapyramidal side effects’, Arch Gen Psychiatry,
49, 538–44.
Faurbye, A. (1968) ‘The role of
amines in the etiology of schizophrenia’, Compr Psychiatry,
9, 155–77.
Faurbye, A., Rasch, P. J., Petersen,
P. B., Brandborg, G. and Pakkenberg, H. (1964) ‘Neurological symptoms in
pharmacotherapy of psychoses’, Acta Psychiatr Scand,
40, 10–27.
Fenton, W. S. and McGlashan, T. H.
(1987) ‘Sustained remission in drug-free schizophrenic patients’, Am J Psychiatry, 144, 1306–9.
Fenton, W. S., Wyatt, R. J. and
McGlashan, T. H. (1994) ‘Risk factors for spontaneous dyskinesia in
schizophrenia’, Arch Gen Psychiatry, 51, 643–50.
Fenton, W. S., Blyler, C. R., Wyatt,
R. J. and McGlashan, T. H. (1997) ‘Prevalence of spontaneous dyskinesia in
schizophrenic and non-schizophrenic psychiatric patients’, Br
J Psychiatry, 171, 265–8.
Ferguson, A. T., Wilson, J. N.,
Jenkins, D. and Swan, H. (1958) ‘The effect of hypothermia on hemorrhagic
shock’, Ann Surg, 147, 281–8.
Fink, M. and Karliner, W. (2007)
‘Primary sources: insulin coma therapy. PBS American Experience’, available at:
www.pbs.org/wgbh/amex/nash/filmmore/ps_ict.html
(accessed 26 April 2013).
Fink, M., Shaw, R., Gross, G. E. and
Coleman, F. S. (1958) ‘Comparative study of chlorpromazine and insulin coma in
therapy of psychosis’, J Am Med Assoc, 166, 1846–50.
Finlay, J. M. and Zigmond, M. J.
(1997) ‘The effects of stress on central dopaminergic neurons: possible
clinical implications’, Neurochem Res, 22, 1387–94.
Fischer, E. (1970) ‘Biogenic amines
and schizophrenia’, Psychosomatics, 11, 495.
Fisk, M. C., Feeley, J. and
Voreacos, D. (2012) ‘J&J said to agree to $2.2 billion drug marketing
accord’, Bloomberg News, 11 Jun.
Flugel, F. (1959) ‘Neuroleptic
treatment in schizophrenia’, in Kline, N. S. (ed.) Psychopharmacology
Frontiers, pp. 45–7 (Boston, MA: Little, Brown & Co).
Food and Drug Administration (2007)
‘Information for healthcare professionals: haloperidol (marketed as haldol,
haldol decanoate and haldol lactate)’, available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085203.htm
(accessed 14 April 2013).
Francis, A. (2011)
‘Seven questions for Patrick McGorry’, available at: http://www.psychologytoday.com/blog/dsm5-in-distress/201108/seven-questions-professor-patrick-mcgorry
(accessed 14 April 2013).
Francis, A. (2012) ‘Wonderful news:
DSM-5 finally begins its belated and necessary retreat’, available at: http://www.psychologytoday.com/blog/dsm5-in-distress/201205/wonderful-news-dsm-5-finally-begins-its-belated-and-necessary-retreat
(accessed 14 April 2013).
Frank, L. R. (1978) The History of Shock Treatment (San Fransisco, CA:
self-published).
Frankenhaeuser, M., Lundberg, U.,
Rauste, v. W., von Wright, J. and Sedvall, G. (1986) ‘Urinary monoamine
metabolites as indices of mental stress in healthy males and females’, Pharmacol Biochem Behav, 24, 1521–5.
Franzen, G. and Ingvar, D. H. (1975)
‘Abnormal distribution of cerebral activity in chronic schizophrenia’, J Psychiatr Res, 12, 199–214.
Fraser Health Authority (2012)
‘Psychosis sucks’, available at: http://www.psychosissucks.ca/treatment.cfm
(accessed 13 December 2012).
Frazier, S. H. (1968) ‘Comprehensive
management of psychiatric emergencies’, Psychosomatics,
9, 7–11.
Frazier, J. A., Biederman, J.,
Tohen, M., Feldman, P. D., Jacobs, T. G., Toma, V., et al. (2001) ‘A
prospective open-label treatment trial of olanzapine monotherapy in children
and adolescents with bipolar disorder’, J Child Adolesc
Psychopharmacol, 11, 239–50.
Freed, E. D. (1975) ‘The drug
management of acute behavioural disturbances’, S Afr Med J,
49, 638–40.
Freedman, D. X. (1973) ‘Neurological
syndromes associated with antipsychotic drug use. A special report’, Arch Gen Psychiatry, 28, 463–7.
Freeman, D. (2007) ‘Suspicious
minds: the psychology of persecutory delusions’, Clin
Psychol Rev, 27, 425–57.
Freyhan, F. A. (1955) ‘The immediate
and long-range effects of chlorpromazine on the mental hospital’, in Smith
Kline & French Laboratories (ed.) Chlorpromazine and
Mental Health, pp. 71–87 (Philadelphia, PA: Lea & Febiger).
Freyhan, F. A. (1959) ‘Clinical and
investigative aspects’, in Kline, N. S. (ed.) Psychopharmaclogy
Frontiers. Second International Congress of Psychiatry Psychopharmacology
Symposium, pp. 7–14) (London: J&A Churchill).
Freyhan, F. A. (1964) ‘Ten years of
clinical psychopharmacology: hopes and frustrations’, in Neuropsychopharmacology
Volume 3. Proceedings of the Third Meeting of the Collegium Internationale
Neuropsychopharmacologium, pp. 559–61 (Amsterdam: Elsevier).
Gaddum, J. H. and Hameed, K. A.
(1954) ‘Drugs which antagonize 5-hydroxy-tryptamine’, Br J
Pharmacol Chemother, 9, 240–8.
Gaebel, W., Janner, M., Frommann,
N., Pietzcker, A., Kopcke, W., Linden, M., et al. (2002) ‘First vs multiple
episode schizophrenia: two-year outcome of intermittent and maintenance
medication strategies’, Schizophr Res, 53, 145–59.
Gaebel, W., Riesbeck, M., Wolwer,
W., Klimke, A., Eickhoff, M., Von Wilmsdorff, M., et al. (2011) ‘Relapse prevention
in first-episode schizophrenia—maintenance vs intermittent drug treatment with
prodrome-based early intervention: results of a randomized controlled trial
within the German Research Network on Schizophrenia’, J Clin
Psychiatry, 72, 205–18.
Gardos, G. and Cole, J. O. (1980)
‘Overview: public health issues in tardive dyskinesia’, Am J
Psychiatry, 137, 776–81.
Geddes, J., Freemantle, N.,
Harrison, P. and Bebbington, P. (2000) ‘Atypical antipsychotics in the
treatment of schizophrenia: systematic overview and meta-regression analysis’, BMJ, 321, 1371–6.
Gelman, S. (1999) Medicating Schizophrenia: a history (New Brunswick, NJ:
Rutgers University Press).
Gerlach, J. (1985)
‘Pathophysiological mechanisms underlying tardive dyskinesia’, Psychopharmacology Suppl, 2, 98–103.
Ghaemi, S. N. (2001) ‘On defining
“mood stabilizer”’, Bipolar Disord, 3, 154–8.
Ghaemi, S. N., Sachs, G. S., Chiou,
A. M., Pandurangi, A. K. and Goodwin, K. (1999) ‘Is bipolar disorder still
underdiagnosed? Are antidepressants overutilized?’, J Affect
Disord, 52, 135–44.
Gil-Ad, I., Shtaif, B., Shiloh, R.
and Weizman, A. (2001) ‘Evaluation of the neurotoxic activity of typical and
atypical neuroleptics: relevance to iatrogenic extrapyramidal symptoms’, Cell Mol Neurobiol, 21, 705–16.
Gillies, D., Beck, A., McCloud, A.,
Rathbone, J. and Gillies, D. (2005) ‘Benzodiazepines alone or in combination
with antipsychotic drugs for acute psychosis’, Cochrane
Database Syst Rev, CD003079.
Gittins,
D. (1998) Madness
in its Place: Narratives of Severall Hospital 1913–1997 (London: Routledge).
GlaxoSmithKline (2009) Available at:
www.paxilcr.com
(accessed 25 February 2009).
Goerendt, I. K., Messa, C.,
Lawrence, A. D., Grasby, P. M., Piccini, P. and Brooks, D. J. (2003) ‘Dopamine
release during sequential finger movements in health and Parkinson’s disease: a
PET study’, Brain, 126, 312–25.
Goldberg, E. (1985) ‘Akinesia,
tardive dysmentia, and frontal lobe disorder in schizophrenia’, Schizophr Bull, 11, 255–63.
Goldstein, L. E., Sporn, J., Brown,
S., Kim, H., Finkelstein, J., Gaffey, G. K., et al. (1999) ‘New-onset diabetes
mellitus and diabetic ketoacidosis associated with olanzapine treatment’, Psychosomatics, 40, 438–43.
Gracie, A., Freeman, D., Green, S.,
Garety, P. A., Kuipers, E., Hardy, A., et al. (2007) ‘The association between
traumatic experience, paranoia and hallucinations: a test of the predictions of
psychological models’, Acta Psychiatr Scand, 116,
280–9.
Granger, B. and Albu, S. (2005) ‘The
haloperidol story’, Ann Clin Psychiatry, 17, 137–40.
Greely, H., Sahakian, B., Harris,
J., Kessler, R. C., Gazzaniga, M., Campbell, P., et al. (2008) ‘Towards
responsible use of cognitive-enhancing drugs by the healthy’, Nature, 456, 702–5.
Green, M. F., Marder, S. R., Glynn,
S. M., McGurk, S. R., Wirshing, W. C., Wirshing, D. A., et al. (2002) ‘The
neurocognitive effects of low-dose haloperidol: a two-year comparison with
risperidone’, Biol Psychiatry, 51, 972–8.
Greenson, P. R. (2012) ‘The
therapeutic role of drugs in the process of repression, dissociation and
synthesis’, Psychanalytic Quarterly, 16, 140–1.
Grob, G. (1983) The
Inner World of American Psychiatry 1890–1940
(New Brunswick, NJ: Rutgers University Press).
Grob, G. (1994) The
Mad Among Us (New York: The Free Press).
Gronfein, W. (1985) ‘Psychotropic
drugs and the origins of deinstitutionalisation’, Social
Problems, 32, 437–54.
Gualtieri, C. T., Sprague, R. L. and
Cole, J. O. (1986) ‘Tardive dyskinesia litigation and the dilemmas of
neuroleptic treatment’, J Psychiatry Law, 14,
187–216.
Guillin, O., Abi-Dargham, A. and
Laruelle, M. (2007) ‘Neurobiology of dopamine in schizophrenia’, Int Rev Neurobiol, 78, 1–39.
Guiraud, P. and David, C. (1950)
‘Treatment de l’agitation mortrice par un antihistaminique (3277 RP)’, C R Congres Med Alien Neurol France, 48, 599–602.
Gunne, L. M. and Barany, S. (1976)
‘Haloperidol-induced tardive dyskinesia in monkeys’, Psychopharmacology
(Berl), 50, 237–40.
Gur, R. E., Cowell, P., Turetsky, B.
I., Gallacher, F., Cannon, T., Bilker, W., et al. (1998) ‘A follow-up magnetic
resonance imaging study of schizophrenia. Relationship of neuroanatomical
changes to clinical and neurobehavioral measures’, Arch Gen
Psychiatry, 55, 145–52.
Gur, R. E., Turetsky, B. I., Bilker,
W. B. and Gur, R. C. (1999) ‘Reduced gray matter volume in schizophrenia’, Arch Gen Psychiatry, 56, 905–11.
Gurd, F. N. (1955) ‘Current trends
in the treatment of shock’, Can Med Assoc J, 73,
977–80.
Guy, W. E. (1976) ‘Clinical Global
Impressions Scale’, in ECDEU Assessment Manual for
Psychopharmacology Revised (Rockville, MD: National Institute of Mental
Health).
Haase, H. J. (1954) [‘Occurrence and
interpretation of psychomotor parkinsonism in megaphen or largactil prolonged
therapy’], Nervenarzt, 25, 486–92 [in German].
Haase, H. J. (1956) [‘Definition and
mode of action of the psychomotor Parkinson syndrome therapeutically induced by
serpasil and largactil’], Monatsschr Psychiatr Neurol,
131, 201–14 [in German].
Haase, H.-J. and Janssen, P. A. J.
(1965) The Action of Neuroleptic Drugs (Chicago, IL:
Yearbook Medical Publishers).
Haddad, P. M. (2004) ‘Antipsychotics
and diabetes: review of non-prospective data’, Br J
Psychiatry Suppl, 47, S80–S86.
Hafeman, D. M., Chang, K. D.,
Garrett, A. S., Sanders, E. M. and Phillips, M. L. (2012) ‘Effects of
medication on neuroimaging findings in bipolar disorder: an updated review’, Bipolar Disord, 14, 375–410.
Hammond, R. C. (1964) ‘Problems
arising from prescribing trends’, Can Med Assoc J,
91, 135.
Hamon, J., Paraire, J. and Velluz,
J. (1952a) [‘Anxiety states and potentialized barbiturates’], Ann Med Psychol (Paris), 110, 403–7.
Hamon, J., Praraire, J. and Velluz,
J. (1952b) ‘Remarques sur l’action du 4560 R.P. sur l’agitation maniaque’, Ann Med Psychol (Paris), 110, 331–5.
Hansen, B. (1996) ‘Workplace
violence in the hospital psychiatric setting. An occupational health
perspective’, AAOHN J, 44, 575–80.
Harris, G. (2009) ‘Pfizer pays $2.3
billion to settle marketing case’, New York Times, 2
Sep.
Harris, D. and Batki, S. L. (2000)
‘Stimulant psychosis: symptom profile and acute clinical course’, Am J Addict, 9, 28–37.
Harris, G. and Carey, B. (2008)
‘Researchers fail to reveal full drug pay’, New York Times,
8 Jun.
Harris, M., Chandran, S.,
Chakraborty, N. and Healy, D. (2005) ‘The impact of mood stabilizers on bipolar
disorder: the 1890s and 1990s compared’, Hist Psychiatry,
16, 423–34.
Harrison, P. J. (1999) ‘The
neuropathology of schizophrenia. A critical review of the data and their
interpretation’, Brain, 122, 593–624.
Harrow, M. and Jobe, T. H. (2007)
‘Factors involved in outcome and recovery in schizophrenia patients not on
antipsychotic medications: a 15-year multifollow-up study’, J
Nerv Ment Dis, 195, 406–14.
Harrow, M., Jobe, T. H. and Faull,
R. N. (2012) ‘Do all schizophrenia patients need antipsychotic treatment
continuously throughout their lifetime? A 20-year longitudinal study’, Psychol Med, 42, 2145–55.
Haukka, J., Tiihonen, J., Harkanen,
T. and Lonnqvist, J. (2008) ‘Association between medication and risk of
suicide, attempted suicide and death in nationwide cohort of suicidal patients
with schizophrenia’, Pharmacoepidemiol Drug Saf, 17,
686–96.
Healy,
D. (1996) The
Psychopharmacologists. Interviews by David Healy. Volume I (London: Chapman and Hall).
Healy, D. (2002) The
Creation of Psychopharmacology (Cambridge, MA: Harvard University
Press).
Healy, D. (2004) ‘Shaping the
intimate: influences on the experience of everyday nerves’, Soc
Stud Sci, 34, 219–45.
Healy, D. (2006a) ‘Academic
stalking’, available at: http://www.healyprozac.com/AcademicStalking/AcademicStalking.htm
(accessed 14 April 2013).
Healy, D. (2006b) ‘The latest mania:
selling bipolar disorder’, PLoS Med, 3, e185.
Healy, D. (2008) Mania:
A Short History of Bipolar Disorder (Baltimore, MD: John Hopkins
University Press).
Healy, D. and Farquhar, G. (1998)
‘Immediate effects of droperidol’, Hum Psychopharmacol,
13, 113–20.
Healy, D. and Le Noury, J. (2007)
‘Pediatric bipolar disorder: An object study in the creation of an illness’, Int J Risk Safety Med, 19, 209–21.
Healy, D., Harris, M., Michael, P.,
Cattell, D., Savage, M., Chalasani, P., et al. (2005) ‘Service utilization in
1896 and 1996: morbidity and mortality data from North Wales’, Hist Psychiatry, 16, 27–42.
Hegarty, J.D., Baldessarini, R.J.,
Tohen, M., Waternaux, C. and Oepen, G. (1994) ‘One hundred years of
schizophrenia: a meta-analysis of the outcome literature’, Am
J Psychiatry, 151, 1409–16.
Hegelstad, W. T., Larsen, T. K.,
Auestad, B., Evensen, J., Haahr, U., Joa, I., et al. (2012) ‘Long-term
follow-up of the TIPS early detection in psychosis study: effects on 10-year
outcome’, Am J Psychiatry, 169, 374–80.
Henderson, D. and Gillespie, R. D.
(1927) Henderson and Gillespie’s Textbook of Psychiatry,
1st edn (Oxford: Oxford University Press).
Henderson, D. and Gillespie, R. D.
(1962) Henderson and Gillespie’s Textbook of Psychiatry,
9th edn (Oxford, Oxford University Press).
Heninger, G., Dimascio, A. and
Klerman, G. L. (1965) ‘Personality factors in variability of response to
phenothiazines’, Am J Psychiatry, 121, 1091–4.
Hennessy, S., Bilker, W. B., Knauss,
J. S., Margolis, D. J., Kimmel, S. E., Reynolds, R. F., et al. (2002) ‘Cardiac
arrest and ventricular arrhythmia in patients taking antipsychotic drugs:
cohort study using administrative data’, BMJ, 325,
1070.
Herman, Z. S. (1970) ‘The effects of
noradrenaline on rat’s behaviour’, Psychopharmacologia,
16, 369–74.
Himwich, H. E. (1955) ‘Prospects in
psychopharmacology’, J Nerv Ment Dis, 122, 413–23.
Hippius, H. (1999) ‘A historical
perspective of clozapine’, J Clin Psychiatry,
60(Suppl. 12), 22–3.
Ho, B. C., Andreasen, N. C., Flaum,
M., Nopoulos, P. and Miller, D. (2000) ‘Untreated initial psychosis: its
relation to quality of life and symptom remission in first-episode
schizophrenia’, Am J Psychiatry, 157, 808–15.
Ho, B. C., Andreasen, N. C.,
Nopoulos, P., Arndt, S., Magnotta, V. and Flaum, M. (2003) ‘Progressive
structural brain abnormalities and their relationship to clinical outcome: a
longitudinal magnetic resonance imaging study early in schizophrenia’, Arch Gen Psychiatry, 60, 585–94.
Ho, B. C., Andreasen, N. C.,
Ziebell, S., Pierson, R. and Magnotta, V. (2011) ‘Long-term antipsychotic
treatment and brain volumes: a longitudinal study of first-episode
schizophrenia’, Arch Gen Psychiatry, 68, 128–37.
Hoch, P. (1959) ‘Drug therapy’, in
Arieti, S. (ed.) American Handbook of Psychiatry, Volume II,
1st edn, pp. 1541–51 (New York: Basic Books).
Hollister, L. E. (1957) ‘Complications
from the use of tranquilizing drugs’, N Engl J Med,
257, 170–7.
Holt, R. I., Bushe, C. and Citrome,
L. (2005) ‘Diabetes and schizophrenia 2005: are we any closer to understanding
the link?’, J Psychopharmacol, 19, 56–65.
Howes, O. D., Kambeitz, J., Kim, E.,
Stahl, D., Slifstein, M., Abi-Dargham, A., et al. (2012) ‘The nature of
dopamine dysfunction in schizophrenia and what this means for treatment’, Arch Gen Psychiatry, 69, 776–86.
Howes, O. D. and Kapur, S. (2009)
‘The dopamine hypothesis of schizophrenia: version III—the final common
pathway’, Schizophr Bull, 35, 549–62.
Huber,
G. (1957) Penumoencephalographische
und Psychopathologische Bilder bei Endogen Psychosen (Berlin: Springer Verlag).
Hulshoff Pol, H. E. and Kahn, R. S.
(2008) ‘What happens after the first episode? A review of progressive brain
changes in chronically ill patients with schizophrenia’, Schizophr
Bull, 34, 354–66.
Hunsberger, J., Austin, D. R.,
Henter, I. D. and Chen, G. (2009) ‘The neurotrophic and neuroprotective effects
of psychotropic agents’, Dialogues Clin Neurosci, 11,
333–48.
Hunter, A. R. (1967) ‘Old unhappy
far off things. Some reflections on the significance of the early work on
shock’, Ann R Coll Surg Engl, 40, 289–305.
Hunter, R., Earl, C. J. and Janz, D.
(1964a) ‘A syndrome of abnormal movements and dementia in leucotomized patients
treated with phenothiazines’, J Neurol Neurosurg Psychiatry,
27, 219–23.
Hunter, R., Earl, C. J. and
Thronicroft, S. (1964b) ‘An apparently irreversible syndrome of abnormal
movements following phenothiazine medication’, Proc R Soc
Med, 57, 758–62.
Hutton, P., Morrison, A. P., Yung,
A. R., Taylor, P. J., French, P. and Dunn, G. (2012) ‘Effects of drop-out on
efficacy estimates in five Cochrane reviews of popular antipsychotics for
schizophrenia’, Acta Psychiatr Scand, 126, 1–11.
Huttunen, M. (1995) ‘The evolution
of the serotonin-dopamine antagonist concept’, J Clin
Psychopharmacol, 15, 4S-10S.
Ichimiya, T., Okubo, Y., Suhara, T.
and Sudo, Y. (2001) ‘Reduced volume of the cerebellar vermis in
neuroleptic-naive schizophrenia’, Biol Psychiatry,
49, 20–7.
Idanpaan-Heikkila, J., Alhava, E.,
Olkinuora, M. and Palva, I. (1975) ‘Letter: Clozapine and agranulocytosis’, Lancet, 2, 611.
Ilyas, S. and Moncrieff, J. (2012)
‘Trends in prescriptions and costs of drugs for mental disorders in England,
1998 to 2010’, British Journal of Psychiatry, 200,
393–8.
IMS Institute for Healthcare
Informatics (2011) ‘The use of medicines in the United States: Review of 2010’,
available at: www.imshealth.com/
(accessed 15 April 2013).
Insel, T. R. (2009) ‘Translating
scientific opportunity into public health impact: a strategic plan for research
on mental illness’, Arch Gen Psychiatry, 66, 128–33.
International Center for the Study
of Psychiatry and Psychology (2009) The Conscience of
Psychiatry: The Reform Work of Peter R. Breggin, MD (Ithaca, NY: Lake
Edge Press).
International Early Psychosis
Association (2012) ‘Sponsorship Prospectus: 8th international conference on
early psychosis’, 11–13 October, 2012 San Fransisco, CA, USA, available at: http://www.iepaconference.org/wordpress/wp-content/uploads/2011/07/sponsorship-prospectus.pdf
[On-line]. Available: http://www.iepaconference.org/wordpress/wp-content/uploads/2011/07/sponsorship-prospectus.pdf
(accessed 15 April 2013).
Iversen, L. (1998) ‘Neuroscience and
drug development’, in Healy, D. (3 ed.) The
Psychopharmacologists, p. 325 (London: Chapman & Hall).
Jablensky, A., Sartorius, N.,
Ernberg, G., Anker, M., Korten, A., Cooper, J. E., et al. (1992) ‘Schizophrenia:
manifestations, incidence and course in different cultures. A World Health
Organization ten-country study’, Psychol Med Monogr Suppl,
20, 1–97.
Jacquy, J., Wilmotte, J., Piraux, A.
and Noel, G. (1976) ‘Cerebral blood flow patterns studied by rheoencephalography
in schizophrenia’, Neuropsychobiology, 2, 94–103.
Janssen, P. (1998) ‘From haloperidol
to risperidone’, in Healy, D. (ed.) The
Psychopharmacologists Volume II, pp. 39–70 (London: Chapman & Hall).
Janssen, P. A., Niemegeers, C. J.,
Awouters, F., Schellekens, K. H., Megens, A. A. and Meert, T. F. (1988)
‘Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2
and dopamine-D2 antagonistic properties’, J Pharmacol Exp
Ther, 244, 685–93.
Jarskog, L. F. and Lieberman, J. A.
(2006) ‘Neuroprotection in schizophrenia’, J Clin Psychiatry,
67, e09.
Jarskog, L. F., Gilmore, J. H.,
Glantz, L. A., Gable, K. L., German, T. T., Tong, R. I., et al. (2007a)
‘Caspase-3 activation in rat frontal cortex following treatment with typical and
atypical antipsychotics’, Neuropsychopharmacology,
32, 95–102.
Jarskog, L. F., Miyamoto, S. and
Lieberman, J. A. (2007b) ‘Schizophrenia: new pathological insights and
therapies’, Annu Rev Med, 58, 49–61.
Jayakumar, P. N.,
Venkatasubramanian, G., Gangadhar, B. N., Janakiramaiah, N. and Keshavan, M. S.
(2005) ‘Optimized voxel-based morphometry of gray matter volume in
first-episode, antipsychotic-naive schizophrenia’, Prog
Neuropsychopharmacol Biol Psychiatry, 29, 587–91.
Jellinger, K. (1977) ‘Neuropathologic
findings after neuroleptic long-term therapy’, in Roizin, L., Shiraki, H. and
Greevic, N. (eds) Neurotoxicology, pp. 25–42 (New
York: Raven Press).
Jenner, F. A., Monteiro, A. C. D.,
Zagalo-Cardoso, J. A. and Cunha-Oliveira, J. A. (1993) Schizophrenia:
A Disease or Some Ways of Being Human (Sheffield: Sheffield Academic
Press).
Jeste, D. V., Caligiuri, M. P.,
Paulsen, J. S., Heaton, R. K., Lacro, J. P., Harris, M. J., et al. (1995) ‘Risk
of tardive dyskinesia in older patients. A prospective longitudinal study of
266 outpatients’. Arch Gen Psychiatry, 52, 756–65.
John, J. P., Chengappa, K. N.,
Baker, R. W., Gupta, B. and Mortimer, M. T. (1995) ‘Assessment of changes in
both weight and frequency of use of medications for the treatment of
gastrointestinal symptoms among clozapine-treated patients’, Ann Clin Psychiatry, 7, 119–25.
Johnson, W. (undated) ‘An
interesting compound’ (unpublished: Smith Kline & French).
Johnstone, E. C., Crow, T. J.,
Frith, C. D., Carney, M. W. and Price, J. S. (1978) ‘Mechanism of the
antipsychotic effect in the treatment of acute schizophrenia’, Lancet, 1, 848–51.
Johnstone, E. C., Crow, T. J.,
Frith, C. D. and Owens, D. G. (1988) ‘The Northwick Park “functional” psychosis
study: diagnosis and treatment response’, Lancet, 2,
119–25.
Jones, B. D. (1985) ‘Tardive
dysmentia: further comments’, Schizophr Bull, 11,
187–9.
Jones, K. (1972) A
History of the Mental Health Services (London: Routledge & Kegan
Paul).
Joshi, G., Petty, C., Wozniak, J.,
Faraone, S. V., Doyle, R., Georgiopoulos, A., et al. (2012) ‘A prospective
open-label trial of quetiapine monotherapy in preschool and school age children
with bipolar spectrum disorder’, J Affect Disord,
136, 1143–53.
Joukamaa, M., Heliovaara, M., Knekt,
P., Aromaa, A., Raitasalo, R. and Lehtinen, V. (2006) ‘Schizophrenia,
neuroleptic medication and mortality’, Br J Psychiatry,
188, 122–7.
Judah, L. N., Josephs, Z. M. and
Murphree, O. D. (1961) ‘Results of simultaneous abrupt withdrawal of ataraxics
in 500 chronic psychotic patients’, Am J Psychiatry,
118, 156–8.
Jureidini, J. N., McHenry, L. B. and
Mansfield, P. R. (2008) ‘Clinical trials and drug promotion: Selective
reporting of study 329’, Int J Risk Saf Med, 20,
73–81.
Kamran, A., Doraiswamy, P. M., Jane,
J. L., Hammett, E. B. and Dunn, L. (1994) ‘Severe hyperglycemia associated with
high doses of clozapine’, Am J Psychiatry, 151, 1395.
Kane, J. M., Honigfeld, G., Singer,
J. and Meltzer, H. (1988) ‘Clozapine in treatment-resistant schizophrenics’, Psychopharmacol Bull, 24, 62–7.
Kapur, S. (2003) ‘Psychosis as a
state of aberrant salience: a framework linking biology, phenomenology, and
pharmacology in schizophrenia’, Am J Psychiatry, 160,
13–23.
Kapur, S. and Seeman, P. (2001)
‘Does fast dissociation from the dopamine d(2) receptor explain the action of
atypical antipsychotics?: A new hypothesis’, Am J Psychiatry,
158, 360–9.
Kapur, S., Remington, G., Zipursky,
R. B., Wilson, A. A. and Houle, S. (1995) ‘The D2 dopamine receptor occupancy
of risperidone and its relationship to extrapyramidal symptoms: a PET study’, Life Sci, 57, L103–7.
KARN, W. N., Jr and Kasper, S.
(1959) ‘Pharmacologically induced Parkinson-like signs as index of the
therapeutic potential’, Dis Nerv Syst, 20, 119–22.
Karow, A., Naber, D., Lambert, M.
and Moritz, S. (2012) ‘Remission as perceived by people with schizophrenia,
family members and psychiatrists’, Eur Psychiatry,
27, 426–31.
Kaye, J. A., Bradbury, B. D. and
Jick, H. (2003) Changes in antipsychotic drug prescribing by general
practitioners in the United Kingdom from 1991 to 2000: a population-based
observational study. Br J Clin Pharmacol, 56, 569–75.
Keefe, R. S., Seidman, L. J.,
Christensen, B. K., Hamer, R. M., Sharma, T., Sitskoorn, M. M., et al. (2006)
‘Long-term neurocognitive effects of olanzapine or low-dose haloperidol in
first-episode psychosis’, Biol Psychiatry, 59,
97–105.
Keefe, R. S., Bilder, R. M., Davis,
S. M., Harvey, P. D., Palmer, B. W., Gold, J. M., et al. (2007) ‘Neurocognitive
effects of antipsychotic medications in patients with chronic schizophrenia in
the CATIE Trial’, Arch Gen Psychiatry, 64, 633–47.
Kendall, T. (2011) ‘The rise and
fall of the atypical antipsychotics’, Br J Psychiatry,
199, 266–8.
Kendell, R. E. and Zealey, A. K.
(1988) Companion to Psychiatric Studies, 4th edn
(Edinburgh: Churchill Livingstone).
Kendler, K. S. and Schaffner, K. F.
(2011) ‘The dopamine hypothesis of schizophrenia: an historical and
philosophical analysis’, Philosophy Psychiatry Psychol,
18, 41–63.
Kessler, R. C., McGonagle, K. A.,
Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., et al. (1994) ‘Lifetime and
12-month prevalence of DSM-III-R psychiatric disorders in the United States.
Results from the National Comorbidity Survey’, Arch Gen
Psychiatry, 51, 8–19.
Kestler, L. P., Walker, E. and Vega,
E. M. (2001) ‘Dopamine receptors in the brains of schizophrenia patients: a
meta-analysis of the findings’, Behav Pharmacol, 12,
355–71.
Kety, S. S. (1974) ‘Prologue’, J Psychiatric Res, 11, ix–xi.
Khin, N. A., Chen, Y. F., Yang, Y.,
Yang, P. and Laughren, T. P. (2012) ‘Exploratory analyses of efficacy data from
schizophrenia trials in support of new drug applications submitted to the US
Food and Drug Administration’, J Clin Psychiatry, 73,
856–64.
Khot, V. and Wyatt, R. J. (1991)
‘Not all that moves is tardive dyskinesia’, Am J Psychiatry,
148, 661–6.
Kinross-Wright, V. (1954)
‘Chlorpromazine; a major advance in psychiatric treatment’, Postgrad
Med, 16, 297–9.
Kinross-Wright,
V. (1956) ‘Clinical application of chlorpormazine’, in Kline, N. S. (ed.) Psychopharmacology.
A Symposium Organised by the Section on Medical Sciences for the American
Association of the Advancement of Science and the American Psychiatric
Association, pp. 31–8 (Washington
DC: American Association for the Advancement of Science).
Kirk, S., Gomery, T. and Cohen, D.
(2013) Mad Science; Psychiatric Coercion, Diagnosis and
Drugs (Rutgers, NJ: Transaction Publishers).
Kirsch, I., Moore, T. J., Scoboria,
A. and Nicholls, S. S. (2002) ‘The emperor’s new drugs: an analysis of
antidepressant medication data submitted to the US Food and Drug
Administration’, Prevention and Treatment, 5.
Kline, N. S. (1954) ‘Use of Rauwolfia serpentina Benth. in neuropsychiatric
conditions’, Ann N Y Acad Sci, 59, 107–32.
Kline, N. S. (1956) ‘Chemotherapy in
psychiatry; recent advances’, Semin Int, 5, 7–10.
Kline, N. S. (1959)
‘Psychopharmaceuticals: effects and side effects’, Bull
World Health Organ, 21, 397–410.
Kline, N. S. (1968) ‘On the rarity
of ‘irreversible’ oral dyskinesias following phenothiaziones’, Am J Psychiatry, 124, 48–51.
Kline, N. S. (1969) ‘Nomenclature
vs. nature’, Int J Psychiatry, 7, 292–3.
Kline, N. S. and Stanley, A. M.
(1955) ‘Use of reserpine in a neuropsychiatric hospital’, Ann
N Y Acad Sci, 61, 85–91.
Kluger, J. and Song, S. (2002)
‘Manic depression: young and bipolar’, Time Magazine,
19 Aug.
Koerner, B. I. (2002) ‘Disorders
made to order’, Mother Jones, 27.
Kohen, D. (2004) ‘Diabetes mellitus
and schizophrenia: historical perspective’, Br J Psychiatry
Suppl, 47, S64–6.
Koval, M. S., Rames, L. J. and
Christie, S. (1994) ‘Diabetic ketoacidosis associated with clozapine
treatment’, Am J Psychiatry, 151, 1520–1.
Kowatch, R. A., Fristad, M.,
Birmaher, B., Wagner, K. D., Findling, R. L. and Hellander, M. (2005)
‘Treatment guidelines for children and adolescents with bipolar disorder’, J Am Acad Child Adolesc Psychiatry, 44, 213–35.
Krakowski, M. I., Czobor, P.,
Citrome, L., Bark, N. and Cooper, T. B. (2006) ‘Atypical antipsychotic agents
in the treatment of violent patients with schizophrenia and schizoaffective disorder’,
Arch Gen Psychiatry, 63, 622–9.
Kramer, P. D. (1993) Listening to Prozac (New York: Viking Penguin).
Kruse, W. (1960) ‘Persistent
muscular restlessness after phenothiazine treatment: report of 3 cases’, Am J Psychiatry, 117, 152–3.
Kulenkampff, C. & Tarnow, G.
(1956) [‘An unusual syndrome in the oral region caused by administration of
megaphen’], Nervenarzt, 27, 178–80 [in German].
Kulkarni, S. K. and Dhir, A. (2011)
‘Animal models of tardive dyskinesia’, Int Rev Neurobiol,
98, 265–87.
Laborit, H. (1949) ‘Etudes
experimentale du syndrome d’irritation et application clinique a la maladie
post-traumatique’, Therapie, 4, 126–39.
Laborit,
H. (1950) Physiologie
et Biologie du Systeme Nerveux Vegetatif au Service de la Chirurgie (Paris: G. Doin).
Laborit, H. (1952) [‘Artificial
hibernation in anesthesiology’], Anesth Anal, 9,
1–15.
Laborit, H. and Huguenard, P. (1951)
[‘Artificial hibernation by pharmacodynamical and physical means’], Presse Med, 59, 1329.
Laborit, H., Huguenard, P. and
Alluaume, R. (1952) [‘A new vegetative stabilizer; 4560 R.P.’], Presse Med, 60, 206–8.
Lacoursiere, R. (1976) ‘Medical
effects of abrupt withdrawal of neuroleptic therapy’, JAMA,
240, 109.
Laing, R. D. (1965) The Divided Self (Harmondsworth: Pelican Books).
Laing, R. D. (1967) The Politics of Experience and The Bird of Paradise
(Harmondsworth: Penguin Books).
Lamberti, J. S., Bellnier, T. and
Schwarzkopf, S. B. (1992) ‘Weight gain among schizophrenic patients treated
with clozapine’, Am J Psychiatry, 149, 689–90.
Lane, C. J., Ngan, E. T., Yatham, L.
N., Ruth, T. J. and Liddle, P. F. (2004) ‘Immediate effects of risperidone on
cerebral activity in healthy subjects: a comparison with subjects with
first-episode schizophrenia’, J Psychiatry Neurosci,
29, 30–7.
Largactil advertisement (1965)
Advertisement, Br J Psychiatry, 111 January, x.
Larsen, T. K., Melle, I., Auestad,
B., Friis, S., Haahr, U., Johannessen, J. O., et al. (2006) ‘Early detection of
first-episode psychosis: the effect on 1-year outcome’, Schizophr
Bull, 32, 758–64.
Laruelle, M., D’Souza, C. D.,
Baldwin, R. M., Abi-Dargham, A., Kanes, S. J., Fingado, C. L., et al. (1997)
‘Imaging D2 receptor occupancy by endogenous dopamine in humans’, Neuropsychopharmacology, 17, 162–74.
Laruelle, M., Abi-Dargham, A., Gil,
R., Kegeles, L. and Innis, R. (1999) ‘Increased dopamine transmission in
schizophrenia: relationship to illness phases’, Biol
Psychiatry, 46, 56–72.
Lazorthes, G., Campan, L. and
Anduze, H. (1952) [‘Indication of artificial hibernation in cerebral surgery
and in cranial traumatology’], Rev Neurol (Paris),
87, 585–7.
Le Noury, J., Khan, A., Harris, M.,
Wong, W., Williams, D., Roberts, T., et al. (2008) ‘The incidence and
prevalence of diabetes in patients with serious mental illness in North West
Wales: two cohorts, 1875–1924 & 1994–2006 compared’, BMC
Psychiatry, 8, 67.
Lee, T. and Seeman, P. (1980)
‘Elevation of brain neuroleptic/dopamine receptors in schizophrenia’, Am J Psychiatry, 137, 191–7.
Lehmann, H. E. (1955) ‘Therapeutic
results with chlorpromazine (largactil) in psychiatric conditions’, Can Med Assoc J, 72, 91–9.
Lehmann, H. (1959) ‘Concepts,
rationale and research’, in Kline, N. S. (ed.) Psychopharmacology
Frontiers. Second International Congress of Psychiatry Psychopharmacology
Symposium, pp. 21–30 (London: J&A Churchill Ltd).
Lehmann, H. E. (1993) ‘Before they
called it psychopharmacology’, Neuropsychopharmacology,
8, 291–303.
Lehmann, H. E. and Hanrahan, G. E.
(1954) ‘Chlorpromazine; new inhibiting agent for psychomotor excitement and
manic states’, AMA Arch Neurol Psychiatry, 71,
227–37.
Lehtinen, V., Aaltonen, J., Koffert,
T., Rakkolainen, V. and Syvalahti, E. (2000) Two-year outcome in first-episode
psychosis treated according to an integrated model. Is immediate
neuroleptisation always needed? Eur Psychiatry, 15,
312–20.
Lemke, R. (1936) ‘Untersuchungen
ueber die soziale prognose der schizophrenie’, Archiv
Psychiatrie, 104, 89–136.
Leucht, S., Kane, J. M., Etschel,
E., Kissling, W., Hamann, J. and Engel, R. R. (2006) ‘Linking the PANSS, BPRS,
and CGI: clinical implications’, Neuropsychopharmacology,
31, 2318–25.
Leucht, S., Heres, S., Hamann, J.,
& Kane, J. M. (2008) ‘Methodological issues in current antipsychotic drug
trials’, Schizophr Bull, 34, 275–85.
Leucht, S., Arbter, D., Engel, R.
R., Kissling, W. and Davis, J. M. (2009) ‘How effective are second-generation
antipsychotic drugs? A meta-analysis of placebo-controlled trials’, Mol Psychiatry, 14, 429–47.
Leucht, S., Tardy, M., Komossa, K.,
Heres, S., Kissling, W., Salanti, G., et al. (2012a) ‘Antipsychotic drugs
versus placebo for relapse prevention in schizophrenia: a systematic review and
meta-analysis’, Lancet, 379, 2063–71.
Leucht, S., Tardy, M., Komossa, K.,
Heres, S., Kissling, W. and Davis, J. M. (2012b) ‘Maintenance treatment with
antipsychotic drugs for schizophrenia’, Cochrane Database
Syst Rev, 5, CD008016.
Lickey, M. E. and Gordon, B. (1986) Medicamentos Para las Enfermadades Mentales (Barcelona:
Labor).
Lieberman, J. A. (1999a) ‘Is
schizophrenia a neurodegenerative disorder? A clinical and neurobiological
perspective’, Biol Psychiatry, 46, 729–39.
Lieberman, J. A. (1999b)
‘Pathophysiologic mechanisms in the pathogenesis and clinical course of
schizophrenia’, J Clin Psychiatry, 60(Suppl.12),
9–12.
Lieberman, J. A., Kinon, B. J. and
Loebel, A. D. (1990) ‘Dopaminergic mechanisms in idiopathic and drug-induced
psychoses’, Schizophr Bull, 16, 97–110.
Lieberman, J. A., Sheitman, B.,
Chakos, M., Robinson, D., Schooler, N. and Keith, S. (1998) ‘The development of
treatment resistance in patients with schizophrenia: a clinical and
pathophysiologic perspective’, J Clin Psychopharmacol,
18, 20S–24S.
Lieberman, J. A., Tollefson, G. D.,
Charles, C., Zipursky, R., Sharma, T., Kahn, R. S., et al. (2005)
‘Antipsychotic drug effects on brain morphology in first-episode psychosis’, Arch Gen Psychiatry, 62, 361–70.
Lindenmayer, J. P. and Patel, R.
(1999) ‘Olanzapine-induced ketoacidosis with diabetes mellitus’, Am J Psychiatry, 156, 1471.
Lion, J. R. (1975) ‘Conceptual
issues in the use of drugs for the treatment of aggression in man’, J Nerv Ment Dis, 160, 76–82.
Liu, H. Y., Potter, M. P.,
Woodworth, K. Y., Yorks, D. M., Petty, C. R., Wozniak, J. R., et al. (2011)
‘Pharmacologic treatments for pediatric bipolar disorder: a review and
meta-analysis’, J Am Acad Child Adolesc Psychiatry,
50, 749–62.
Lloyd-Evans, B., Crosby, M.,
Stockton, S., Pilling, S., Hobbs, L., Hinton, M., et al. (2011) ‘Initiatives to
shorten duration of untreated psychosis: systematic review’, Br J Psychiatry, 198, 256–63.
Loebel, A. D., Lieberman, J. A.,
Alvir, J. M., Mayerhoff, D. I., Geisler, S. H. and Szymanski, S. R. (1992)
‘Duration of psychosis and outcome in first-episode schizophrenia’, Am J Psychiatry, 149, 1183–8.
Lu, M. L., Pan, J. J., Teng, H. W.,
Su, K. P. and Shen, W. W. (2002) ‘Metoclopramide-induced supersensitivity
psychosis’, Ann Pharmacother, 36, 1387–90.
Lui, S., Deng, W., Huang, X., Jiang,
L., Ma, X., Chen, H., et al. (2009) ‘Association of cerebral deficits with
clinical symptoms in antipsychotic-naive first-episode schizophrenia: an
optimized voxel-based morphometry and resting state functional connectivity
study’, Am J Psychiatry, 166, 196–205.
Maas, J. W. and Garver, D. L. (1975)
‘Linkage of basic neuropharmacology and clinical psychopharmacology’, in
Hamburg, D. A. and Brodie, H. K. H. (eds) American Handbook
of Psychiatry, Volume 6; New Psychiatric Frontiers, 2nd edn, pp. 427–59
(New York: Basic Books).
McClelland, G. R., Cooper, S. M. and
Pilgrim, A. J. (1990) ‘A comparison of the central nervous system effects of haloperidol,
chlorpromazine and sulpiride in normal volunteers’, Br J
Clin Pharmacol, 30, 795–803.
McCreadie, R. G., Thara, R.,
Padmavati, R., Srinivasan, T. N. and Jaipurkar, S. D. (2002) ‘Structural brain
differences between never-treated patients with schizophrenia, with and without
dyskinesia, and normal control subjects: a magnetic resonance imaging study’, Arch Gen Psychiatry, 59, 332–36.
McElroy, S. L., Weisler, R. H.,
Chang, W., Olausson, B., Paulsson, B., Brecher, M., et al. (2010) ‘A
double-blind, placebo-controlled study of quetiapine and paroxetine as
monotherapy in adults with bipolar depression (EMBOLDEN II)’, J Clin Psychiatry, 71, 163–74.
McGlashan, T. H. (2005) ‘Early
detection and intervention in psychosis: an ethical paradigm shift’, Br J Psychiatry Suppl, 48, s113–s115.
McGlashan, T. H. (2006) ‘Rationale
and parameters for medication-free research in psychosis’, Schizophr
Bull, 32, 300–2.
McGlashan, T. H., Zipursky, R. B.,
Perkins, D., Addington, J., Miller, T., Woods, S. W., et al. (2006) ‘Randomized,
double-blind trial of olanzapine versus placebo in patients prodromally
symptomatic for psychosis’, Am J Psychiatry, 163,
790–9.
McGorry, P. D. (2008) ‘Is early
intervention in the major psychiatric disorders justified? Yes’, BMJ, 337, a695.
McGorry, P. (2011) ‘Merchants of
doubt do no favours for people with mental illness’, available at: http://www.patmcgorry.com.au/blog/pmcgorry/merchants-doubt-do-no-favours-people-mental-illnesses
(accessed 15 April 2013).
McGorry, P. D., Yung, A. R.,
Phillips, L. J., Yuen, H. P., Francey, S., Cosgrave, E. M., et al. (2002)
‘Randomized controlled trial of interventions designed to reduce the risk of
progression to first-episode psychosis in a clinical sample with subthreshold
symptoms.’, Arch Gen Psychiatry, 59, 921–8.
McGorry, P., Nordentoft, M. and
Simonsen, E. (2005) ‘Introduction to “Early psychosis: a bridge to the
future”’, Br J Psychiatry Suppl, 48, s1–s3.
McGorry, P., Johanessen, J. O.,
Lewis, S., Birchwood, M., Malla, A., Nordentoft, M., et al. (2010) ‘Early
intervention in psychosis: keeping faith with evidence-based health care’, Psychol Med, 40, 399–404.
McGorry, P. D., Nelson, B., Phillips,
L. J., Yuen, H. P., Francey, S. M., Thampi, A., et al. (2013) ‘Randomized
controlled trial of interventions for young people at ultra-high risk of
psychosis: twelve-month outcome’, J Clin Psychiatry,
74, 349–56.
McGowan, S., Lawrence, A. D., Sales,
T., Quested, D. and Grasby, P. (2004) ‘Presynaptic dopaminergic dysfunction in
schizophrenia: a positron emission tomographic [18F]fluorodopa study’, Arch Gen Psychiatry, 61, 134–42.
Mackay, A. V., Iversen, L. L.,
Rossor, M., Spokes, E., Bird, E., Arregui, A., et al. (1982) ‘Increased brain
dopamine and dopamine receptors in schizophrenia’, Arch Gen
Psychiatry, 39, 991–997.
McQuade, R. D., Stock, E., Marcus,
R., Jody, D., Gharbia, N. A., Vanveggel, S., et al. (2004) ‘A comparison of
weight change during treatment with olanzapine or aripiprazole: results from a
randomized, double-blind study’, J Clin Psychiatry,
65(Suppl. 18), 47–56.
Malitz, S. and Hoch, P. (1966) ‘Drug
therapy: neuroleptics and tranquilizers’, in Arieti, S. (ed.) American Handbook of Psychiatry, Volume III, 2nd edn, pp.
458–76 (New York: Basic Books).
Manji, H. K., Moore, G. J. and Chen,
G. (1999) ‘Lithium at 50: have the neuroprotective effects of this unique
cation been overlooked?’, Biol Psychiatry, 46,
929–40.
Manji, H. K., Moore, G. J., &
Chen, G. (2000) ‘Lithium up-regulates the cytoprotective protein Bcl-2 in the
CNS in vivo: a role for neurotrophic and neuroprotective effects in manic
depressive illness’, J Clin Psychiatry, 61(Suppl. 9),
82–96.
Manji, R. A., Wood, K. E. and Kumar,
A. (2009) ‘The history and evolution of circulatory shock’, Crit
Care Clin, 25, 1–29, vii.
Mapp, Y. and Nodine, J. H. (1962)
‘Psychopharmacology. II. Tranquilizers and antipsychotic drugs’, Psychosomatics, 3, 458–463.
Marder, S. R. and Meibach, R. C.
(1994) ‘Risperidone in the treatment of schizophrenia’, Am J
Psychiatry, 151, 825–35.
Marshall, M. and Rathbone, J. (2011)
‘Early intervention for psychosis’, Schizophr Bull,
37, 1111–14.
Marshall, M., Lewis, S., Lockwood,
A., Drake, R., Jones, P. and Croudace, T. (2005) ‘Association between duration
of untreated psychosis and outcome in cohorts of first-episode patients: a
systematic review’, Arch Gen Psychiatry, 62, 975–83.
Martinot, J. L., Peron-Magnan, P.,
Huret, J. D., Mazoyer, B., Baron, J. C., Boulenger, J. P., et al. (1990)
‘Striatal D2 dopaminergic receptors assessed with positron emission tomography
and [76Br]bromospiperone in untreated schizophrenic patients’, Am J Psychiatry, 147, 44–50.
Matthysse, S. (1973) ‘Antipsychotic
drug actions: a clue to the neuropathology of schizophrenia?’, Fed Proc, 32, 200–5.
Matthysse, S. (1974a) ‘Dopamine and
the pharmacology of schizophrenia: the state of the evidence’, J Psychiatr Res, 11, 107–13.
Matthysse, S. (1974b) ‘Epilogue’, J Psychiatric Res, 11, xiii–xvi.
Maudsley, H. (1895) The Pathology of the Mind (London: Macmillan).
Maxman, A. (2012) ‘Psychosis risk
syndrome excluded from DSM-5’, Nature News, 9 May.
May, P. R., Tuma, A. H., Dixon, W.
J., Yale, C., Thiele, D. A. and Kraude, W. H. (1981) ‘Schizophrenia. A follow-up
study of the results of five forms of treatment’, Arch Gen
Psychiatry, 38, 776–84.
May, P. R. A. (1968) Treatment of Schizophrenia (New York City: Science House).
May, R. (2001) ‘Taking a stand:
Fergus Keane interview with Rufus May’, BBC Radio 4,
6 Feb.
Mayer-Gross, W., Slater, E. and
Roth, M. (1954) Clinical Psychiatry, 1st edn (London:
Cassell & Co.).
Mayer-Gross, W., Slater, E. and
Roth, M. (1960) Clinical Psychiatry, 2nd edn (London:
Cassell & Co.).
Mayer-Gross, W., Slater, E. and
Roth, M. (1969) Clinical Psychiatry, 3rd edn (London:
Bailliere Tindall).
Medew, J. (2010) ‘McGorry
“misleading the public”’, The Age, 9 Aug.
Melander, H., Ahlqvist-Rastad, J.,
Meijer, G. and Beermann, B. (2003) ‘Evidence b(i)ased medicine—selective
reporting from studies sponsored by pharmaceutical industry: review of studies
in new drug applications’, BMJ, 326, 1171–3.
Melle, I., Larsen, T. K., Haahr, U.,
Friis, S., Johannessen, J. O., Opjordsmoen, S., et al. (2004) ‘Reducing the
duration of untreated first-episode psychosis: effects on clinical
presentation’, Arch Gen Psychiatry, 61, 143–50.
Melleril advertisement (1960)
Advertisement, J Mental Sci, 106 (April), iii–vii.
Melleril advertisement (1970)
Advertisement, Br J Psychiatry, 117 (Sept), xii–xiii.
Meltzer, H. Y. (1991) ‘The mechanism
of action of novel antipsychotic drugs’, Schizophr Bull,
17, 263–87.
Meltzer, H. Y. (1994) ‘An overview
of the mechanism of action of clozapine’, J Clin Psychiatry,
55(Suppl. B), 47–52.
Meltzer, H. Y. (1995) ‘The role of
serotonin in schizophrenia and the place of serotonin-dopamine antagonist
antipsychotics’, J Clin Psychopharmacol, 15, 2S–3S.
Meltzer, H. Y. and Stahl, S. M.
(1976) ‘The dopamine hypothesis of schizophrenia: a review’, Schizophr Bull, 2, 19–76.
Meltzer, H. Y., Matsubara, S. and
Lee, J. C. (1989) ‘Classification of typical and atypical antipsychotic drugs
on the basis of dopamine D-1, D-2 and serotonin2 pKi values’, J Pharmacol Exp Ther, 251, 238–46.
Meyers, F. H. (1956) ‘Pharmacology
of chlorpormazine, reserpine and related drugs’, in Kline, N. S. (ed.) Psychopharmacology. A Symposium Held by the Section on Medical
Sciences of the American Association for the Advancement of Science and the
American Psychiatric Association, pp. 131–40 (Washington DC: American
Association for the Advancement of Science).
MHRA (1992) Clinical
assessment report on ripseridone – Final (London: obtained through
Freedom of Information Act request to Medicines and Healthcare products
Regulatory Agency (MHRA)).
Miller, D. D., McEvoy, J. P., Davis,
S. M., Caroff, S. N., Saltz, B. L., Chakos, M. H., et al. (2005) ‘Clinical
correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE
schizophrenia trial’, Schizophr Res, 80, 33–43.
Mindfreedom (2012) ‘Occupy American
Psychiatric Association New York City’, available at: http://www.mindfreedom.org/as/act-archives/us/new-york/occupy-apa-nyc-2012
(accessed 15 April 2013).
Mintzes, B., Barer, M. L., Kravitz,
R. L., Kazanjian, A., Bassett, K., Lexchin, J., et al. (2002) ‘Influence of
direct to consumer pharmaceutical advertising and patients’ requests on
prescribing decisions: two site cross sectional survey’, BMJ,
324, 278–9.
Mittal, V., Kurup, L., Williamson,
D., Muralee, S. and Tampi, R. R. (2011) ‘Risk of cerebrovascular adverse events
and death in elderly patients with dementia when treated with antipsychotic
medications: a literature review of evidence’, Am J
Alzheimers Dis Other Demen, 26, 10–28.
Mizrahi, R., Bagby, R. M., Zipursky,
R. B. and Kapur, S. (2005) ‘How antipsychotics work: the patients’
perspective’, Prog Neuropsychopharmacol Biol Psychiatry,
29, 859–64.
Mizrahi, R., Kiang, M., Mamo, D. C.,
Arenovich, T., Bagby, R. M., Zipursky, R. B., et al. (2006) ‘The selective
effect of antipsychotics on the different dimensions of the experience of
psychosis in schizophrenia spectrum disorders’, Schizophr
Res, 88, 111–18.
Modestin, J., Huber, A., Satirli,
E., Malti, T. and Hell, D. (2003) ‘Long-term course of schizophrenic illness:
Bleuler’s study reconsidered’, Am J Psychiatry, 160,
2202–8.
Moffat, L. E., Hamilton, D. N. and
Ledingham, I. M. (1985) ‘To stop his wounds, lest he do bleed to death. A
history of surgical shock’, J R Coll Surg Edinb, 30,
73–81.
Mogilnicka, E. and Braestrup, C.
(1976) ‘Noradrenergic influence on the stereotyped behaviour induced by
amphetamine, phenethylamine and apomorphine’, J Pharm
Pharmacol, 28, 253–5.
Moncrieff, J. (1999) ‘An
investigation into the precedents of modern drug treatment in psychiatry’, Hist Psychiatry, 10, 475–90.
Moncrieff, J. (2001) ‘Are
antidepressants overrated? A review of methodological problems in
antidepressant trials’, J Nerv Ment Dis, 189,
288–295.
Moncrieff, J. (2003) ‘Clozapine v.
conventional antipsychotic drugs for treatment-resistant schizophrenia: a
re-examination’, Br J Psychiatry, 183, 161–6.
Moncrieff, J. (2006) ‘Does
antipsychotic withdrawal provoke psychosis? Review of the literature on rapid
onset psychosis (supersensitivity psychosis) and withdrawal-related relapse’, Acta Psychiatr Scand, 114, 3–13.
Moncrieff,
J. (2008a) The Myth of the Chemical Cure: A Critique of
Psychiatric Drug Treatment
(Basingstoke: Palgrave Macmillan).
Moncrieff, J. (2008b) ‘The creation
of the concept of the antidepressant: an historical analysis’, Soc Sci Med, 66, 2346–55.
Moncrieff, J. (2009) ‘A critique of
the dopamine hypothesis of schizophrenia and psychosis’, Harv
Rev Psychiatry, 17, 214–25.
Moncrieff, J. and Cohen, D. (2005)
‘Rethinking models of psychotropic drug action’, Psychother
Psychosom, 74, 145–53.
Moncrieff, J. and Crawford, M. J.
(2001) ‘British psychiatry in the 20th century—observations from a psychiatric
journal’, Soc Sci Med, 53, 349–56.
Moncrieff, J. and Cohen, D. (2006)
‘Do antidepressants cure or create abnormal brain states?’, PLoS
Med, 3, e240.
Moncrieff, J. and Leo, J. (2010) ‘A
systematic review of the effects of antipsychotic drugs on brain volume’, Psychol Med, 40, 1–14.
Moncrieff, J., Cohen, D. and Mason,
J. P. (2009) ‘The subjective experience of taking antipsychotic medication: a
content analysis of Internet data’, Acta Psychiatr Scand,
120, 102–11.
Monroe, R. R. (1975)
‘Anticonvulsants in the treatment of aggression’, J Nerv
Ment Dis, 160, 119–26.
Montgomery, A. J., Mehta, M. A. and
Grasby, P. M. (2006) ‘Is psychological stress in man associated with increased
striatal dopamine levels?: A [11C]raclopride PET study’, Synapse,
60, 124–31.
Moorhead, T. W., McKirdy, J.,
Sussmann, J. E., Hall, J., Lawrie, S. M., Johnstone, E. C., et al. (2007)
‘Progressive gray matter loss in patients with bipolar disorder’, Biol Psychiatry, 62, 894–900.
Morrison, A. P., French, P.,
Stewart, S. L., Birchwood, M., Fowler, D., Gumley, A. I., et al. (2012) ‘Early
detection and intervention evaluation for people at risk of psychosis:
multisite randomised controlled trial’, BMJ, 344,
e2233.
Mukherjee, S. (1984) ‘Tardive
dysmentia: a reappraisal’, Schizophr Bull, 10, 151–3.
Muller, P. and Seeman, P. (1978)
‘Dopaminergic supersensitivity after neuroleptics: time-course and
specificity’, Psychopharmacology (Berl), 60, 1–11.
Myslobodsky, M. S. (1993) ‘Central
determinants of attention and mood disorder in tardive dyskinesia (“tardive
dysmentia”)’, Brain Cogn, 23, 88–101.
Naidoo, D. (1956) ‘The effect of
reserpine (serpasil) on the chronic disturbed schizophrenic: a comparative
study of Rauwolfia alkaloids and electroconvulsive therapy’, J Nerv Ment Dis, 123, 1–13.
National Collaborating Centre for
Mental Health (2010) ‘Schizophrenia. the NICE guideline on core interventions
in the treatment and management of schizophrenia in adults in primary and
secondary care – updated’, Rep. No. 82 (London: British Psychological Society
and Royal College of Psychiatrists).
National Institute for Health and
Clinical Excellence (2002) Schizophrenia: Core Interventions
in the Treatment and Management of Schizophrenia in Primary and Secondary Care
(London: National Institute for Clinical Excellence).
National
Institute for Health and Clinical Excellence (2005) Violence:
The Short-term Management of Distrubed/Violent Behaviour in In-patient
Psychiatric Settings and Emergency Departments (London: Royal College of Nursing).
National Institute for Health and
Clinical Excellence (2006) ‘Bipolar Disorder. the management of bipolar
disorder in adults, children and adolescents, in primary and secondary care’,
Rep. No. NICE Clinical Guideline 38 (London: National Institute for Clinical
Excellence).
National Institute of Mental Health
Psychopharmacology Service Center Collaborative Study Group (1964)
‘Phenothiazine treatment in acute schizophrenia’, Arch Gen
Psychiatry, 10, 246–58.
Navari, S. and Dazzan, P. (2009) ‘Do
antipsychotic drugs affect brain structure? A systematic and critical review of
MRI findings’, Psychol Med, 39, 1763–77.
Newcomer, J. W., Haupt, D. W.,
Fucetola, R., Melson, A. K., Schweiger, J. A., Cooper, B. P., et al. (2002)
‘Abnormalities in glucose regulation during antipsychotic treatment of
schizophrenia’, Arch Gen Psychiatry, 59, 337–45.
Ngan, E. T., Lane, C. J., Ruth, T.
J. and Liddle, P. F. (2002) ‘Immediate and delayed effects of risperidone on
cerebral metabolism in neuroleptic naive schizophrenic patients: correlations
with symptom change’, J Neurol Neurosurg Psychiatry,
72, 106–10.
NHS Information Centre for Health
and Social Care (1998–2010) ‘Prescription Cost Analysis. London: The Health and
Social Care Information Centre’, available at: http://www.hscic.gov.uk/searchcatalogue?q=title%3A%22prescription+cost+analysis%22&area=&size=10&sort=Relevance
(accessed 26 April 2013).
NHS
Information Centre for Health and Social Care (2010) In-patients
Formally Detained in Hospitals Under the Mental Health Act 1983 and Patients
Subject to Supervised Community Treatment, Annual Figures, England 2009/10 (London: The Health and Social Care Information Centre).
NHS
Information Centre for Health and Social Care (2011) In-patients
Formally detained in Hospitals Under the Mental Health Act 1983 and Patients
Subject to Supervised Community Treatment, Annual Figures, England 2010/2011 (London: The Health and Social Care Information Centre).
NHS Prescription Services (2009) Prescribing Review April–June 2009. Antipsychotic drugs.
(London: NHS Business Services Authority).
Nieoullon, A. and Coquerel, A.
(2003) ‘Dopamine: a key regulator to adapt action, emotion, motivation and
cognition’, Curr Opin Neurol, 16(Suppl. 2), S3–S9.
Noce, R. H., Williams, D. B. and
Rapaport, W. (1954) ‘Reserpine (serpasil) in the management of the mentally ill
and mentally retarded; preliminary report’, JAMA,
156, 821–4.
Nozaki, S., Kato, M., Takano, H.,
Ito, H., Takahashi, H., Arakawa, R., et al. (2009) ‘Regional dopamine synthesis
in patients with schizophrenia using L-[beta-11C]DOPA PET’, Schizophr
Res, 108, 78–84.
Nyberg, S., Nordstrom, A. L.,
Halldin, C. and Farde, L. (1995) ‘Positron emission tomography studies on D2
dopamine receptor occupancy and plasma antipsychotic drug levels in man’, Int Clin Psychopharmacol, 10(Suppl. 3), 81–5.
Oaks, D. (2011) ‘Users views on
coercive treatment’, in Kallert, T. W., Mezzich, J. E. and Monahan, J. (eds) Coercive Treatment in Psychiatry: Clinical Legal and Ethical
aspects, 1st edn, pp. 187–211 (Hoboken, NJ: John Wiley).
Odegaard, O. (1964) ‘Pattern of
discharge from Norwegian psychiatric hospitals before and after the
introduction of psychiatric drugs’, Am J Psychiatry,
70, 772–8.
Olfson, M., Blanco, C., Liu, L.,
Moreno, C. and Laje, G. (2006) ‘National trends in the outpatient treatment of
children and adolescents with antipsychotic drugs’, Arch Gen
Psychiatry, 63, 679–85.
Osby, U., Correia, N., Brandt, L.,
Ekbom, A. and Sparen, P. (2000) ‘Mortality and causes of death in schizophrenia
in Stockholm county, Sweden’, Schizophr Res, 45,
21–8.
Otsuka America
Pharmaceutical (2012) ‘Understanding bipolar I disorder’, available at: http://www.abilify.com/bipolar/about/bipolar-disorder.aspx?tc=89340&utm_source=google&utm_medium=organic_search&utm_term=&sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=1&ved=0CDAQFjAA&url=http%3A%2F%2Fwww.abilify.com%2F&ei=nAS-UMiwJ8TT0QWBroDgCg&usg=AFQjCNEmuZnhqoRv2cM0IGq_-bFnCG8QJw&sig2=liuonlDgERjWI6SxmKQOKA
(accessed 16 April 2013).
Overholser, W. (1956) ‘Has
chlorpromazine inaugurated a new era in mental hospitals?’, J
Clin Exp Psychopathol, 17, 197–201.
Overton, R. C. and De Bakey, M. E.
(1956) ‘Experimental observations on the influence of hypothermia and autonomic
blocking agents on hemorrhagic shock’, Ann Surg, 143,
439–47.
Owen, F., Cross, A. J., Crow, T. J.,
Longden, A., Poulter, M. and Riley, G. J. (1978) ‘Increased dopamine-receptor
sensitivity in schizophrenia’, Lancet, 2, 223–6.
Owens, D. G. (1985) ‘Involuntary
disorders of movement in chronic schizophrenia—the role of the illness and its
treatment’, Psychopharmacology Suppl, 2, 79–87.
Owens, D. C. (2008) ‘How CATIE
brought us back to Kansas: a critical re-evaluation of the concept of atypical
antipsychotics and their place in the treatment of schizophrenia’, Adv Psychiatr Treat, 14, 17–28.
Owens, D. G., Johnstone, E. C. and
Frith, C. D. (1982) ‘Spontaneous involuntary disorders of movement: their
prevalence, severity, and distribution in chronic schizophrenics with and
without treatment with neuroleptics’, Arch Gen Psychiatry,
39, 452–61.
Owens, D. G., Johnstone, E. C.,
Crow, T. J., Frith, C. D., Jagoe, J. R. and Kreel, L. (1985) ‘Lateral
ventricular size in schizophrenia: relationship to the disease process and its
clinical manifestations’, Psychol Med, 15, 27–41.
Pacatal advertisement (1957)
Advertisement. J Mental Sci, 103, April, vii.
Pariante, C. M., Vassilopoulou, K.,
Velakoulis, D., Phillips, L., Soulsby, B., Wood, S. J., et al. (2004)
‘Pituitary volume in psychosis’, Br J Psychiatry,
185, 5–10.
Paterson,
A. S. (1963) Electrical and Drug Treatments in Psychiatry (London: Elsevier).
Paulsen, J., Heaton, R. and Jeste,
D. (1994) ‘Neuropsychological impairment in tardive dyskinesia’, Neuropsychology, 8, 227–41.
Paulson, G. W. (2005) ‘Historical
comments on tardive dyskinesia: a neurologist’s perspective’, J Clin Psychiatry, 66, 260–4.
Pellegrino, E. D. (1979) ‘The
socio-cultural impact of twentieth century therapeutics’, in Vogel, M. J. and
Rosenberg, C. E. (eds) The Therapeutic Revolution,
pp. 245–66 (Philadelphia, PA: University of Pennsylvania Press).
Peltonen, L. (1962)
‘Pneumoencephalographic studies on the third ventricle of 644 neuropsychiatric
patients’, Acta Psychiatr Scand, 38, 15–34.
Perceval,
J. (1961) Perceval’s
Narrative. A Patient’s Account of his Psychosis 1830–1832 (Stanford, CA: Stanford University Press).
Peretti, C. S., Danion, J. M.,
Kauffmann-Muller, F., Grange, D., Patat, A. and Rosenzweig, P. (1997) ‘Effects
of haloperidol and amisulpride on motor and cognitive skill learning in healthy
volunteers’, Psychopharmacology (Berl), 131, 329–38.
Perkins, D. O., Gu, H., Boteva, K.
and Lieberman, J. A. (2005) ‘Relationship between duration of untreated
psychosis and outcome in first-episode schizophrenia: a critical review and
meta-analysis’, Am J Psychiatry, 162, 1785–804.
Petersen, L., Jeppesen, P., Thorup,
A., Abel, M. B., Ohlenschlaeger, J., Christensen, T. O., et al. (2005) ‘A
randomised multicentre trial of integrated versus standard treatment for
patients with a first episode of psychotic illness’, BMJ,
331, 602.
Pfizer (2006) Pfizer website,
available at: www.geodon.com/s_WhatCauses.asp (accessed 6 February
2002).
Pfizer (2011) ‘About bipolar
disorder’, available at: https://www.geodon.com/what-is-bipolar-disorder.aspx
(accessed 16 April 2013).
Phatak, P., Shaldivin, A., King, L.
S., Shapiro, P. and Regenold, W. T. (2006) ‘Lithium and inositol: effects on
brain water homeostasis in the rat’, Psychopharmacology
(Berl), 186, 41–7.
Phillips, L. J., Yung, A. R. and
McGorry, P. D. (2000) ‘Identification of young people at risk of psychosis:
validation of Personal Assessment and Crisis Evaluation Clinic intake
criteria’, Aust N Z J Psychiatry, 34(Suppl.), S164–9.
PIER (2012) ‘The PIER programme’,
available at: http://www.mmc.org/pier_body.cfm?id=2184 (accessed 16
April 2013).
Pillay, P. and Moncrieff, J. (2011)
‘Contribution of psychiatric disorders to occupation of NHS beds: analysis of
Hospital Episode Statistics’, Psychiatrist, 35, 56–9.
Pilowsky, L. S., Costa, D. C., Ell,
P. J., Verhoeff, N. P., Murray, R. M. and Kerwin, R. W. (1994) ‘D2 dopamine
receptor binding in the basal ganglia of antipsychotic-free schizophrenic
patients. An 123I-IBZM single photon emission computerised tomography study’, Br J Psychiatry, 164, 16–26.
Pinfold, V., Smith, J. and Shiers, D.
(2007) ‘Audit of early intervention in psychosis service development in England
in 2005’, Psychiatric Bull, 31, 7–10.
Pletscher, A., Shore, P. A. and
Brodie, B. B. (1955) ‘Serotonin release as a possible mechanism of reserpine
action’, Science, 122, 374–5.
Polak, P. and Laycob, L. (1971)
‘Rapid tranquilization’, Am J Psychiatry, 128, 640–3.
Post, A., Holsboer, F. and Behl, C.
(1998) ‘Induction of NF-kappaB activity during haloperidol-induced oxidative
toxicity in clonal hippocampal cells: suppression of NF-kappaB and
neuroprotection by antioxidants’, J Neurosci, 18,
8236–46.
PREP (2012) ‘Prevention and recovery
in early psychosis’, available at: http://www.prepwellness.org/videos.html
(accessed 16 April 2013).
Priebe, S., Badesconyi, A.,
Fioritti, A., Hansson, L., Kilian, R., Torres-Gonzales, F., et al. (2005)
‘Reinstitutionalisation in mental health care: comparison of data on service
provision from six European countries’, BMJ, 330,
123–6.
Pringsheim, T., Lam, D., Ching, H.
and Patten, S. (2011) ‘Metabolic and neurological complications of
second-generation antipsychotic use in children: a systematic review and
meta-analysis of randomized controlled trials’, Drug Saf,
34, 651–68.
Promazine advertisement (1957)
Advertisement, J Mental Sci, 103, October, vi.
Ramaekers, J. G., Louwerens, J. W.,
Muntjewerff, N. D., Milius, H., de Bie, A., Rosenzweig, P., et al. (1999)
‘Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy
volunteers during treatment with an atypical (amisulpride) and a classic
(haloperidol) antipsychotic’, J Clin Psychopharmacol,
19, 209–21.
Ramaswamy, K., Masand, P. S. and
Nasrallah, H. A. (2006) ‘Do certain atypical antipsychotics increase the risk
of diabetes? A critical review of 17 pharmacoepidemiologic studies’, Ann Clin Psychiatry, 18, 183–94.
Rammsayer, T. and Gallhofer, B.
(1995) ‘Remoxipride versus haloperidol in healthy volunteers: psychometric
performance and subjective tolerance profiles’, Int Clin
Psychopharmacol, 10, 31–7.
Randrup, A. and Munkvad, I. (1967)
‘Brain dopamine and amphetamine-induced stereotyped behaviour’, Acta Pharmacol Toxicol (Copenh), 25(Suppl. 4), 62.
Randrup, A. and Munkvad, I. (1972)
‘Influence of amphetamines on animal behaviour: stereotypy, functional
impairment and possible animal-human correlations’, Psychiatr
Neurol Neurochir, 75, 193–202.
Randrup, A., Munkvad, I. and Udsen,
P. (1963) ‘Adrenergic mechanisms and amphetamine induced abnormal behaviour’, Acta Pharmacol Toxicol (Copenh), 20, 145–57.
Rauste-von Wright, M. and
Frankenhaeuser, M. (1989) ‘Females’ emotionality as reflected in the excretion
of the dopamine metabolite HVA during mental stress’, Psychol
Rep, 64, 856–8.
Ray, W. A., Meredith, S., Thapa, P.
B., Meador, K. G., Hall, K. and Murray, K. T. (2001) ‘Antipsychotics and the
risk of sudden cardiac death’, Arch Gen Psychiatry,
58, 1161–7.
Ray, W. A., Chung, C. P., Murray, K.
T., Hall, K. and Stein, C. M. (2009) ‘Atypical antipsychotic drugs and the risk
of sudden cardiac death’, N Engl J Med, 360, 225–35.
Read, J., Agar, K., Argyle, N. and
Aderhold, V. (2003) ‘Sexual and physical abuse during childhood and adulthood
as predictors of hallucinations, delusions and thought disorder’, Psychol Psychother, 76, 1–22.
Redeptin advertisement (1975)
Advertisement, Br J Psychiatry, 126 June.
Remington, G. (2005) ‘Rational
pharmacotherapy in early psychosis’, Br J Psychiatry Suppl,
48, s77–s84.
Remington, G. (2008) ‘Alterations of
dopamine and serotonin transmission in schizophrenia’, Prog
Brain Res, 172, 117–40.
Reserpine advertisement (1956)
Advertisement, J Ment Sci, 102, January vi.
Reynolds, G. P., Riederer, P.,
Jellinger, K. and Gabriel, E. (1981) ‘Dopamine receptors and schizophrenia: the
neuroleptic drug problem’, Neuropharmacology, 20,
1319–20.
Risperdal Consta advertisement
(2007) Advertisement, Br J Psychiatry, 191, October,
backcover.
Ritalin advertisement (1964)
Advertisement, BMJ, 2.
Roberts, M. H. T. (1973)
‘Pharmacology of drugs of importance in psychiatry’, in Forrest, A. (ed.) Companion to Psychiatric Studies Volume 1, 1st edn, pp.
348–85 (Edinburgh: Churchill Livingstone).
Robertson, M. M. and Trimble, M. R.
(1982) ‘Major tranquillisers used as antidepressants. A review’, J Affect Disord, 4, 173–93.
Rogers, A. and Pilgrim, D. (2001) Mental Health Policy in Britain, 2nd edn (Basingstoke:
Palgrave Macmillan).
Rogers, A., Day, J. C., Williams,
B., Randall, F., Wood, P., Healy, D., et al. (1998) ‘The meaning and management
of neuroleptic medication: a study of patients with a diagnosis of
schizophrenia’, Soc Sci Med, 47, 1313–23.
Rollin, H. R. (1990) ‘The dark
before the dawn’, J Psychopharmacol, 4, 109–14.
Rosenhan, D.L. (1973) ‘On being sane
in insane places’, Science, 179, 250–8.
Rothman, R. B., Baumann, M. H.,
Dersch, C. M., Romero, D. V., Rice, K. C., Carroll, F. I., et al. (2001)
‘Amphetamine-type central nervous system stimulants release norepinephrine more
potently than they release dopamine and serotonin’, Synapse,
39, 32–41.
Royal College of Psychiatrists
(2004) ‘Mental health and growing up’ (pamphlet).
Royal Commission (1926) ‘Report of
the royal commission on lunacy and mental disorders’, Rep. No. Cmd. 2700
(London: Stationery Office).
Ruhrmann, S., Bechdolf, A., Kuhn, K.
U., Wagner, M., Schultze-Lutter, F., Janssen, B., et al. (2007) ‘Acute effects
of treatment for prodromal symptoms for people putatively in a late initial
prodromal state of psychosis’, Br J Psychiatry Suppl,
51, s88–s95.
Rummel-Kluge, C., Komossa, K.,
Schwarz, S., Hunger, H., Schmid, F., Lobos, C. A., et al. (2010) ‘Head-to-head
comparisons of metabolic side effects of second generation antipsychotics in
the treatment of schizophrenia: a systematic review and meta-analysis’, Schizophr Res, 123, 225–33.
Rush, A. J., Wisniewski, S. R.,
Zisook, S., Fava, M., Sung, S. C., Haley, C. L., et al. (2012) ‘Is prior course
of illness relevant to acute or longer-term outcomes in depressed out-patients?
A STAR*D report’, Psychol Med, 42, 1131–49.
Rushton, P. (1988) ‘Lunatics and
idiots: mental disability, the community, and the poor law in North-East
England, 1600–1800’, Med Hist, 32, 34–50.
Ryan, M. C., Collins, P. and
Thakore, J. H. (2003) ‘Impaired fasting glucose tolerance in first-episode,
drug-naive patients with schizophrenia’, Am J Psychiatry,
160, 284–9.
Sacher, J., Mossaheb, N.,
Spindelegger, C., Klein, N., Geiss-Granadia, T., Sauermann, R., et al. (2008)
‘Effects of olanzapine and ziprasidone on glucose tolerance in healthy
volunteers’, Neuropsychopharmacology, 33, 1633–41.
Sacks, O. (1990) Awakenings,
revised edn (New York: Vintage Books).
Sadler, W. S. (1953) Practice of Psychiatry (London: Henry Kimpton).
Sagara, Y. (1998) ‘Induction of
reactive oxygen species in neurons by haloperidol’, J
Neurochem, 71, 1002–12.
Sainz, A. A. (1956) ‘Considerations
on the cerebral action of Reserpine’, in Kline, N. S. (ed.) Psychopharmacology.
A Symposium Held by the Section on Medical Sciences of the American Association
for the Advancement of Science and the American Psychiatric Association,
pp. 59–63 (Washington DC: American Association for the Advancement of Science).
Sakel, M. (1958) Schizophrenia
(New York: Philosophical Library).
Salgado-Pineda, P., Baeza, I.,
Perez-Gomez, M., Vendrell, P., Junque, C., Bargallo, N., et al. (2003)
‘Sustained attention impairment correlates to gray matter decreases in first
episode neuroleptic-naive schizophrenic patients’, Neuroimage,
19, 365–75.
Salokangas, R. K., Vilkman, H.,
Ilonen, T., Taiminen, T., Bergman, J., Haaparanta, M., et al. (2000) ‘High
levels of dopamine activity in the basal ganglia of cigarette smokers’, Am J Psychiatry, 157, 632–4.
Samaha, A. N., Seeman, P., Stewart,
J., Rajabi, H. and Kapur, S. (2007) ‘“Breakthrough” dopamine supersensitivity
during ongoing antipsychotic treatment leads to treatment failure over time’, J Neurosci, 27, 2979–86.
Sankaranarayanan, J. and Puumala, S.
E. (2007) ‘Antipsychotic use at adult ambulatory care visits by patients with
mental health disorders in the United States, 1996–2003: national estimates and
associated factors’, Clin Ther, 29, 723–41.
Sartorius, N., Jablensky, A. and
Shapiro, R. (1977) ‘Two-year follow-up of the patients included in the WHO
International Pilot Study of Schizophrenia’, Psychol Med,
7, 529–41.
Sarwer-Foner, G. J. (1960) ‘The role
of neuroleptic medication in psychotherapeutic interaction’, Compr Psychiatry, 1, 291–300.
Sawamoto, N., Hotton, G., Pavese,
N., Piccini, P. and Brooks, D. J. (2005) ‘Frontal endogenous dopamine release
detected with [11C]-raclopride PET during a visual search task in healthy
subjects and Parkinson’s disease patients’, Neurology,
64, A274.
Scherk, H. and Falkai, P. (2006)
‘Effects of antipsychotics on brain structure’, Curr Opin
Psychiatry, 19, 145–50.
Schizophrenia Commission (2012) ‘The
abandoned illness: a report from the schizophrenia commission’ (London: Rethink
Mental Illness).
schizophrenia.com (2012) ‘Worldwide early diagnosis and
tretament centres for schizophrenia’, available at: http://www.schizophrenia.com/earlypsychosis.htm
(accessed 16 April 2013).
Schleifer, J. J. (2011) ‘Management
of acute agitation in psychosis: an evidence based approach in the USA’, Adv Psychiatr Treat, 17, 91–100.
Schmeid, K. and Ernst, K. (1983)
[‘Isolation and forced injection in the opinion of affected patients and
patient care personnel. An accompanied quarter year sample’], Arch Psychiatr Nervenkr, 233, 211–22 [in German].
Schmidt, W. R. and Jarcho, L. W.
(1966) ‘Persistent dyskinesias following phenothiazine therapy. Report of five
cases and a review of the literature’, Arch Neurol,
14, 369–77.
Schneider, L. S., Dagerman, K. S.
and Insel, P. (2005) ‘Risk of death with atypical antipsychotic drug treatment
for dementia: meta-analysis of randomized placebo-controlled trials’, JAMA, 294, 1934–43.
Schneider, L. S., Dagerman, K. and
Insel, P. S. (2006) ‘Efficacy and adverse effects of atypical antipsychotics
for dementia: meta-analysis of randomized, placebo-controlled trials’, Am J Geriatr Psychiatry, 14, 191–210.
Schoenecker, M. (1957) [‘Paroxysmal
dyskinesia as the effect of megaphen’]. Nervenarzt,
28, 550–3 [in German].
Schooler, N. R., Goldberg, S. C.,
Boothe, H. and Cole, J. O. (1967) ‘One year after discharge: community
adjustment of schizophrenic patients’, Am J Psychiatry,
123, 986–95.
Schooler, N., Rabinowitz, J.,
Davidson, M., Emsley, R., Harvey, P. D., Kopala, L., et al. (2005) ‘Risperidone
and haloperidol in first-episode psychosis: a long-term randomized trial’, Am J Psychiatry, 162, 947–53.
Scull, A. (1993) The
Most Solitary of Afflictions (New Haven, CT: Yale University Press).
Scull, A. (1994) ‘Somatic treatments
and the historiography of psychiatry’, Hist Psychiatry,
5, 1–12.
Sedgwick, P. (1982) Psychopolitics (London: Harper & Row).
Sengupta, S., Parrilla-Escobar, M.
A., Klink, R., Fathalli, F., Ying, K. N., Stip, E., et al. (2008) ‘Are
metabolic indices different between drug-naive first-episode psychosis patients
and healthy controls?’, Schizophr Res, 102, 329–36.
Serenace advertisement (1965a)
Advertisement, Br J Psychiatry, 111, January xiii.
Serenace advertisement (1965b)
Advertisement, Br J Psychiatry, 111, July viii.
Sernyak, M. J., Leslie, D. L.,
Alarcon, R. D., Losonczy, M. F. and Rosenheck, R. (2002) ‘Association of diabetes
mellitus with use of atypical neuroleptics in the treatment of schizophrenia’, Am J Psychiatry, 159, 561–6.
Sheitman, B. B., Lee, H., Strous, R.
and Lieberman, J. A. (1997) ‘The evaluation and treatment of first-episode
psychosis’, Schizophr Bull, 23, 653–61.
Shepherd, M. (1994) ‘Neurolepsis and
the psychopharmacological revolution: myth and reality’, Hist
Psychiatry, 5, 89–96.
Shepherd, M., Goodman, N. and Watt,
D. C. (1961) ‘The application of hospital statistics in the evaluation of
pharmacotherapy in a psychiatric population’, Comp
Psychiatry, 2, 11–19.
Shopsin, B., Klein, H., Aaronsom, M.
and Collora, M. (1979) ‘Clozapine, chlorpromazine, and placebo in newly
hospitalized, acutely schizophrenic patients: a controlled, double-blind
comparison’, Arch Gen Psychiatry, 36, 657–64.
Shorter,
E. (1997) A
History of Psychiatry. From the Era of the Asylum to the Age of Prozac (New York: John Wiley).
Sigwald, J. and Bouttier, D. (1953)
[‘3-Chloro-10-(3’-dimethylaminopropyl)-phenothiazine hydrochloride in current
neuro-psychiatry’], Ann Med Interne (Paris), 54,
150–82.
Sigwald, J., Bouttier, D.,
Raymondeaud, C. and Piot, C. (1959) [‘4 cases of facio-bucco-linguo-masticatory
dyskinesis of prolonged development following treatment with neuroleptics’], Rev Neurol (Paris), 100, 751–5.
Singh, S. P., Wright, C., Burns, T.,
Joyce, E. and Barnes, T. R. E. (2003) ‘Developing early intervention services
in the NHS: a survey to guide workforce and training needs’, The Psychiatrist, 27, 254–8.
Smieskova, R., Fusar-Poli, P.,
Allen, P., Bendfeldt, K., Stieglitz, R. D., Drewe, J., et al. (2009) ‘The
effects of antipsychotics on the brain: what have we learnt from structural
imaging of schizophrenia?—a systematic review’, Curr Pharm
Des, 15, 2535–49.
Smith
Kline & French Laboratories (1955) Chlorpormazine and
Mental Health: Proceedings Held Under the Auspices of Smith Kline & French
Laboratories (Philadelphia, PA: Lea
& Febiger).
Smith, R. C., Lindenmayer, J. P.,
Hu, Q., Kelly, E., Viviano, T. F., Cornwell, J., et al. (2010) ‘Effects of
olanzapine and risperidone on lipid metabolism in chronic schizophrenic
patients with long-term antipsychotic treatment: a randomized five month
study’, Schizophr Res, 120, 204–9.
Smythies, J. R. (1973) ‘Drug
treatment of schizophrenia’, in Forrest, A. (ed.) Companion
to Psychiatric Studies, Volume 2, pp. 250–88 (Edinburgh: Churchill
Livingstone).
Snyder, S. H. (1972) ‘Catecholamines
in the brain as mediators of amphetamine psychosis’, Arch
Gen Psychiatry, 27, 169–79.
Snyder, S. H. (1974) ‘Stereoselective
features of catecholamine dispostion and their behavioral implications’, J Psychiatr Res, 11, 31–9.
Snyder, S. H. (1980) ‘Basic science
of psychopharmacology’, in Kaplan, H. I., Freedman, A. M. and Sadock, B. J.
(eds) Comprehensive Textbook of Psychiatry, 3rd edn,
pp. 154–65 (Baltimore, MD: Williams & Wilkins).
Snyder, S. H., Banerjee, S. P.,
Yamamura, H. I. and Greenberg, D. (1974) ‘Drugs, neurotransmitters, and
schizophrenia’, Science, 184, 1243–53.
Soreff, S. M. and Bazemore, P. H.
(2006) ‘Confronting chaos’, Behav Healthc, 26, 16–20.
Spielmans, G. I. (2009) ‘The
promotion of olanzapine in primary care: an examination of internal industry
documents’, Soc Sci Med, 69, 14–20.
Spielmans, G.I. and Parry P.I.
(2010) ‘From evidence-based medicine to marketing-based medicine: evidence from
internal industry documents’, J Bioethic Inq, 7,
13–29.
Spitzer, R. L. (1975) ‘On
pseudoscience in science, logic in remission, and psychiatric diagnosis: a
critique of Rosenhan’s “On being sane in insane places”’, J
Abnorm Psychol, 84, 442–52.
Spivak, B., Mester, R., Abesgaus,
J., Wittenberg, N., Adlersberg, S., Gonen, N., et al. (1997a) ‘Clozapine
treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic
akathisia in schizophrenic patients’, J Clin Psychiatry,
58, 318–22.
Spivak, B., Mester, R., Wittenberg,
N., Maman, Z. and Weizman, A. (1997b) ‘Reduction of aggressiveness and
impulsiveness during clozapine treatment in chronic neuroleptic-resistant
schizophrenic patients’, Clin Neuropharmacol, 20,
442–6.
Stahl, S. M. (2008) Antipsychotics and Mood Stablizers (Cambridge: Cambridge
University Press).
Stark, J. (2011) ‘McGorry aborts
teen drug trial’, Sydney Morning Herald, 21 Aug.
Stawarz, R. J., Hill, H., Robinson,
S. E., Setler, P., Dingell, J. V. and Sulser, F. (1975) ‘On the significance of
the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus
striatum and limbic forebrain’, Psychopharmacologia,
43, 125–30.
Steck, H. (1954) [‘The
extra-pyradmial and di-encephalic syndrome during treatment with largactil and
serpasil’], Annales Medico-psychologiques, 112,
737–43.
Stelazine advertisement (1959a)
Advertisement, J Mental Sci, 105, January, i.
Stelazine advertisement (1959b)
Advertisement, J Mental Sci, 105, April, i
Stelazine advertisement (1965a)
Advertisement, Br J Psychiatry, 111, September, xiv.
Stelazine advertisement (1965b)
Advertisement. Br J Psychiatry, 111, June, xiv.
Stengers, I. (1995) [‘The physician
and the quack’], in Nathan, T. and Stengers, I. (eds), [Doctors
and Sorcerers], pp. 115–61 (Paris: Les Empecheurs de Penser en Rond) [in
French].
Stepnisky, J. (2007) ‘The biomedical
self: hermeneutic considerations’, Soc Theory Health,
5, 187–207.
Storey, P. B. (1966) ‘Lumbar air
encephalography in chronic schizophrenia: a controlled experiment’, Br J Psychiatry, 112, 135–44.
Straus, S. M., Bleumink, G. S.,
Dieleman, J. P., van der, L. J., ‘t Jong, G. W., Kingma, J. H., et al. (2004)
‘Antipsychotics and the risk of sudden cardiac death’, Arch
Intern Med, 164, 1293–7.
Strudwick, P. (2012) ‘How a
stressful job lead to my bipolar diagnosis’, The Times,
26 May.
Sullivan, E. V., Shear, P. K., Lim,
K. O., Zipursky, R. B. and Pfefferbaum, A. (1996) ‘Cognitive and motor
impairments are related to gray matter volume deficits in schizophrenia’, Biol Psychiatry, 39, 234–40.
Suppes, T., Baldessarini, R. J.,
Faedda, G. L. and Tohen, M. (1991) ‘Risk of recurrence following
discontinuation of lithium treatment in bipolar disorder’, Arch
Gen Psychiatry, 48, 1082–8.
Sussman, N. (2009) ‘General
principles of psychopharmacology’, in Saddock, B. J., Saddock, V. A. and Ruiz,
P. (eds), 9th edn, pp. 2965–88 (Philadelphia, PA: Wolters Kluwer/Lippincott
Williams & Wilkins).
Swazey, J. (1974) Chlorpromazine in Psychiatry (Cambridge, MA: Massachusetts
Institute of Technology).
Szasz,
T. (1970) Ideology
and Insanity; Essays on the Psychiatric Dehumanization of Man (New York: Anchor Books).
Szasz, T. S. (1957) ‘Some
observations on the use of tranquilizing drugs’, AMA Arch
Neurol Psychiatry, 77, 86–92.
Tamminga, C. A., Thaker, G. K.,
Moran, M., Kakigi, T. and Gao, X. M. (1994) ‘Clozapine in tardive dyskinesia:
observations from human and animal model studies’, J Clin
Psychiatry, 55(Suppl B), 102–6.
Tandon, R., Mazzara, C., DeQuardo,
J., Craig, K. A., Meador-Woodruff, J. H., Goldman, R., et al. (1991)
‘Dexamethasone suppression test in schizophrenia: relationship to
symptomatology, ventricular enlargement, and outcome’, Biol
Psychiatry, 29, 953–64.
Tarsy, D. (1983) ‘History and
definition of tardive dyskinesia’, Clin Neuropharmacol,
6, 91–9.
Taylor, D., Paton, C. and Kapur, S.
(2009) The Maudsley Prescribing Guidelines (London:
Informa Healthcare).
Thomas, K. (2012) ‘J&J fined
$1.2 billion in drug case. New York Times’, available at: http://www.nytimes.com/2012/04/12/business/drug-giant-is-fined-1-2-billion-in-arkansas.html
(accessed 17 April 2013).
Thorup, A., Petersen, L., Jeppesen,
P., Ohlenschlaeger, J., Christensen, T., Krarup, G., et al. (2005) ‘Integrated
treatment ameliorates negative symptoms in first episode psychosis—results from
the Danish OPUS trial’, Schizophr Res, 79, 95–105.
Thuillier, J. (2000) ‘Ten years that
changed psychiatry’, in Healy, D. (ed.) The
Psychopharmacologists Volume III, pp. 543–59 (London: Arnold).
Tien, A. Y. and Eaton, W. W. (1992)
‘Psychopathologic precursors and sociodemographic risk factors for the
schizophrenia syndrome’, Arch Gen Psychiatry, 49,
37–46.
Tiihonen, J., Walhbeck, K.,
Lonnqvist, J., Klaukka, T., Ioannidis, J. P., Volavka, J., et al. (2006)
‘Effectiveness of antipsychotic treatments in a nationwide cohort of patients
in community care after first hospitalisation due to schizophrenia and
schizoaffective disorder: observational follow-up study’, BMJ,
333, 224.
Tiihonen, J., Lonnqvist, J.,
Wahlbeck, K., Klaukka, T., Niskanen, L., Tanskanen, A., et al. (2009) ‘11-year
follow-up of mortality in patients with schizophrenia: a population-based
cohort study (FIN11 study)’, Lancet, 374, 620–7.
Time Magazine (1954) ‘Wonder drug of
1954’, Time Magazine, 14 Jun.
Time Magazine (1955) ‘Pills for the
mind’, Time Magazine, 7 Mar.
Timimi, S., Gardner, N. and McCabe,
B. (2011) Myth of Autism (Basingstoke: Palgrave Macmillan).
Tohen, M., Baker, R. W., Altshuler,
L. L., Zarate, C. A., Suppes, T., Ketter, T. A., et al. (2002) ‘Olanzapine
versus divalproex in the treatment of acute mania’, Am J
Psychiatry, 159, 1011–17.
Tohen, M., Calabrese, J. R., Sachs,
G. S., Banov, M. D., Detke, H. C., Risser, R., et al. (2006) ‘Randomized,
placebo-controlled trial of olanzapine as maintenance therapy in patients with
bipolar I disorder responding to acute treatment with olanzapine’, Am J Psychiatry, 163, 247–56.
Tohen, M., Sanger, T. M., McElroy,
S. L., Tollefson, G. D., Chengappa, K. N., Daniel, D. G., et al. (1999)
‘Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH
Study Group’, Am J Psychiatry, 156, 702–9.
Tohen, M., Goldberg, J. F.,
Gonzalez-Pinto Arrillaga, A. M., Azorin, J. M., Vieta, E., Hardy-Bayle, M. C.,
et al. (2003) ‘A 12-week, double-blind comparison of olanzapine vs haloperidol
in the treatment of acute mania’, Arch Gen Psychiatry,
60, 1218–26.
Torniainen, M., Suvisaari, J.,
Partonen, T., Castaneda, A. E., Kuha, A., Suokas, J., et al. (2012) ‘Cognitive
impairments in schizophrenia and schizoaffective disorder: relationship with
clinical characteristics’, J Nerv Ment Dis, 200,
316–22.
Torrey, E. F. (2002) ‘Studies of
individuals with schizophrenia never treated with antipsychotic medications: a
review’, Schizophr Res, 58, 101–15.
TREC Collaborative Group (2003)
‘Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a
randomised trial of midazolam versus haloperidol plus promethazine’, BMJ, 327, 708–13.
Tyhurst, J. S. and Richman, A.
(1955) ‘Clinical experience with psychiatric patients on reserpine—preliminary
impressions’, Can Med Assoc J, 72, 458–9.
Tyrer, P. (2012) ‘From the Editor’s
desk’, Br J Psychiatry, 201, 168.
Tyrer, P. and Kendall, T. (2009)
‘The spurious advance of antipsychotic drug therapy’, Lancet,
373, 4–5.
Tyrer, P., Oliver-Africano, P. C.,
Ahmed, Z., Bouras, N., Cooray, S., Deb, S., et al. (2008) ‘Risperidone,
haloperidol, and placebo in the treatment of aggressive challenging behaviour
in patients with intellectual disability: a randomised controlled trial’, Lancet, 371, 57–63.
Uhrbrand, L. and Faurbye, A. (1960)
‘Reversible and irreversible dyskinesia after treatment with perphenazine,
chlorpromazine, reserpine and electro-convulsive therapy’, Psychopharmacologia,
1, 408–18.
Ukai, W., Ozawa, H., Tateno, M.,
Hashimoto, E. and Saito, T. (2004) ‘Neurotoxic potential of haloperidol in
comparison with risperidone: implication of Akt-mediated signal changes by
haloperidol’, J Neural Transm, 111, 667–81.
United States Department of Justice
(2009) ‘Pharmaceutical company Eli Lilly to pay record $1.415 billion for off
label drug marketing’, available at: http://www.justice.gov/usao/pae/News/2009/jan/lillyrelease.pdf
(accessed 25 April 2013).
United States Department of Justice
(2010) ‘Pharmaceutical giant AstraZeneca to pay $520 million for off label drug
marketing’, available at: http://www.justice.gov/opa/pr/2010/April/10-civ-487.html
(accessed 25 April 2013).
Unsworth, C. (1987) The Politics of Mental Health Legislation (Oxford: Oxford
University Press).
USA Today (2009) ‘Experts raise
concerns over Seroquel to treat depression’, available at: http://usatoday30.usatoday.com/news/health/2009-04-08-fda-seroquel_N.htm?csp=34
(accessed 17 April 2013).
Van Praag, H. M. and Korf, J. (1975)
‘Neuroleptics, catecholamines, and psychoses: a study of their interrelations’,
Am J Psychiatry, 132, 593–7.
van Rossum, J., van der, S. C. H. O.
and Hurkmans, J. A. (1962) ‘Mechanism of action of cocaine and amphetamine in
the brain’, Experientia, 18, 229–31.
van Rossum, J. M. (1966a) ‘The
significance of dopamine-receptor blockade for the mechanism of action of
neuroleptic drugs’, Arch Int Pharmacodyn Ther, 160,
492–4.
van Rossum J.M. (1966b) ‘The
significance of dopamine receptor blockade for the action of neuroleptic
drugs’, in Brill, H. (ed.) Neuro-psycho-pharmacology,
pp. 321–9 (Amsterdam: Excerpta Medica Foundation).
Van Voris, R. and Lawrence, J.
(2010) ‘Pfizer told to pay $142.1 million for Neurontin marketing fraud’,
available at: http://www.bloomberg.com/apps/news?pid=email_en&sid=a_9aVylZQGjU
(available at 17 April 2013).
Venkatasubramanian, G., Jayakumar,
P. N., Gangadhar, B. N. and Keshavan, M. S. (2008) ‘Automated MRI parcellation
study of regional volume and thickness of prefrontal cortex (PFC) in
antipsychotic-naive schizophrenia’, Acta Psychiatr Scand,
117, 420–31.
Verdoux, H. and Cougnard, A. (2006)
‘Schizophrenia: who is at risk? Who is a case?’, Int Clin
Psychopharmacol, 21(Suppl. 2), S17–19.
Verdoux, H., Tournier, M. and
Begaud, B. (2010) ‘Antipsychotic prescribing trends: a review of
pharmaco-epidemiological studies’, Acta Psychiatr Scand,
121, 4–10.
Verhoeff, N. P., Kapur, S., Hussey,
D., Lee, M., Christensen, B., Psych, C., et al. (2001) ‘A simple method to
measure baseline occupancy of neostriatal dopamine D2 receptors by dopamine in
vivo in healthy subjects’, Neuropsychopharmacology,
25, 213–23.
Vernaleken, I., Kumakura, Y.,
Cumming, P., Buchholz, H. G., Siessmeier, T., Stoeter, P., et al. (2006)
‘Modulation of [18F]fluorodopa (FDOPA) kinetics in the brain of healthy
volunteers after acute haloperidol challenge’, Neuroimage,
30, 1332–9.
Vernon, A. C., Natesan, S., Modo, M.
and Kapur, S. (2011) ‘Effect of chronic antipsychotic treatment on brain
structure: a serial magnetic resonance imaging study with ex vivo and
postmortem confirmation’, Biol Psychiatry, 69,
936–44.
Vigen, C. L., Mack, W. J., Keefe, R.
S., Sano, M., Sultzer, D. L., Stroup, T. S., et al. (2011) ‘Cognitive effects
of atypical antipsychotic medications in patients with Alzheimer’s disease:
outcomes from CATIE-AD’, Am J Psychiatry, 168, 831–9.
Volavka, J., Czobor, P., Nolan, K.,
Sheitman, B., Lindenmayer, J. P., Citrome, L., et al. (2004) ‘Overt aggression
and psychotic symptoms in patients with schizophrenia treated with clozapine,
olanzapine, risperidone, or haloperidol’, J Clin
Psychopharmacol, 24, 225–8.
Volkow, N. D., Brodie, J. D., Wolf,
A. P., Angrist, B., Russell, J. and Cancro, R. (1986) ‘Brain metabolism in
patients with schizophrenia before and after acute neuroleptic administration’,
J Neurol Neurosurg Psychiatry, 49, 1199–202.
Volz, A., Khorsand, V., Gillies, D.
and Leucht, S. (2007) ‘Benzodiazepines for schizophrenia’, Cochrane
Database Syst Rev, CD006391.
Voruganti, L. N. and Awad, A. G.
(2006) ‘Subjective and behavioural consequences of striatal dopamine depletion
in schizophrenia—findings from an in vivo SPECT study’, Schizophr
Res, 88, 179–86.
Waddington, J. L., Youssef, H. A.
and Kinsella, A. (1990) ‘Cognitive dysfunction in schizophrenia followed up
over 5 years, and its longitudinal relationship to the emergence of tardive
dyskinesia’, Psychol Med, 20, 835–42.
Waddington, J. L., O’Callaghan, E.,
Larkin, C. and Kinsella, A. (1993) ‘Cognitive dysfunction in schizophrenia:
organic vulnerability factor or state marker for tardive dyskinesia?’, Brain Cogn, 23, 56–70.
Waddington, J. L., Youssef, H. A.
and Kinsella, A. (1998) ‘Mortality in schizophrenia. Antipsychotic polypharmacy
and absence of adjunctive anticholinergics over the course of a 10-year
prospective study’, Br J Psychiatry, 173, 325–9.
Wade, J. B., Taylor, M. A.,
Kasprisin, A., Rosenberg, S. and Fiducia, D. (1987) ‘Tardive dyskinesia and
cognitive impairment’, Biol Psychiatry, 22, 393–5.
Waldmeier, P. C. and Delini-Stula,
A. A. (1979) ‘Serotonin–dopamine interactions in the nigrostriatal system’, Eur J Pharmacol, 55, 363–73.
Walker, E. F., Cornblatt, B. A., Addington,
J., Cadenhead, K. S., Cannon, T. D., McGlashan, T. H., et al. (2009) ‘The
relation of antipsychotic and antidepressant medication with baseline symptoms
and symptom progression: a naturalistic study of the North American Prodrome
Longitudinal Sample’, Schizophr Res, 115, 50–7.
Wallace, M. (1994) ‘Schizophrenia—a
national emergency: preliminary observations on SANELINE’, Acta
Psychiatr Scand Suppl, 380, 33–5.
Warner,
R. (2004) Recovery
from Schizophrenia: Psychiatry and Political Economy, 3rd edn (Hove: Brunner-Routledge).
Warner, R. (2005) ‘Problems with
early and very early intervention in psychosis’, Br J
Psychiatry Suppl, 48, s104–7.
Waters, F., Woodward, T., Allen, P.,
Aleman, A. and Sommer, I. (2010) ‘Self-recognition Deficits in Schizophrenia Patients
With Auditory Hallucinations: A Meta-analysis of the Literature’, Schizophr Bull, 38, 741–750.
Watts, G. (2012) ‘Critics attack
DSM-5 for overmedicalising normal human behaviour’, Br Med J,
344, e1020.
Weinmann, S., Read, J. and Aderhold,
V. (2009) ‘Influence of antipsychotics on mortality in schizophrenia:
systematic review’, Schizophr Res, 113, 1–11.
Weisler, R., Joyce, M., McGill, L.,
Lazarus, A., Szamosi, J. and Eriksson, H. (2009) ‘Extended release quetiapine
fumarate monotherapy for major depressive disorder: results of a double-blind,
randomized, placebo-controlled study’, CNS Spectr,
14, 299–313.
Wen, P. (2009) ‘Psychiatric drug
sought on streets’, Boston Globe 13 Jul.
Wen, P. (2010) ‘Father convicted of
1st degree murder in death of Rebecca Riley’, Boston Globe
26 Mar.
Wescott, P. (1979) ‘One man’s
schizophrenic illness’, Br Med J, 1, 989–90.
Whitaker, R. (2002) Mad in America (Cambridge, MA: Perseus Publishing).
Whitaker, R. (2010) Anatomy of an Epidemic (New York: Crown Publishers).
Whitty, P. F., Owoeye, O. and
Waddington, J. L. (2009) ‘Neurological signs and involuntary movements in
schizophrenia: intrinsic to and informative on systems pathobiology’, Schizophr Bull, 35, 415–24.
Wilson, M. (1993) ‘DSM-III and the
transformation of American psychiatry: a history’, Am J
Psychiatry, 150, 399–410.
Wilson, I. C., Garbutt, J. C.,
Lanier, C. F., Moylan, J., Nelson, W. and Prange, A. J., Jr (1983) ‘Is there a
tardive dysmentia?’, Schizophr Bull, 9, 187–92.
Wilson, M. P., Pepper, D., Currier,
G. W., Holloman, G. H., Jr and Feifel, D. (2012) ‘The psychopharmacology of
agitation: consensus statement of the american association for emergency
psychiatry project Beta psychopharmacology workgroup’, West
J Emerg Med, 13, 26–34.
Winkelman, N. W., Jr (1954) ‘Chlorpromazine
in the treatment of neuropsychiatric disorders’, JAMA,
155, 18–21.
Winokur, G. (1975) ‘The Iowa 500:
heterogeneity and course in manic-depressive illness (bipolar)’, Compr Psychiatry, 16, 125–31.
Winterer, G. (2006) ‘Cortical
microcircuits in schizophrenia—the dopamine hypothesis revisited’, Pharmacopsychiatry, 39(Suppl. 1), S68–71.
Wise, C. D., Baden, M. M. and Stein,
L. (1974) ‘Post-mortem measurement of enzymes in human brain: evidence of a
central noradrenergic deficit in schizophrenia’, J Psychiatr
Res, 11, 185–98.
Wolf, M. E., Ryan, J. J. and
Mosnaim, A. D. (1983) ‘Cognitive functions in tardive dyskinesia’, Psychol Med, 13, 671–4.
Wolkowitz, O. M. and Pickar, D.
(1991) ‘Benzodiazepines in the treatment of schizophrenia: a review and reappraisal’,
Am J Psychiatry, 148, 714–26.
Wong, D. F., Wagner, H. N., Jr.,
Tune, L. E., Dannals, R. F., Pearlson, G. D., Links, J. M., et al. (1986)
‘Positron emission tomography reveals elevated D2 dopamine receptors in
drug-naive schizophrenics’, Science, 234, 1558–63.
Woodberry, K. A., Giuliano, A. J.
and Seidman, L. J. (2008) ‘Premorbid IQ in schizophrenia: a meta-analytic
review’, Am J Psychiatry, 165, 579–87.
Woods, S. W., Morgenstern, H.,
Saksa, J. R., Walsh, B. C., Sullivan, M. C., Money, R., et al. (2010)
‘Incidence of tardive dyskinesia with atypical versus conventional
antipsychotic medications: a prospective cohort study’, J
Clin Psychiatry, 71, 463–74.
Woolley, D. W. and Campbell, N. K.
(1962a) ‘Exploration of the central nervous system serotonin in humans’, Ann N Y Acad Sci, 96, 108–17.
Woolley, D. W. and Campbell, N. K.
(1962b) ‘Serotonin-like and antiserotonin properties of psilocybin and
psilocin’, Science, 136, 777–8.
Woolley, D. W. and Shaw, E. (1954)
‘A biochemical and pharmacological suggestion about certain mental disorders’, Proc Natl Acad Sci U S A, 40, 228–31.
Wozniak, J., Mick, E., Waxmonsky,
J., Kotarski, M., Hantsoo, L. and Biederman, J. (2009) ‘Comparison of
open-label, 8-week trials of olanzapine monotherapy and topiramate augmentation
of olanzapine for the treatment of pediatric bipolar disorder’, J Child Adolesc Psychopharmacol, 19, 539–45.
Wright, D. (1997) ‘Getting out of
the asylum: understanding the confinement of the insane in the nineteenth
century’, Soc Hist Med, 10, 137–55.
Wright, P., Stern, J. and Phelan, M.
(2012) Core Psychiatry, 3rd edn (Edinburgh: Saunders
Elsevier).
Wunderink, L., Nienhuis, F. J.,
Sytema, S., Slooff, C. J., Knegtering, R. and Wiersma, D. (2007) ‘Guided
discontinuation versus maintenance treatment in remitted first-episode
psychosis: relapse rates and functional outcome’, J Clin
Psychiatry, 68, 654–61.
Wyatt, R. J. (1991) ‘Neuroleptics
and the natural course of schizophrenia’, Schizophr Bull,
17, 325–51.
Wyatt, R. J. (1995) ‘Early
intervention for schizophrenia: can the course of the illness be altered?’, Biol Psychiatry, 38, 1–3.
Yilmaz, Z., Zai, C. C., Hwang, R.,
Mann, S., Arenovich, T., Remington, G., et al. (2012) ‘Antipsychotics, dopamine
D(2) receptor occupancy and clinical improvement in schizophrenia: a
meta-analysis’, Schizophr Res, 140, 214–20.
Yood, M. U., DeLorenze, G.,
Quesenberry, C. P., Jr, Oliveria, S. A., Tsai, A. L., Willey, V. J., et al.
(2009) ‘The incidence of diabetes in atypical antipsychotic users differs
according to agent—results from a multisite epidemiologic study’, Pharmacoepidemiol Drug Saf, 18, 791–9.
Young, D. and Scoville, W. B. (1938)
‘Paranoid psychosis in narcolepsy and the possible dangers of benzedrine
treatment’, Med Clin N Am, 22, 637–46.
Youssef, H. A. and Waddington, J. L.
(1988) ‘Involuntary orofacial movements in hospitalised patients with mental
handicap or epilepsy: relationship to developmental/intellectual deficit and
presence or absence of long-term exposure to neuroleptics’, J
Neurol Neurosurg Psychiatry, 51, 863–5.
Yu, X. (2011) ‘Three professors face
sanctions after Harvard medical school inquiry’, The Harvard
Crimson, 2 Jul.
Yung, A. R., McGorry, P. D.,
McFarlane, C. A., Jackson, H. J., Patton, G. C. and Rakkar, A. (1996)
‘Monitoring and care of young people at incipient risk of psychosis’, Schizophr Bull, 22, 283–303.
Zakzanis, K. K. and Hansen, K. T.
(1998) ‘Dopamine D2 densities and the schizophrenic brain’, Schizophr
Res, 32, 201–6.
Zeeberg, B. R., Gibson, R. E. and
Reba, R. C. (1988) ‘Elevated D2 dopamine receptors in drug-naive
schizophrenics’, Science, 239, 789–91.
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