Medicine, to its great credit, has over the past 60 years become the most visible symbol of the Great Enlightenment Project where scientific progress would vanquish the twin evils of ignorance and suffering to the benefit of all. So dramatically successful has it been, it is now almost impossible to imagine what life was like at the close of the World War II when death in childhood was commonplace, there were no effective drugs for virtually any of the illnesses doctors encountered—at a time when the ‘chronic’ wards at Fulbourn Mental Hospital outside Cambridge were ‘a scene of human degradation’.

‘I was taken in by someone who had a key to unlock the door and lock it behind you,’ recalls Dr David Clark on his first visit to the hospital in 1953 as a newly appointed psychiatrist. ‘The crashing of the keys in the lock was an essential part of asylum life then just as it is today in jail. This led into a big bare room with scrubbed floors, bare wooden tables, benches screwed to the floor, overcrowded with people milling around in shapeless clothing. The disturbed women’s ward was a phantasmagorical place. They were in “strong clothes” made of reinforced cotton that couldn’t be torn. Many of them were in locked boots which couldn’t be taken off and thrown. They all had their hair chopped off short giving them identical wiry grey mops. As soon as you came in they’d rush up and crowd around you. Hands would go into your pockets grabbing at you, pulling at you, clambering for release, for food, for anything until they were pushed back by the sturdy nurses who shouted at them to sit down and shut up. At the back of the ward were the padded cells, in which would be one or two naked women, smeared with faeces, shouting obscenities at anybody who came near …’.

In the same year, across the Atlantic, in the Verdun Protestant Hospital in Montreal, psychiatrist Heinz Lehmann had obtained a small supply of the antihistamine derivative chlorpromazine famously observed by French naval surgeon Henri Laborit to induce a state of ‘euphoric quietude’ in his patients. Lehmann, a Jewish refugee from Nazi Germany had over the years experimented with ‘all kinds of drugs’ convinced that psychotic illness must have a biological cause—large amounts of caffeine, typhoid antitoxin, injections of turpentine and sulphur suspended in oil. ‘Nothing helped’, but with chlorpromazine:

‘two or three patients with schizophrenia became symptom-free. Now I had never seen that happen before. I thought it was a fluke – something that would never happen again, but anyhow there they were. At the end of four or five weeks there were several more whose hallucinations, delusions and thought disorders seemed to have disappeared.’

Chlorpromazine would be followed over the next few years by several further classes of similarly serendipitously discovered drugs, most notably lithium and the tricyclic antidepressants with apparently similar dramatic results. ‘The patients became generally more lively,’ wrote Roland Kuhn of the effects of imipramine on his patients in the Munsterlingen Clinic in Switzerland noting how they ‘now jumped out of bed in the morning to take part in the general life of the hospital and interested themselves again in their family affairs’.

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This was to be sure an immensely fertile period for drug discovery but the impact upon psychiatry of so many novel compounds in so short a time was probably greater than for any other discipline—culminating a decade later in the elegant demonstration of their role in blocking the action of the neurotransmitters dopamine and serotonin.

Surveying these extraordinary events, and their consequences, from the high vantage point of a historical perspective 50 years later, Professor Edward Shorter of Toronto University in a much cited passage from his A History of Psychiatry claimed: ‘The smashing success of the biological approach to psychiatry – treating mental illness as a genetically influenced disorder of brain chemistry,’ to be ‘the central intellectual reality at the end of the twentieth century’.

There are and always have been dissenting voices arguing that the ‘medicalisation’ of psychiatry with these powerful drugs is a ‘chemical fix’ that fails to tackle the underlying psychological problems of the mentally ill. But Shorter’s verdict would seem unassailable being grounded not only in everyday clinical experience but in the cumulative evidence from clinical trials. It would be as perverse to suggest otherwise as to deny the value of antihypertensives in preventing stroke.

That, at least until recently, was the conventional view. It is thus more than surprising that a couple of years ago the editor of the British Journal of Psychiatry Peter Tyrer should assert, ‘the time has now come to call an end to the psychopharmacological revolution as, for many, the risk of [antipsychotic drugs] outweighs the benefits’. Professor Tyrer’s opinion is echoed and elaborated in the shelf-full of books published over the last decade with self-explanatory titles such as Richard Bentall’s Doctoring the Mind: Why Psychiatric Treatments Fail, Peter Breggin’s Toxic Psychiatry and Irving Kirsch’s The Emperor’s New Drugs: Exposing the Antidepressant Myth.

Over the past 10 years Joanna Moncrieff, Consultant Psychiatrist and Senior Lecturer at University College London has argued the intellectual case for this radical re-evaluation of the achievements of post-War psychiatry in numerous scholarly articles in the British Medical Journal, the British Journal of Psychiatry and elsewhere. Her previous book The Myth of the Chemical Cure (2008), critically examined the evidence for the effectiveness of antipsychotics, antidepressants, lithium in the treatment of bipolar disorder and stimulants for attention deficit hyperactivity disorder. The Bitterest Pills: The Troubling Story of Antipsychotic Drugs locates her interpretation of that evidence as it applies to antipsychotics in the broader historical context it merits and requires.

Her central thesis is certainly very persuasive and, put simply, runs as follows. The triumphalist account of psychiatry, epitomized by Shorter’s ‘smashing success story’, conceals a dramatic shift in the perception of how drugs such as chlorpromazine exerted their therapeutic effect from ‘the drug centred’ to ‘the disease centred’.

For the first decade and a half following their introduction, antipsychotics were presumed to influence the thought processes and behaviour of patients with schizophrenia by inducing an altered brain state—in a way not dissimilar to the intoxicating effect of alcohol. Specifically, their tendency to induce a Parkinsonian-type syndrome of tardive dyskinesia with reduced movement and initiative and blunted emotions was inseparable from the process by which they ameliorated the characteristic symptoms of over-arousal and abnormal perceptions. Indeed German psychiatrist Hanz-Joachim Haas calibrated the dose of haloperidol administered to his patients by the ‘hard handwriting test’—based on its characteristic shrinking in Parkinson’s disease—measured each day as patients were given gradually increasing doses until the size of the script had decreased by one-fifth.

This ‘drug-centred’ view, reflected in their description as ‘major tranquilisers’ or ‘neuroleptics,’ would be displaced from the mid-1970s onwards by the ‘disease-centred’ view prompted by Nobel prize winning Swedish pharmacologist Arvid Carlsson’s investigation of the neurotransmitters dopamine and serotonin whose ‘over activity’ it was presumed, must be the underlying biochemical cause of schizophrenia. By 1980 the section on antipsychotic drugs in The Comprehensive Textbook of Psychiatry claimed they had ‘a normalising effect’ and exerted ‘a selective anti-schizophrenic action’. The previous drug-centred view, observes Dr Moncrieff, ‘simply faded away and descriptions of the neurological effects [in inducing tardive dyskinesia] disappeared from the literature, henceforth referred to, if at all, only as side-effects or an inconvenient nuisance’.

Further, the ostensibly self-evident value of antipsychotics in ‘normalising’ brain chemistry in a way, it was presumed, not dissimilar to insulin normalizing the blood sugar of those with diabetes, obscured the reality of the subjective experience of those taking them that they were indeed very powerful tranquilizing drugs deadening the emotions and stifling the intellect.

These serious adverse effects, both physical and mental, of antipsychotics are in themselves persuasive evidence against the disease-centred model as indeed is the curiously equivocal evidence for the long-term benefits of antipsychotic therapy. Thus, Dr Moncrieff points out that the only study lasting longer than 12 weeks comparing chlorpromazine with psychotherapy—conducted by the California-based British psychiatrist Phillip May in the late 1960s—certainly favoured drug therapy as measured by the outcome of discharge from hospital. But in a follow-up review of the same group of patients 20 years later, Dr May observed, ‘the outlook in general was grim whatever treatment the patient received, with no discernible difference, clinically or socially’. More disconcerting still, a similar 15-year follow-up of patients who had ‘opted out of the mental healthcare system’ noted how ‘a surprising number experienced periods of recovery and functioned well without antipsychotics’—better indeed than those on prolonged therapy.

Despite such observations, which one might suppose to have prompted a more critical attitude to the disease-centred ‘normalising’ model, it remains as seductive and influential as ever—reflected in the staggering success of the second generation antipsychotics introduced in the 1990s, commonly known as the ‘atypicals’—clozapine, risperidone, olanzapine and quetiapine. They are certainly much more costly than the original antipsychotics they have displaced and thus immensely profitable—to the tune of $17 billion a year in the United States. This could be a factor in the favourable outcome of the clinical trials organized and funded by the pharmaceutical industry demonstrating their dual advantage of both being more potent and with fewer side effects. This contrasts with the findings of two large non-commercial trials that, with the exception of clozapine, found them to be ‘no more effective and better tolerated than the older drugs’.

Nonetheless the perception of that greater tolerability adds a further twist to Dr Moncrieff’s ‘troubling story’—the drive to broaden the range of conditions for which they might be prescribed to include not only those at risk of developing psychosis (‘where any teenager with unusual behaviour might qualify’) but bipolar disorder, depression and dementia. The upshot has been, in Britain, an increase by two-thirds in the number of prescriptions for antipsychotics between 1998 and 2010 facilitated at least in part, Dr Moncrieff maintains, by ‘legal and illegal marketing strategies, changing concepts of mental disorders and manipulating damaging data about the drugs’ adverse effects’.

There is, to be sure, no novelty in being critical about psychiatry and its practice and one might readily wonder what more there is to add to the many revelations in recent years of the devious methods and sharp practices by which a powerful pharmaceutical industry has subverted the intellectual apparatus of science to its own considerable advantage. The merits of The Bitterest Pills is in placing those concerns in their wider historical context in a way that reconciles the dramatic (and immensely influential for subsequent perceptions) accounts of the transformative effect of these antipsychotic drugs in alleviating acute psychotic illnesses, with the reality that, 60 years on, such illnesses remain obstinate and intractable and the prospect of ‘a cure’ as elusive as ever.

This schematic account cannot do justice to the tightness of the arguments and numerous illustrative examples with which Dr Moncrieff charts the all-important transition from the drug-centred to the disease-centred model and its adverse consequences. It is particularly disquieting too to learn of the, rarely commented on, impact of long-term antipsychotic therapy on brain function—where the ‘withdrawal’ effects of discontinuing medication not infrequently induce a relapse in psychotic symptoms and, through their effect on brain chemistry, contribute to the chronicity of psychotic illness.

Dr Moncrieff takes no hostages and her outspoken criticisms of several prominent psychiatric colleagues have prompted the counterclaim that her interpretation of the evidence is selective and her critical stance ‘eccentric’. This would seem unlikely—though her comments that the ‘disease-centred model’ has ‘played a major part in the obfuscation of the social control function that has always been embedded at the heart of psychiatry’ does at least imply leftist sympathies. Still this can scarcely detract from this most impressive exposition of what is indeed a very ‘troubling story’.