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The Human Nature Review Human Nature Review  2002 Volume 2: 534-539 ( 28 November )
URL of this document http://human-nature.com/nibbs/02/healy.html

Book Review

The Creation of Psychopharmacology 
by David Healy
Harvard University Press, Cambridge, MA, 2002

Reviewed by Donald F. Klein, M.D., Professor of Psychiatry, Department of Psychiatry at the College of Physicians and Surgeons of Columbia University, Director of Psychiatric Research and of the Department of Therapeutics, New York State Psychiatric Institute, New York, NY, USA.

David Healy, a Reader in Psychological Medicine at the University of Wales, College of Medicine, is best known among research psychopharmacologists, for his stimulating three volume set of interviews; The Psychopharmacologists. This oral history candidly describes, in lively, entertaining style, the vicissitudes of life, career, scientific funding and the commercial and social context of discovery of internationally known figures.

Healy prepared extremely well for these interviews, showing a detailed knowledge of specific antecedents and implications of each scientist’s work. He used these interviews in a previous historical survey, The Antidepressant Era and now in an even more broad ranging study of the discovery and development of anti-psychotic medication. The book is aimed at the general readership interested in mental health, psychiatric treatment and science history.

The author does not hesitate to present his own opinions, sweeping generalizations and pointed conclusions. At issue is whether these views are personal or ideological reactions or derive from thoughtful analysis of the relevant facts.

This reviewer (interviewed kindly in Healy’s initial oral history) gives ready assent to many of his conclusions; the key role of serendipity in discovery or as Pasteur says “chance and the prepared mind”, that the distinctive American contribution was a systematic effort to evaluate reliably using double blind, randomized, placebo controlled trials (RCT) under Jonathan Cole’s leadership of the Psychopharmacology Research Center within the National Institute of Mental Health, that multiple seminal meetings during the 1950’s were held in France, the United States, Italy and elsewhere to grapple with the amazing clinical and scientific impact of chlorpromazine, that clinical rating scales become of validating importance, that there were vigorous disputes about lithium utility and the concept of panic disorder, that there was an unfortunate shift away from clinical significance to statistical significance, that the pharmaceutical industry dominates clinical research, that this is facilitated by the abdication by NIMH and academia of clinical psychopharmacological science in pursuit of the sub-synaptic, that industry’s narrow, profit maximization focus on patent time limits and rapid approval by national regulatory agencies (e.g., FDA) dominates marketing strategies, dissemination of positive information, downplays side effects, limits research to acute efficacy studies, limits post-marketing surveillance, and promotes debatable ,simplistic, theories of drug action to provide a persuasive veneer of scientific solidity to therapeutic claims.

So far, so good. But these useful views are immersed in so many problematic statements that their credibility is damaged by their dubious context.

Healy’s central theme is, “Is the West leading the way toward some biomedical truth, or does the development tell us more about marketing truths? In other words, has recent prescribing in the West been culture bound? The possibility that marketing now determines culture is at the heart of this book”. (p. 67)

The importance of industry’s profit maximization motive is not exactly news, given our capitalist society. Industries are not charitable organizations but are driven by competition, market share, etc. Many believe that when marketing fails to promote the public welfare that supplementary institutional arrangements and federal regulations are necessary. (For instance see : Klein, D. F., Thase, M., Endicott, J., Adler, L., Glick, I., Kalali, A., Levanter, S., Mattes, J., Ross, P., Bystritsky, A., "Improving clinical trials: American Society of Clinical Psychopharmacology Recommendations". Archives of General Psychiatry 59: 272-278, 2002.)

Strangely ,Healy makes no such suggestions but rather emphasizes that reforms often produce the opposite of what they set out to achieve (p, 368) which leads him to equate the FDA with the Catholic Church magisterium. He states with regard to the law requiring that drugs be both safe and effective, “the 1962 amendments were passed as part of an effort to guard the people from the unfettered forces of capitalism. It is a moot point whether the reforms have fostered instead the growth of a psychopharmaceutical complex whose power to penetrate markets is now all but comprehensive.”(p.368).

The context indicates clearly that Healy does not consider this “a moot point” at all.

In the Preface to his third interview volume, Healy states that some psychopharmacologists deride “the value of history by interviews. They tell me that the views of so and so are not to be believed”… “He is just trying to prop up his reputation…” “I was there too and this is not the way it happened…” “The complainants have a point. The history of the present, or the almost present, poses considerable problems”. Mark Twain’s point, that as he grows older he remembers more and more events that never happened, is cited.

One major concern is the author’s conclusory language, which is often insufficiently documented. Many points are only referenced to the often stimulating interviews, that still do not rank as primary contemporary data.

The Disease Model

A key focus is Healy’s assertion that psychiatry is dominated by a disease model with an unwarranted focus upon specific and distinct etiologies, which he traces to the bacterial theory of infection. He cites Kraepelin’s sixth edition, which launched the distinctions between manic depressive disease and schizophrenia, (p. 31). However, this is questionable.

Edward Shorter states in The History of Psychiatry (p. 106), that in his 5th edition Kraepelin considered “dementia precox” a “metabolic disorder” similar to thyroid psychosis and neuro-syphilis, which then had no determinant single causes. Shorter quotes Kraepelin, “as long as we are unable clinically to group illnesses on the basis of cause, and to separate dissimilar causes, our views about etiology will necessarily remain unclear and contradictory”, and comments, “In other words cause is something that we in our present state of knowledge cannot know”.

Kraepelin’s major concern was to develop a classification that enabled accurate prognosis, a recurrence to the 17th century views of Thomas Sydenham who developed syndromes on the basis of both symptoms and course. Psychiatric classification, (DSM-IV, ICD 10) maintains this syndromal approach.

Sweeping Questionable Generalizations

The statement (p. 25) “The work of Freud, Janet, Ivan Pavlov and Jung opened up a realm of psychic as distinct from moral functioning, where some of individual’s behaviors could be seen to lie outside his conscious control” is surprisingly out of date. In 1978 Henri Ellenberger effectively dispelled this myth in his classic The Discovery of the Unconscious.

“It is probably no coincidence that biological thinking crept into psychiatry on the back of a group of drugs like the psychedelics which gave rise to “spiritual” thinking,” (p. 202). Without LSD, chlorpromazine would have failed?

Mogens Schou is given proper credit, “without Schou, it is doubtful that lithium would have survived its rebirth”. But does it follow that “the use of lithium will almost certainly end when Schou dies? Another agent, probably of lesser efficacy, will displace it by virtue of a marketing strategy that depends on offering a “biological rationale”. (p. 49)

“A series of 20th century studies have proven that anticholinergic agents have antinervousness and antidepressant properties (reference 48, p.59). These studies make it reasonably certain that when 19th-century clinicians claimed that they saw beneficial effects from hyoscine, they were almost surely correct….As popular awareness of the traditional origins of these drugs vanished, extraordinarily it became possible to call the anticholinergic effects side effects. This process culminated with SSRI’s (selective serotonin reuptake inhibitors) like Prozac being sold on the basis that they are free of anticholinergic “side effects”. … The new situation is one in which some critics of pharmacotherapy have argued that antidepressants may in fact work only by virtue of their side effects”. (reference 49) (p. 59)

Reference 48 is primarily to a set of ancient books and chapters in non-peer reviewed edited volumes. The most recent paper; Kasper, S., “The anticholinergic biperidin in depressive disordersPharmacopsychiatria (1981) 14:195-198 , is an open study of ten patients, whose modest improvement was countered by two patients who discontinued because, respectively, of a paranoid syndrome and inner restlessness. This is far from definitive.

Reference 49 is to the severely criticized work of R. P. Greenberg and S. Fisher. See book review by Klein, D. F., Quitkin, F: "Review of From Placebo to Panacea: Putting Psychiatric Drugs to the Test by Seymour Fisher and Roger P. Greenberg (Eds.) (Wiley; New York, 1997)" Contemporary Psychology 43(9):628-630, 1998. These references do not build confidence in Healy’s critical judgment.

“But throughout most of human history, what are now called side effects have been taken as indicators that the drug was working. These “side effects” almost certainly contributed to what would now be called the placebo effect of former treatments.” (p.60) However, the critique mentioned above by Quitkin and Klein reviewed trials of “active placebos”. There was no superiority to the usual effects of inactive placebos—which is the assumption made by active placebo advocates. Also see Quitkin, F., Rabkin, J., Gerald, J., Davis, J., Klein, D. et al (2000) "Validity of clinical trials of antidepressants". American Journal of Psychiatry 157 (3) 327-337.

Randomized Controlled Trials

Healy repeatedly infers that controlled trials are superfluous. “Does a drug work when it produces an obviously useful effect, such as the analgesia caused by morphine, or does it ‘work’ only when controlled trials prove it does?” (p. 60)

This actually refers to historical controls which only work given such stark black and white contrasts as rabies. Healy has a surprising affection for clinically attested, but unproven remedies, as insulin therapy, isoniazid, hyoscine, St. John’s Wort, etc. It should be remembered that bleeding and purging “obviously worked”.

“…the overwhelming majority of patients with depressive disorders now treated with antidepressants are not hospitalized. In these patients, it is clear that dexamphetamine and methylphenidate are as effective as the SSRI ‘antidepressants’.” (reference 57) (p. 62)

Is this really “clear?” The single reference is to R. J. Chiarello and J. O. Cole, “The Use of Psychostimulants in General PsychiatryArchives of General Psychiatry (1987) 44:286-295 who state, “Generally, the existing studies are old and inadequate. However, there is some evidence to support the judicious use of psychostimulants in selected clinical instances of several adult psychiatric syndromes.” This is not a “clear” sweeping endorsement of equivalent efficacy but rather a judicious suggestion, that Healy distorts.

Healy points to the current lack of inpatient studies, “Had the SSRI’s been tested clinically in the 1950’s, therefore, it is highly likely that they would never have been designated antidepressants”, (p 63). Healy does not refer to the current overwhelming difficulty of finding a sample of depressed patients hospitalized for the 8 weeks required to conduct such a trial, given the extremely short lengths of stay now mandated.

Nor does he cite Schatzberg, A. F., Depression/Anxiety 1996-97, 4(4) 182-9 who reviewed the treatment of severe depression with the selective serotonin reuptake inhibitors “This review assesses 16 control studies of SSRI’s in severe depression. The findings from a majority of studies found the SSRI’s to be superior to placebo and as effective as, but better tolerated, than the tricyclic antidepressants (TCA’s) in severely depressed patients. Although future studies are needed to corroborate and elaborate on these data, studies still support the use of SSRI’s in this patient population.” Healy deals too glibly with difficult evaluative situations.

Healy inconsistently uses the term “cure” while making doom laden predictions on the basis of tenuous evidence. “There has been a shift from viewing certain conditions as problems of living, sometimes inappropriately treated with tranquilizers, to viewing them as diseases appropriately treated with antidepressants. The evidence that antidepressants cure these diseases, however, is meager. And since a diagnosis can be disabling, if the agents being used to treat the condition that has been diagnosed does not produce substantial benefits, it is less than clear that we are not sowing the seeds of an iatrogenic crisis on a grand scale”.

I would say that there is no evidence that antidepressants “cure” anything given the rate of relapse without maintenance medication and our ignorance about etiology. Cure usually means the total rooting out of the disease process. Confusingly, Healy argues that “cures for catatonia” have been neglected (p. 69).

Healy asserts (p. 114) “…the availability from 1955 on of good trial evidence that it [reserpine] was as effective an antidepressant as Prozac.” The reference is D. L. Davies and M. Shepherd “Reserpine in the treatment of anxious and depressed patients” Lancet 1955; 117-121. This single ancient reference is hardly “evidence from 1955 on” and the reference to Prozac is clearly gratuitous.

Healy oscillates in his description of medication. In his introduction (p. 2) he states, “This book is about a series of discoveries of medications for mania, delusions, and poorly behaved children, discoveries that stand among the greatest triumphs in modern medicine.” But he then goes on to say, “But arguably, the main impact of chlorpromazine, like that of psychoanalysis, has been on the culture in which we live.” (p.130).

On page 173 he states that methylphenidate is “a drug widely prescribed for children, and used with few, if any, qualms by millions of parents, even though it differs little in its pharmacological profile from cocaine”. This is a dismaying remark at both clinical and basic levels. That methylphenidate has clinical effects mimicking cocaine is remarkably inaccurate although promulgated widely by Scientologists. Further, Nora Volkow has shown clear differences in brain receptor dynamics.

“In the late 1960’s and early 1970’s psychiatry was battered by the forces of antipsychiatry. Psychologists had demonstrated that psychiatric diagnosis was unreliable to the extent that perfectly normal people might be diagnosed as having schizophrenia”. (p. 215) Actually the studies that demonstrated the unreliability of psychiatric diagnosis occurred during the 1950’s It was later shown that this was caused by criterion variance which the DSM process addresses by explicit inclusion and exclusion criteria. The perfectly normal people cited had actually malingered auditory hallucinations, thus presenting unsuspecting psychiatrists with a clinically irrelevant rare bird.

To conceal the extrapyramidal side effects of the antipsychotics, “…treatment-resistant schizophrenia had become a certain kind of negative schizophrenia that was essentially a creation of the pharmaceutical industry.” (p 270) Healy argues, using vivid language, that antipsychotic side effects were often unrecognized and that “there were obvious difficulties for clinicians in accepting that even part of the benefits they were witnessing with the new drugs might stem from the fact that they were not now poisoning their patients to the same extent as previously. These difficulties led to the need for myths to disguise what was happening, and marketing campaigns for the new treatments that used the concept of negative schizophrenia vigorously provided the required mythologies. As patients recovered from drug induced negativity, the resulting benefits in turn seemed to validate the concept that atypicals had unique effects on negative states.” (p. 270) Thus the benefits of clozapine are dismissed.

“Haloperidol and other potent neuroleptics also caused akathisia, but the megadose regimes of these drugs used in the 1970’s and 1980’s minimized the problem because in high doses these neuroleptics degraded the capacity to act on any of the murderous or suicidal impulses that akathisia can give rise to. It was only in the later 1970’s that the work of Philip May and Theodore van Putten again began to draw attention to the pernicious character of this side effect…for many there was little doubt that akathisia led to a toll of suicides and violence”. (p.275)

However, akathisia was extensively discussed in the 1960’s. My 1969 textbook (co-authored with John Davis) states “this side effect consists of involuntary motor restlessness, constant pacing, and inability to sit still, often accompanied by fidgeting, chewing and lip movements and finger and leg movements. This syndrome is frequently misdiagnosed as anxiety, tension or psychotic exacerbation”. (p. 98)

The provocative statement by Healy, “For many there was little doubt that akathisia led to a toll of suicides and violence,” is completely unreferenced. A MedLine search reveals over 200 articles on akathisia, but only 3 case reports of a possible association with suicide, so it is not clear how Healy arrived at his estimate of “many”.

“The nature of science favors a hunt for specificity…specificity, in addition, is, in healthcare at least, the best way ever yet invented to make money”. (p. 279) However, Healy also notes that chlorpromazine was initially named Largactil precisely because it covered a large range of nervous conditions. He also claims “the insurance and pharmaceutical industries had been content with DSM-II, which may be true but certainly does not indicate any desire for specificity. (p. 270 for specificity and 284 for largactil)

Healy makes the remarkable claim that drugs affect personality rather than illness and states “There are in fact studies showing that the personality traits of patients can predict up to 50% of their likelihood to respond to antidepressants on either the serotonergic or the noradrenergic system (reference 108) and also to antipsychotics (reference 109). Why aren’t more studies like this done? A company that engaged in such trials would then only be licensed to claim that its drug worked on individuals with particular personality types. Such a claim would reduce the company’s profits”. (p. 314)

This is an example of a glib handling of a complicated area. Healy cites one article with regard to personality predicting drug effects, but not several other articles that specifically deny this, and with regard to antipsychotics he only refers to an unpublished paper of his own. For the general reader, this misleading statement has the effect of once again impugning the relevance of disease. However, it does not fit well with Healy’s assertion that claims of specificity are money-makers.

I am puzzled by Healy’s social recommendations. He clearly distrusts the goals and honesty of industry yet he believes that prescriptions (and therefore FDA investigation for both safety and efficacy) are unnecessary and socially undesirable. The consumer should make their own (medically uninformed) decisions. Good luck to them. The recent plague of prescription free “nutraceuticals”, and the ready availability (in bodegas, etc.) of potent antibiotics whose misuse breeds resistant bacteria, stand as counter arguments.

Unfortunately, the list of unwarranted conclusions can be extended (see review by Meltzer, H. Y. Science Vol 297 (16) August 2002). To conclude, this reviewer finds too much substantively questionable or downright misleading to recommend this book. Sadly, the dross obscures the gold.

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Klein, D. F. (2002). Review of The Creation of Psychopharmacology by David Healy. Human Nature Review. 2: 534-539.

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