In the last quarter century, Psychiatry has undergone a dramatic identity shift, and a big part of that change is the rising prominence of neurobiology and psychopharmacology. Recently, it’s become apparent that the pharmaceutical industry has been a big player in that transition. So we’re becoming used to hearing about clandestine advertising through paid speaker’s bureaus, relationships with Academic Psychiatry, ghost-written articles, Continuing Medical Education programs, and a panoply of other undisclosed conflicts of interest. But the Mifepristone narrative is different. It’s about a similar situation arising from within Academic Medicine. After widespread hypothesizing and research about the functioning of the hypothalamic-pituitary-adrenal axis in severe depressive syndromes, the group at Stanford involved in these studies proposed treating Psychotically Depressed patients with RU-486, a drug that blocks Cortisol in high doses. Stanford University picked up the patent for the drug, and the Chairman of their Department of Psychiatry,
Alan Schatzberg, founded a private company along with colleagues aiming to bring the drug to market. He later explained this move in a
letter to APA members after being elected APA President as follows:
Over the past 25 years, my colleagues and I have studied psychotic major depression and developed a hypothesis that excessive activity of the Hypothalamic-Pituitary-Axis played a role in the development of psychosis of this often lethal illness. We hypothesized that blocking cortisol activity in brain could produce relief and, from 1995-1997, we studied mifepristone, a progesterone and glucocorticoid receptor antagonist, in a small number of patients with the disorder. As required by the Federal Bayh-Dole Act, Stanford applied for a use patent for the drug and attempted to license the drug to pharmaceutical companies. But none would license it, perhaps because mifepristone is an abortofacient. My colleagues and I then founded a biotech company, Corcept Therapeutics, to develop mifepristone to help treat psychotic depression.
In essence he argues that their motives were to bring this [as yet unproven] treatment to suffering patients, but was blocked because the drug is also a controversial "morning after" abortion inducing medication – and abortion is a hot political topic in the US. The other interpretation of this highly unusual move is obvious – he and others were entrepreneurs looking to capitalize of a potentially lucrative new medication. Motives aside, the Conflict of Interest is immediately obvious. Dr. Schatzberg was the Principal Investigator of an ongoing NIMH Grant to study the hypothalamic-pituitary-adrenal axis in depression [including Mifepristone] as were some of his colleagues who were involved with this new company [
Corcept]. He
explains:
In 1999, we informed the NIMH of a possible conflict of interest on a grant on which I had been the P.I. Stanford, the NIMH, and I agreed that I would abstain from involvement with the conduct of the mifepristone component of the grant. Stanford’s patent for the use of mifepristone in psychotic depression was issued at the end of 2000… Results were reported in 2006. I am one of the authors because I was instrumental in study design before the conflict, in obtaining the funding, and because I was engaged with writing the paper. In 2002, Corcept reported on a small series of patients My name appears on this paper because I helped write the discussion. In both cases, the conflict was disclosed and my authorship met Stanford’s requirements for authorship even though I was not engaged in treating or assessing patients or in data analysis. In 2004, I applied for a renewal of our grant and once again disclosed the conflict in the application. After rigorous peer review, the NIMH agreed to renew the grant. Part of our extensive discussion to address the conflict of interest question resulted in an NIMH DSMB that provides oversight for the grant.
My own reaction is what my father said when I tried out some creative adolescent rationalization, "I don’t mind you peeing in my boot, but don’t tell me it’s water." I won’t even bother to argue my case. It just seems absurd to deny that this is a terminal conflict of interest. It just is.
Those only two published studies were hardly compelling, but were hyped repeatedly in presentations and reviews by Psychiatrists with direct financial interests in this drug, without disclosure. I mentioned several in the last post. Here’s another from Dr. Charles Nemeroff [
Treatment of mood disorders. Nature Neuroscience 2002; 5 (supplement): 1068 – 1070.]:
Although most investigators believe that hypercortisolemia is a consequence of CRF hypersecretion associated with depression, the marked hypercortisolemia observed in psychotic depression, a subtype of depressives characterized by delusions and/or hallucinations, has led to impressive studies indicating that the glucocorticoid receptor antagonist mifepristone (RU486) is very effective in the treatment of psychotic depression. Large-scale, double-blind, randomized clinical trials are currently being conducted by Corcept in the United States.
… the authors state "…the marked hypercortisolemia observed in psychotic depression…has led to impressive studies indicating that…mifepristone [RU486] is very effective in the treatment of psychotic depression…clinical trials are currently being conducted by Corcept…" What Dr. Nemeroff also did not indicate in the article is that he is a member of the Scientific Advisory Board of Corcept Therapeutics and as such was given an option to purchase 72,000 shares of Corcept stock at $0.0003 per share [a total cost of $21.60]. We presume Dr. Nemeroff exercised his option, because he has publicly acknowledged being a stockholder in Corcept. The "impressive studies" consist of two reports on small samples, neither of which demonstrated a statistically significant treatment effect. Corcept Therapeutics has only one product: mifepristone for psychiatric disorders. When the projected initial public offering of shares by Corcept occurs at the corporation’s estimated share price of $14−16, Dr. Nemeroff’s equity will be valued at more than $1,000,000. It again would appear that Dr. Nemeroff stands potentially to profit from the interest his positive assessment of mifepristone might generate for Corcept in advance of a public stock offering.
Carroll and Rubin were making several complaints: the studies mentioned were not statistically significant; Dr. Nemeroff had not disclosed his financial ties to Corcept; and those ties called his positive comments into question. Dr. Nemeroff and his coauthor responded [Nature Neuroscience 6, 1000 – 1001 (2003)]:
… In terms of the specific allegations raised in the Carroll-Rubin letter, we would offer the following: First, we wish to reiterate that in contrast to their statement in the first paragraph, Nature Neuroscience had no established policy on financial conflicts of interest for review authors at the time of submission or publication of our report.
… The criticisms concerning mifepristone and the relationship of one of us (C.B.N.) to Corcept Therapeutics bears discussion. The stated information in their letter is incorrect. No initial public offering of this stock has occurred, nor is any imminently planned, to the best of our knowledge. The articles in question appeared in peer-reviewed publications. The latest article published in Biological Psychiatry was of sufficient interest that the Editor-in-Chief, Dennis S. Charney, Chief of the Mood and Anxiety Disorders Branch at the NIH, co-authored an accompanying editorial. We stand by our enthusiasm for this novel approach of the treatment of psychotic depression.
… We applaud the recent increase in complete disclosure of potential financial conflicts of interest by professional organizations and journals. We have always and will continue to comply with all requests for such disclosures and prominently display this information on a variety of websites. Going forward, we intend to provide all financial disclosure information, even if it is not requested by the journal editor. We believe it unfortunate that Drs. Carroll and Rubin would attribute the views expressed in our Nature Neuroscience article to be motivated by personal avarice. That is not the case.
This exchange is emblematic of a more cosmic conflict in Academic Medicine/Psychiatry at that time. Dr. Nemeroff [a Psychiatry Department Chairman] was favorably reviewing an experimental treatment reported by Dr. Schatzberg [another Psychiatry Department Chairman] on a drug [Mifepristone] from a company where Dr. Schatzberg chaired the Board and Dr. Nemeroff sat on the Scientific Advisory Board. This obvious Conflict of Interest was not disclosed. Dr. Nemeroff [and later Dr. Shatzberg] claimed that this was not a problem – not wrongdoing. Drs. Carroll and Rubin also complained that the quoted studies were being reported as "very effective" when they were, in fact, not even statistically significant – implying that the Conflict of Interest was driving the favorable review. Finally, they presented detailed evidence of the reviewer’s potential profit from the positive review. Dr. Nemeroff countered that there was no requirement for financial disclosure by the Journal, that there was no stock offering and none planned, and that they were wrong about his motives. My opinion is obvious. I’ve quoted the text for you to reach your own conclusions.
I didn’t think those two studies looked very promising myself [Mifepristone I: the outer layer…], so I would’ve liked to see Carroll’s and Rubin’s statistical analysis. They apparently submitted it to several Journals, but it wasn’t published after the original authors responded to the criticisms. So they presented their scientific and Conflict of Interest complaints as a poster at a neuroscience meeting. The result was a war of contentious ethics complaints [filed ultimately in both directions]. The point is that the scientific question [Is Mifepristone an effective treatment option for psychotic depression?] got lost in the story and we never saw the statistical analysis.
I said there was a "cosmic conflict in Academic Medicine/Psychiatry at that time." Research science requires transparency. Doctors don’t want to just read conclusions, we want to see the data itself. We want to know about Conflicts of Interest – anything that might bias what we’re seeing. We want the assurance of proper statistical analysis of the data train. We want full access to the debate of conflicting opinions and we want to know what "experts think." In the last decade, there were significant intrusions into that discourse by powerful interests. We couldn’t know if we were reading the work of a scientist, or a ghostwriter hired by a drug company. We didn’t know if an author or reviewer was being paid by people with a financial interest in the outcome. We couldn’t always tell an unbiased "expert" from a "key opinion leader" hired by industry. There was a gaping hole in the fabric of time-honored scientific dialog, and in this case, the powerful interests that stood to gain from the fate of Mifepristone were the very same scientists who were studying it – reviewing it in the literature.
So what was happening with this drug was a snapshot of a much larger issue – a corruption of science and its methodology, particularly in the halls of Academic Psychiatry. And the story didn’t end in 2003…
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