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Rebuttal: questioning the validity of 'anatomy of an epidemic (part II); do Whitaker's allegations endanger the trust that doctors develop with their patients?

Editor's note: In the October issue, Dr. Glazer offered the first part of his rebuttal to the Ashcraft-Anthony "Tools for Transformationv interviews with Robert Whitaker, which appeared in two parts in the July/August and September issues. He focused on three arguments that emerged from these articles:

1. That psychiatric medications have increased disability over the last 20 years;

2. That there is a pharmacological basis to explain this increased morbidity; and

3. That psychiatry conspired with the pharmaceutical companies to keep these "facts" from prescribers and the public.

Dr. Glazer used epidemiologic principles to argue that there are many plausible explanations for the observed rise in psychiatric disability in the past 20 years and that Whitaker's argument that psychiatric medications caused this trend is "speculative." In this article, he addresses the second and third arguments noted above.

Argument #2: There is a pharmacological basis to explain how psychiatric medications have led to increased disability

To make this allegation, Whitaker tapped into the work of a small coterie of legitimate investigators who have suggested that long-term use of antipsychotic and antidepressant medications may contribute to more psychosis or depression.

Chouinard and colleagues from McGill University in Montreal first suggested that chronic antipsychotic treatment induces relapse in some schizophrenic patients. (1) The mechanism of action to explain this phenomenon involved the dopamine receptors of the brain. The idea was that antipsychotic medications blocked dopamine receptors and, in response to that blockade, the neurons developed more receptors, resulting in more psychotic symptoms.

While appealing at first, this idea did not bear out, despite considerable analysis, for several reasons:

* It has never been proven that dopamine blockade is the necessary and sufficient explanation for psychosis,

* This "post-synaptic super sensitivity" response has never been physically demonstrated in human subjects, and,

* Evidence from long-term studies in large patient samples did not support the observations that had been described in case reports.

So, while this idea received considerable attention in peer-reviewed journals during the 1980s, an authoritative review of the literature concluded in the early 1990s that "research has not established that neuroleptics cause the proposed effect, and considerations of mechanism have not been separated from those of causation." (2)

In Part II of the Ash-craft and Anthony articles, Whitaker refers to the work of Martin Harrow and Nancy Andreasen in an attempt to argue that long-term treatment with antipsychotic medications causes increased pathology. The Harrow study involving a 15-year follow-up of 64 schizophrenic patients, was not an easy study to perform. Twenty of these patients did not receive antipsychotic medications, and the investigators noted that their outcomes were more likely to be better than what was seen in the 44 patients who received antipsychotics. Whitaker argues that this study means that long-term antipsychotics are not necessary, or may be harmful.

In January, Dr. Andrew Nierenberg, Professor of Psychiatry at Harvard Medical School and Massachusetts General Hospital, debated Mr. Whitaker in a grand rounds format sponsored by the Massachusetts General Hospital Department of Psychiatry. In a subsequent interview, Dr. Nierenberg stated, "Mr. Whitaker needs a basic course on principles of epidemiologic research, specifically on the concept of 'susceptibility bias.'"

Even a casual look at the Harrow study reveals that the patients who were not taking psychiatric medications at 15 years were self-selected; they had exhibited better and earlier prognostic features from the beginning. Yet, Whitaker reverses cause and effect in his argument. Patients who stopped antipsychotic medications did so because they were doing well. Standard clinical logic would conclude that the poor outcomes in the antipsychotic treated patients were a function of their illness, not of their treatment. Would anyone conclude that lone-term insulin treatment causes nerve and blood vessel damage in diabetic patients? Or, that chronic use of digitalis causes heart attacks?

Andreasen's studies of brain anatomy have found that the brains of people with schizophrenia who take antipsychotic medications are diminished in size. While this of course is concerning, it must be noted that these brains were compared to those of normal control subjects, not to those of untreated schizophrenia patients. Thus, it is impossible to examine whether it is the medications or the illness that lead to the smaller brain size.

It is worth noting that it would be impossible to get approval from a human investigation committee to follow untreated schizophrenic patients, because withholding such treatment over a long term would be considered unethical. Additionally, brain imaging studies such as the recent one by Malla et al, are adding support to the idea that it is schizophrenic illness, not antipsychotic medications, that causes the observed loss of brain tissue over time.(4)

One of the best demonstrations of the beneficial impact of long-term antipsychotic therapy can be seen in a study of relapses among 104 newly diagnosed schizophrenic patients who had responded to antipsychotic therapy. (5) Over a five-year period, patients treated with antipsychotics were five times less likely to relapse than were patients who stopped such medication. In other words, the risk of schizophrenic relapse was reduced by the use of antipsychotic medications, not increased.

The idea that antidepressant drugs might contribute to unfavorable outcomes by inducing biochemical vulnerability was introduced by Giovanni Fava in 1994. (6) More recently, El Mallakh and colleagues introduced the term "tardive dysphoria" to describe the occurrence of chronic depression resulting from antidepressant use. (7)

These proponents suggest an "oppositional model of tolerance" whereby continued drug treatment engages processes that oppose the initial acute effects of a drug or of alterations made by neuronal receptors. For example, Fava speculated that the therapeutic action of antidepressant drugs (e.g., down-regulation of post-synaptic 5HT2 receptors) "may--under certain conditions--trigger changes in post-receptor signal transduction, in intraneuronal signaling pathways, or in neuronal architecture, that are likely to affect the balance of serotonin receptors." (8)

However, this theory thus far suffers in three ways. First, there is a lack of evidence that serotonergic dysregulation (or any other specific mechanism of pathology) is the necessary and sufficient explanation for depression itself Second, Fava's suggested mechanisms of action have never been physically demonstrated in human subjects. Third, while there have been case reports that would be consistent with the hypothesis, data from long-term studies in large patient samples are not supportive.


In his debate with Whitaker, Dr. Nierenberg identified what he felt was the best of those long-term studies: Leon et al.'s analysis from the NIMH-sponsored Collaborative Depression Study.9 In this study, 285 patients who had been followed from 1978 to 1999 received varying levels of antidepressant medication. The authors examined the effectiveness of treatment as a function of the degree of exposure to antidepressant medications: high, medium or low.

This analysis serves as a natural experiment to assess the impact of antidepressant exposure. If antidepressants cause pathology, then greater exposure over time should yield poorer outcomes.

The study found that those who received higher levels of antidepressant treatment were significantly more likely to recover from affective episodes. In contrast, those treated with lower levels were no more likely to recover than those who did not receive somatic treatment. In other words, over the 20 years of study, vigorous treatment resulted in better short-term and long-term outcomes than did suboptimal treatments or no treatment at all.


According to Dr. Nierenberg, "at the very least, these data are inconsistent with the hypothesis that antidepressants cause depression. The proponents of this hypothesis need to explain the discrepancy between their hypothesis and these longitudinal data."

An elemental principal of scientific inquiry is that associations between events do not mean that one event causes another. Most research results involve associations. But in order to establish causation, an extensive line of investigation is required.

The investigation of effects of psychiatric medications must involve epidemiologic as well as basic and clinical pharmacologic studies of varying durations. The knowledge base for psychiatric medications is evolving, but it has not come anywhere near the point where conclusions can be reached about whether they cause disability. Such a conclusion should rest in the hands of scientists, not reporters. In the meantime, practice guidelines for treating depression and schizophrenia clearly call for long-term treatment when indicated.

So how do reporters end up writing whole books counter to prevailing expert opinion? Well, maybe if there was a conspiracy going on ...

Argument #3: There is a conspiracy between the pharmaceutical industry and psychiatry to mislead the public

If there has been a conspiracy among psychiatrists or the American Psychiatric Association (APA) and the pharmaceutical industry to hide or distort existing data about psychiatric medications, I have not seen it. When I was at Yale, I ran the largest tardive dyskinesia (TD) clinic in the United States. TD is thought to be an iatrogenic illness--an illness caused by long-term exposure to antipsychotic medications.

With the support of Yale, the NIMH, the Connecticut Department of Mental Health and several pharmaceutical companies, we published a number of refereed papers addressing the epidemiology, pathogenesis, phenomenology and treatment of TD. My experience involved no "cover up" of the undesirable effects of antipsychotic medications. In fact, my collaboration with the pharmaceutical industry contributed to efforts that resulted in the development of better antipsychotic medications.

As a Distinguished Life Fellow of the APA, I am struck by what I feel are the overzealous steps that the association has recently taken to avoid the perception of any "conflict of interest" with the pharmaceutical companies. I use the term overzealous because I believe that collaborations among industry and academia, professional organizations and individual specialists result in new and more effective medications, lifesaving innovations and a better-educated profession. To eliminate such collaborations would return medicine to the Stone Age.

It is true that the expert groups that participate in guidelines for psychiatric disorders often consist of members who have financial relationships with the pharmaceutical industry of various types. It only stands to reason that the most knowledgeable individuals would serve in both arenas. Critics like Whitaker try to argue that these experts, by virtue of their financial relationships alone, are biased and that resulting guidelines are driven by industry, rather than expert opinion.

There is not one shred of convincing evidence that the expert guideline groups make decisions that are driven by financial relationships with industry. Further, if all experts who had industry relationships were eliminated, who would be left to develop guidelines? Not the "experts" that I would want. I worry that professional organizations, in knee-jerk response to criticisms from a minority of stakeholders, will "dumb down" the membership of guideline committees.

While I have seen overzealous marketing efforts by drug companies over the years, I think that most of these companies have responded in positive directions to the inquiries of the Grassley Committee. Two examples of such response include the 1) disclosure of clinicians with whom they collaborate and 2) the disclosure of an online database containing all studies that they initiate, along with their results.

Of course, my view is arguable depending on one's perspective. Insinuations of conspiracy require quantitative evidence--for a start, providing a denominator as well as a numerator to establish a frequency rate. A few "scandals" do not make a conspiracy.

To support his conspiracy theory, Whitaker relies on stories composing the numerator: cases of alleged corruption due to industry influence on individual researchers. The cases that have involved psychiatry are now familiar to all and have been published repeatedly and assembled into a narrative framework.

But as Stossel and Stell have written, "the storytelling suffers from serious 'denominator neglect'--the non-nefarious, non-corrupt, beneficial collaborations over decades that dwarf the comparatively few cases that populate the numerator. (10)

If we cake a breath and actually count the alleged cases of corruption that compose the numerator, and then consider that over 90 percent of physicians have some type of financial interaction with industry, the denominator is orders of magnitude greater and the rate of misconduct is extremely low.10 Whitaker has a lot of work to do if he wants to prove that there has been a conspiracy to distort data and mislead the public.

For this article, I interviewed two of the experts cited above who conducted some of the work that Whitaker used to argue that the antidepressants could cause harm.

Dr. Rifaat S. El-Mallakh from the University of Louisville School of Medicine, who coined the term "tardive dysphoria," said about Whitaker's work, "I think the data need to be generated before anyone should begin to believe this. Ideas like tardive dysphoria simply need to be tested."

Dr. Giovanni A. Fava, from the Department of Psychology, University of Bologna, indicated that he did not believe that there was a conspiracy in play. Of Whitaker, he said, "for being a journalist he is pretty good." Dr. Fava said that he has started his own journal, Psychotherapy and Psychosomatic, in part to provide a forum for his ideas about the long-term effects of antidepressants. He feels that the readership is growing and that the journal is having an impact on the field.

Conspiracy? It sounds to me that the experts from the minority disagree.

Why should we pay any attention?

When the article by Ash-craft and Anthony appeared in Behavioral Healthcare, I got concerned for several reasons. I was concerned that colleagues whom I respect elected to include Whitaker's pseudoscientific allegations in a journal that I also respect. I was concerned because in order to treat my patients effectively, I have to select medications on an individual basis. In the absence of biological tests to measure the existence of disorders like of schizophrenia or depression, I have to rely on existing practice guidelines, clinical acumen. and most importantly my relationship with my patient.

When I collaborate with my patient to find the best treatment, I need his or her trust. Public allegations of the kind that Whitaker has published have dangerous implications for that relationship: they can intrude upon and erode that trust.

If this discourse must be publicized, we need to be aware that it is subject to misinterpretation by mental health professionals and patients. Such misinterpretation can translate to delay of necessary treatment, inappropriate discontinuation of medications, and to divisions between the mental health specialties that should be collaborating to design the best treatment programs for patients. Examples of such misinterpretations in clinical practice are emerging.

Many of my colleagues and I are disconcerted with Whitaker's brand of journalism. As Dr. Nierenberg said of Whitaker in their January debate, "he has used a journalistic stage to present misinformation, simplistic misinterpretations of statistics, faulty reasoning, and wrong conclusions." We are all for scientific discourse with careful consideration of the complexities of hypotheses and evidence. Whitaker's journalism may sell books, but it hardly constitutes such a scientific discourse.


(1.) Chouinard G. Jones BD, Annable L. Neuroleptic-induced supersensitivity psychosis. Am J Psychiatry. 1978 Nov;135(11): l409-10

(2.) Kirkpatrick B, AlphsL, Buchanan RW. The concept of supersensitivity psychosis. J Nerv Ment Dis. 1992 Apr;180(4):265-70

(3.) Harrow M, Jobc TH. Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year mulrifollow-up study. J Nerv Ment Dis. 2007 May;195(5):406-14

(4.) Malla AK ct at: Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis. Schizophrenia Research 125 (2011) 13-2

(5.) Robinson D Predictors of Relapse Following Response From a First Episode of Schizophrenia or Schizoaffective Disorder Arch Gen Psychiatry. 1999; 56:241-247]

(6.) Fava GA: Do antidepressant and antianxiety drugs increase chronicity in affective disorders? Psychother Psychosom 1994; 61: 125-131]

(7.) El-Mallakh RS, Gao Y, Jeannie Roberts R. Tardive dysphoria: the role of long term antidepressant use in inducing chronic depression Med Hypotheses. 2011 Jun;76(6):769-73

(8.) Fava GA and Offidani E: The mechanisms of tolerance in antidepressant action. Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) p 1599.

(9.) Leon AC, ct al: A 20-Year Longitudinal Observational Study of Somatic Antidepressant Treatment Effectiveness. Am J Psychiatry 160:727-733, April 2003

(10.) Stossel TP & Stell LK: Time to 'walk the walk' about industry ties to enhance health. Nature Medicine 2011;7(4)p 437

Disclosure: Dr. Glazer receives funding from Eli Lilly and Merck.


William M. Glazer, MD, is President of Giazer Medical Solutions ("" of Key West, Fla., and Menemsha, Mass. He is a clinician, researcher, lecturer, and consultant, and has been a member of faculty of the departments of psychiatry at the Yale and Harvard schools of medicine.
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Title Annotation:RX RESOURCES
Author:Glazer, William M.
Publication:Behavioral Healthcare
Geographic Code:1USA
Date:Nov 1, 2011
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