Elsevier

Medical Hypotheses

Volume 62, Issue 1, January 2004, Pages 5-13
Medical Hypotheses

The case against antipsychotic drugs: a 50-year record of doing more harm than good☆

https://doi.org/10.1016/S0306-9877(03)00293-7Get rights and content

Abstract

Although the standard of care in developed countries is to maintain schizophrenia patients on neuroleptics, this practice is not supported by the 50-year research record for the drugs. A critical review reveals that this paradigm of care worsens long-term outcomes, at least in the aggregate, and that 40% or more of all schizophrenia patients would fare better if they were not so medicated. Evidence-based care would require the selective use of antipsychotics, based on two principles: (a) no immediate neuroleptisation of first-episode patients; (b) every patient stabilized on neuroleptics should be given an opportunity to gradually withdraw from them. This model would dramatically increase recovery rates and decrease the percentage of patients who become chronically ill.

Introduction

The standard of care for schizophrenia calls for patients to be maintained indefinitely on antipsychotic drugs. The evidence for this practice comes from research showing the drugs are effective in treating acute psychotic symptoms and in preventing relapse [1], [2]. Historians also argue that the introduction of neuroleptics in the 1950s made it possible to empty the mental hospitals, and that this is further proof of the drugs’ merits [3]. Yet, long-term outcomes with schizophrenia remain poor, and may be no better than they were 100 years ago, when water therapies and fresh air were the treatment of the day [4], [5], [6], [7].

There is an evident paradox in the research record. The efficacy of neuroleptics appears to be well established, yet there is a lack of evidence showing that these drugs have improved patients’ lives over the long-term. That paradox recently stirred an unusual editorial in Eur. Psychiatry, which posed this question: “After fifty years of neuroleptic drugs, are we able to answer the following simple question: Are neuroleptics effective in treating schizophrenia?” [8] A close review of the research literature provides a surprising answer. The preponderance of evidence shows that the current standard of care – continual medication therapy for all patients so diagnosed – does more harm than good.

Section snippets

Did neuroleptics enable deinstutionalization?

The belief that the introduction of chlorpromazine, marketed in the US as Thorazine, made it possible to empty state hospitals stems from research by Brill and Patton. In the early 1960s, they reported that the patient census at state mental hospitals in the US declined from 558,600 in 1955 to 528,800 in 1961. Although they did not compare discharge rates for drug-treated versus placebo-treated patients, they nevertheless concluded that neuroleptics must have played a role in the decline since

Establishing efficacy: the pivotal NIMH trial

The study that is still cited today as proving the efficacy of neuroleptics for curbing acute episodes of schizophrenia was a nine-hospital trial of 344 patients conducted by the National Institute of Mental Health in the early 1960s. At the end of six weeks, 75% of the drug-treated patients were “much improved” or “very much improved” compared to 23% of the placebo patients. The researchers concluded that neuroleptics should no longer be considered mere “tranquilizers” but “antischizophrenic”

The NIMH withdrawal studies

In the wake of that disturbing report, the NIMH conducted two medication-withdrawal studies. In each one, relapse rates rose in correlation with neuroleptic dosage before withdrawal. In the two trials, only 7% of patients who were on placebo relapsed during the following six months. Twenty-three percent of the patients on less than 300 mg of chlorpromazine daily relapsed following drug withdrawal; this rate climbed to 54% for those receiving 300–500 mg and to 65% for patients taking more than

Drug treatment versus experimental forms of care

With debate over the merits of neuroleptics rising, the NIMH revisited the question of whether newly admitted schizophrenia patients could be successfully treated without drugs. There were three NIMH-funded studies conducted during the 1970s that examined this possibility, and in each instance, the newly admitted patients treated without drugs did better than those treated in a conventional manner.

The world health organization studies

In 1969, the World Health Organization initiated a study to compare outcomes for schizophrenia in “developed” countries with outcomes in “undeveloped” countries. Once again, the results were surprising. Patients in the three poor countries – India, Nigeria and Colombia – were doing dramatically better at two-year and five-year follow-ups than patients in the US and four other developed countries. They were more likely to be fully recovered and faring well in society – “an exceptionally good

MRI studies

While most researchers have used MRIs to investigate possible causes of schizophrenia, a small number have employed this technology to study the effects of neuroleptics on the brain. These investigators have found that the drugs cause atrophy of the cerebral cortex and an enlargement of the basal ganglia [28], [29], [30]. Moreover, researchers at the University of Pennsylvania reported in 1998 that the drug-induced enlargement of the basal ganglia is “associated with greater severity of both

Relapse studies

As discussed earlier, evidence for the efficacy of neuroleptics is stated to be two-fold. First, the NIMH trial in the 1960s found that neuroleptics are more effective than placebo in curbing acute episodes of psychosis. Second, the drugs have been shown to prevent relapse. In 1995, Gilbert reviewed 66 relapse studies, involving 4365 patients, and summed up the collective evidence: Fifty-three percent of patients withdrawn from neuroleptics relapsed within 10 months, versus 16% of those

Doing more harm than good

Although this review of neuroleptics may seem surprising, the research record actually is quite consistent. The pivotal NIMH study in the early 1960s found that the drugs had a short-term benefit, but that over the long-term the drug-treated patients had higher relapse rates. Similarly, in his retrospective study, Bockoven found that patients treated with neuroleptics were more likely to become chronically ill. The experiments by Carpenter, Mosher, and Rappaport all showed higher relapse rates

A better model: the selective use of neuroleptics

At the very least, this history argues that the best model of care would involve selective use of neuroleptics. The goal would be to minimize their use. Several investigators in Europe have developed programs based on that goal, and in every instance they have reported good results. In Switzerland, Ciompi established a house modeled on Mosher’s Soteria Project, and in 1992 he concluded that first-episode patients treated with no or very low doses of medication “demonstrated significantly better

The atypicals: dawn of a new era?

Admittedly, the record of poor long-term results reviewed here was produced by standard neuroleptics. The poor outcomes may also reflect prescribing practices in the US that, until the late 1980s, involved putting patients on high dosages. The long-term research record for clozapine and other atypicals like risperidone and olanzapine has yet to be written.

One hopes that these newer drugs will lead to better outcomes, but there are reasons to be skeptical. As is now widely acknowledged, the

Summary

The history of medicine is replete with examples of therapies that were eagerly embraced for a period and then later discarded as harmful. A scientific examination of the evidence is supposed to save us from such folly today. And science has in fact provided research data to guide prescribing practices. The evidence consistently reveals that maintaining all schizophrenia patients on antipsychotics produces poor long-term outcomes, and that there is a large group of patients – at least 40% of

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    ☆

    Mad in America: Bad Science, Bad Medicine, and the Enduring Mistreatment of the Mentally Ill (Perseus Publishing, 2002).

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