Tuesday, 28.09.2021

Jay D. Amsterdam and Leemon B. McHenry : The Paroxetine 352 Bipolar Study Revisited : Desconstruction of Corporate and Academic  Misconduct 

 

Edward Tobe’s comments

The Iceberg of Improbity

 

        Authors need to reflect on their ambitions and readers remain vigilant. In this regard, in 2012 and in 2019 Amsterdam and McHenry published papers dissecting a fraudulent publication (Nemeroff, Evans, Gyulai et al. 2001) in a prominent journal. Both Amsterdam and McHenry’s papers deconstruct intentional falsification of data.

 

        “The problem of truth and transparency in published scientific reports of corporate-sponsored clinical trials has been an on-going concern in the medical and bioethics literature. The difference between what a trial should report and what is actually reported in the medical journals in the past 30 years is so alarming that some editors have declared a crisis of credibility” (Amsterdam and McHenry 2012).

        “This report describes how a ‘negative’ clinical trial was published as a ‘positive’ study with unsubstantiated claims of efficacy and safety. It is based upon public evidence presented in a complaint of research misconduct filed with the Office of Research Integrity (ORI) of the Department of Health and Human Services (HHS) [4]. Additional supporting documents are available but remain under current court seal” (Amsterdam and McHenry 2012).

        “Because ghostwriting is designed to evade detection and is only revealed as a result of litigation or government inquiries, it is therefore imperative to document the cases in which ghostwriting has facilitated misrepresentation of clinical trial results” (Amsterdam and McHenry 2019).

        The second Amsterdam and McHenry paper benefited from documents obtained by subpoenas during litigation. The documents contain verbatim emails that describe the naked ambitions of a corporation, a prominent scientific journal, colluding specious academics, ghost writers and pharmaceutical company marketers.  The colluders reaped profits at the expense of medical and academic integrity. In reference to Paxil and two other drugs, in 2012 GSK pled guilty to criminal charges leading to a $3 billion settlement divided into criminal and civil fines. The fines represent the cost of doing business.   Although medical care was jeopardized, those responsible for creating such jeopardy faced no consequences. The corporation is a mirror reflecting the values of both the people within that corporation and those academics who are paid to collude through the sale of human dignity. 

        Physicians and patients must skeptically review medical papers regardless of author or publisher. The corrupt paper has never been retracted. At the date of this written response, according to Google Scholar, there have been 500 citations of the Nemeroff fraudulent publication, 15 citations of the 2012 Amsterdam and McHenry paper and no citation of the latest 2019 Amsterdam and McHenry paper.  The editors of the American Journal of Psychiatry have elected to not inform their readers that the information in the Nemeroff paper is flawed. 

 

Devaluation of Research and Treatment

        Contrary to the warnings of Joseph Schildkraut (1965), over the last quarter of a century pharmaceutical companies have adopted the catecholamine hypothesis to direct research and marketing.  Joseph Schildkraut recognized that the evidence supporting the co-relationship of biogenic amines to mood disorder was only indirect evidence that faced obstacles of daily life such as "the significant effects which social and interpersonal factors have on the clinical response to antidepressant drugs." Yet, pharmaceutical companies market antidepressants as if the pharmacodynamic profile of the marketed drug perfectly complements the pathophysiology of mood disorder.  Because mood disorders lack reproducible organic markers, pharmaceutical companies have employed rating scales that do not measure biological disorder but rather rate phenomenological presentation as if such were equivalent to the biology of an illness. Changes in the rating scale are assumed related to the drug’s effects on brain function. The assumption that phenomenology can reflect changes in brain function in a biologically heterogeneous group of illnesses is very distant from describing altered brain metabolism and then determining its phenomenology.

        A positive response to a psychotropic is measured by a 50% reduction in the phenomenological rating scale. Yet many studies find more than half of the participants respond to placebo. Perhaps placebo should be offered FDA approval. Even if the psychotropic were associated to a 50% reduction of the rating score, such may not prevent the individual from suicide or enable them to function in the workplace.

        Misinformation about the pathophysiology of depression and conjectured pharmacodynamics was well marketed with the introduction of Prozac (fluoxetine) in 1988.  Physicians have been taught that depression responds to selective serotonin reuptake inhibitors (SSRIs).  As new SSRIs emerged, the gambit became the more selective the SSRI the better its effect. Patients commonly report an understanding that their depression is a lack of serotonin. The marketing of serotonin / noradrenergic reuptake inhibitors (SNRI) required pharmaceutical companies to shift their marketing from SSRI drugs (i.e., the “‘cleaner” the better) to the SNRI drugs (whereby the “dirtier” the better).  

        However, in Europe in 1988 an atypical tricyclic antidepressant, tianeptine, was released.  When first marketed, the mechanism of action of tianeptine suggested a selective serotonin reuptake enhancer (SSRE), the opposite of a SSRI.  Tianeptine provided relief of depressive symptomatology within seven days without weight gain or sexual dysfunction. The US medical educational system ignored the overt contradiction in pharmacodynamic theory. Tianeptine was later suggested to pharmacodynamically reduce 5-HT availability, indirectly modulate adrenergic and dopaminergic systems, inhibit cholinergic hyperactivity and modulate the effects of excitatory amino acids on N-methyl-D-aspartate receptors (Tobe and Rybakowski 2013).  

        An additional extraordinary consequence of the marketing of SSRIs was to essentially end the education and training of specialists in psychiatry to value and prescribe monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Nescience has allowed MAOIs and TCAs to become old medicines, falsely perceived as inferior to newer putative antidepressant agents.  Physicians have not been trained to create a balanced algorithm of care. As a practicing psychiatrist I have observed many instances of patients prescribed multiple SSRIs or SNRIs and then back to another SSRI without considerations outside of those groupings. I have often noted that prescriptions reflect the latest sales pitch.

        Educational CME talks provide speakers who use slides designed by the sponsoring corporation. The speaker lists potential financial conflicts in a meaningless statement of a few seconds duration. I have never heard any speaker with personal or family financial conflicts provide the exact or approximate monies, received or promised, to permit the audience to access the risk of potential influence. There is a big difference between being paid $1,800 in a year to offer talks and being paid more than $500,000 a year.

        Moreover, DSM diagnostic labels are influenced by vested financial interests. Committees with authority to create or clarify criteria for various disorders contain members receiving monies from pharmaceutical firms. In law, lawyers and judges are expected to recuse themselves when facing conflict. Why do the individuals receiving monies from sources of financial conflict not recuse themselves? The answer is arrogance and money.  In 2009 Lisa Cosgrove, Harold J. Bursztain and Sheldon Krimsky wrote, “…it is clear that transparency alone is not enough of a safeguard: approximately 68% of the members of the DSM-5 task force reported having industry ties, which represents a relative increase of 20% over the proportion of DSM-IV task-force members with such ties.”

        Meetings of the American Psychiatric Association and other medical groups are partly sponsored by pharmaceutical industry. Acceptance of such support opens the door to vested financial interest becoming the force guiding current and future medicine.

        The emphasis on prescribing drugs as the major psychiatric contribution to treatment without knowing the patient has become an unfortunate consequence of insurance industry control of medical care initially through the formation of HMOs. Today, psychiatrists perform a “med check” that may range from 10 to 30 minutes during which a patient, often not in remission, is psychiatrically evaluated to determine medical and psychological changes and current mental status, response to pharmaceuticals, changes in their life, compliance, ability to function vocationally and avocationally.  The psychiatrist writes prescriptions for drugs with minimal knowledge of the patient. Drug sales benefit.

        Those involved in fraud can be rewarded in socioeconomic and academic stature. Lies gratify. An essay entitled “Of Truth” written by Sir Francis Bacon in 1625 offers insight.

        “But it is not only the difficulty and labor, which men take in finding out of truth, nor again, that when it is found, it imposeth upon men’s thoughts, that doth bring lies in favor, but a natural though corrupt love, of the lie itself.” 

        Contemptuous exploitation of other people appears throughout human history. The exploiter validates their action through disassociation from the reality of their conduct through the dehumanization of the exploited.  The refusal to recognize their misconduct may reflect fears of exposure leading to legal and social ramifications.  Except for psychopaths, there is a fear of shame; a fear that enhances righteous arrogance to ward off shame.  In the case of systematic medical fraud involving numerous people, some of whom gained prominence in their own mind, their idealized self needs to love their lie or face shame.  

        Regardless of education, humans have always faced the reality principle versus the pleasure principle.  In childhood development, slowly the pleasure principle gives way to reality. This is not completely resolved by adult life.

        “Doth any man doubt, that if there were taken out of men's minds, vain opinions, flattering hopes, false valuations, imaginations as one would, and the like, but it would leave the minds, of a number of men, poor shrunken things, full of melancholy and indisposition, and unpleasing to themselves?” (Bacon 1625).

        Whistleblowers often face enmity in the form of allegations of corruption and incompetence to lessen the merit of the disclosure.

        We may define “atrocity” as something that is “atrocious” such as an execrable situation or circumstance. Sadly,

        “If there were a progressive learning curve from generation to generation the prevalence of atrocity would be a study for history learned” (Tobe 2017).

        I thank Jay Amsterdam and Leemon McHenry for providing a crucible of probity that encourages the reader’s vigilance and warns against idealizations that obscure truth.

 

References:

Amsterdam JD, McHenry L. The paroxetine 352 bipolar trial: A study in medical ghostwriting. Int J Risk Saf Med. 2012; 24(4):221-31.

Amsterdam, J.D., McHenry, L.B.: The Paroxetine 352 Bipolar Study Revisited: Deconstruction of Corporate and Academic Misconduct. Journal of Scientific Practice and Integrity. 2019.

Bacon F. Of Truth. In: Essays, Civil and Moral. The Harvard Classics. 1909-14.

Cosgrove L, Bursztajn HJ, Krimsky S. Developing Unbiased Diagnostic and Treatment Guidelines in Psychiatry. N Engl J Med. 2009; 360(19):2035-6.

Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, Oakes R, Pitts CD. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001; 158(6):906-12.

Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965; 122(5):509-22.

Tobe EH, Rybakowski JK. Possible usefulness of tianeptine in treatment-resistant depression. Int J Psychiatry Clin Pract. 2013; 17(4):313-6.

Tobe EH. Why Atrocities, a Hypothesis. EC Psychology and Psychiatry. 2017; 126-30.

 

April 23, 2020