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Posted on Saturday 17 September 2011

In a recent post, I referenced one of Dr. Nemeroff’s review articles, guessing that it was ghostwritten during Janssen’s mid-decade literature Blitzkrieg for Risperdal. As it turns out, this was just one boxcar on a very long train.

December 2004:

Charles Nemeroff [Emory], Mark Rapaport [Cedars-Sinai], and six Janssen authors presented this Risperdal augmentation in depression study in a poster session at the ACNP 2004 Meeting, concluding:
    Risperidone augmentation resulted in symptomatic remission in a substantial number of patients with chronic resistant depression who were nonresponsive to standard antidepressant therapy. Time to relapse in these remitted patients was similar with risperidone vs. placebo augmentation. In the population of fully nonresponsive patients, relapse was significantly delayed with risperidone augmentation.

Fall 2005:

Dr. Nemeroff’s review article is published in a Supplement to the Journal of Clinical Psychiatry. That review contained a report of the study mentioned above:
Use of Atypical Antipsychotics in Refractory Depression and Anxiety
by Charles B. Nemeroff, M.D., Ph.D.
Journal of Clinical Psychiatry 2005 66[suppl 8]:13–21.
[full text on-line]

Treatment options for bipolar depression and treatment-resistant unipolar depression include augmentation of antidepressant therapy with a nonantidepressant drug, including atypical antipsychotics. Risperidone is effective in combination with fluvoxamine, paroxetine, or citalopram in treatment resistant unipolar depression, with reported remission rates of 61% to 76%. Olanzapine in combination with fluoxetine is safe and effective in patients with bipolar depression and those with fluoxetine-resistant unipolar depression. Ziprasidone and aripiprazole augmentation of various selective serotonin reuptake inhibitors has been reported to be effective in refractory unipolar depression in open-label studies. Data on use of quetiapine or clozapine as augmentation therapy for depression or anxiety are not yet available. Further double-blind, placebo-controlled studies of augmentation of antidepressants with atypical antipsychotics in refractory depression and anxiety are justified based on the available literature.

June 2006:

The study was published on-line in Neuropsychopharmacology by Mark Rapaport [Cedars-Sinai], Martin Keller [Brown], Charles Nemeroff [Emory], and nine Janssen employees. Dr. Nemeroff was the editor of the Journal at the time:
Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation.
by Rapaport MH, Gharabawi GM, Canuso CM, Mahmoud RA, Keller MB, Bossie CA, Turkoz I, Lasser RA, Loescher A, Bouhours P, Dunbar F, and Nemeroff CB
Neuropsychopharmacology. 2006 31(11):2505-13.
[full text on-line]

Erratum in
  • Neuropsychopharmacology. 2007 May;32(5):1208.
  • Neuropsychopharmacology. 2006 Nov;31(11):2514.
Abstract
Approximately one-third of persons with depression do not respond to antidepressant monotherapy. Studies suggest that atypical antipsychotic augmentation may benefit these patients. We investigated the longer-term efficacy of risperidone augmentation of serotonin-selective reuptake inhibitor treatment for resistant depression. In 57 in- and outpatient centers in three countries, we conducted a three-phase study with 4-6 weeks of open-label citalopram monotherapy, 4-6 weeks of open-label risperidone augmentation, and a 24-week double-blind, placebo-controlled discontinuation phase. A total of 489 patients with major depressive disorder and 1-3 documented treatment failures entered the citalopram monotherapy phase (20-60 mg/day). Patients with <50% reduction in HAM-D-17 scores entered the risperidone augmentation phase (0.25-2.0 mg/day). Patients with HAM-D-17< or =7 or CGI-S < or = 2 were randomized to risperidone or placebo augmentation. The primary outcome was time to relapse during the double-blind phase. During citalopram monotherapy, 434 patients had <50% HAM-D-17 reduction; 299 (68.9%) were fully nonresponsive (<25% reduction) and 135 were partially nonresponsive (25-49% reduction). Of the 386 nonresponders who entered the augmentation phase, 243 remitted and 241 entered the double-blind phase. Median time to relapse was 102 days with risperidone augmentation and 85 days with placebo (NS); relapse rates were 53.3 and 54.6%, respectively. In a post hoc analysis of patients fully nonresponsive to citalopram monotherapy, median time to relapse was 97 days with risperidone augmentation and 56 with placebo (p = 0.05); relapse rates were 56.1 and 64.1%, respectively (p < or = 0.05). Open-label risperidone augmentation substantially enhanced response in treatment-resistant patients, but the longer-term benefits of augmentation were not demonstrated in this study.

Comment in

August 2006:

At this point, one could insert another timeline and make this post reach all the way to the floor. The short version of this well known story is that in April 2006, Dr. Nemeroff et al had published a review article in Neuropsychopharmacology [on-line] about VNS therapy in depression with no acknowledgement that the authors were all Janssen employees or paid consultants, an article likely written by ghost-writer Sally Laden, in the Journal Nemeroff himself edited [VNS Therapy in Treatment-Resistant Depression: Clinical Evidence and Putative Neurobiological Mechanisms]. In the outrage that followed, Dr. Nemeroff resigned his editorship of Neoropsychopharmacology in August 2006 and was subsequently widely [but lightly] censured. This scandal takes up a sizable chunk of the Internet [an example], and seems to me to be a nodal point in our awakening to how pervasive the corruption within academic psychiatry had become.

November 2006:

The paper above [Rapaport et al] did not have conflict of interest statements included in the on-line version. They were added as a Corrigendum in November 2006 [Neuropsychopharmacology 2006 31, 2514.] when the journal issue came out in print. All three [non-Janssen] authors had ties to Janssen Pharmaceutica. One can only conclude that this correction was a response to the then recent scandal involving Dr. Nemeroff’s earlier VNS review article.

May 2007:

Another Corrigendum was published [Neuropsychopharmacology. 2007 32(5):1208], apparently in response to reader complaints:
    Following the publication of this article, the authors noted that in the abstract and in the next to last paragraph of the results section, a P-value for part of one of the post hoc analyses was incorrectly reported. A significant P-value was reported for both the difference in time to relapse and for relapse rates in a subgroup of patients fully non-responsive to citalopram monotherapy. Although the P-value for time to relapse was correctly reported, the correct P-value for the comparison of relapse rates is not significant [P=0.4; CMH test]. This change does not alter the major findings of the study nor any of the conclusions of the report. We appreciate the assistance of a diligent reader in identifying this error.

November 2007:

In November 2007, Neuropsychopharmacology published a letter from Dr. Bernard Carroll about the study above by Rapaport et al and the response by Dr. Mark Rapaport, the first author of that paper:
This exchange needs to be read in full. Dr. Carrol noted that the Corrigendum above only partially retracts the paper’s claims of the efficacy of Rispeidal augmentation and details his objections to what was not retracted. Dr. Rapaport responded essentially saying that the paper makes no claims of efficacy:
      "The paper repeatedly states in Abstract, Methods and in Discussion that continuation of risperidone augmentation therapy was not more beneficial than placebo, and hence the working hypothesis was disproven…."
     "I would like to thank the reviewers and the editors of Neuropsychopharmacology for having the courage to allow us to publish this negative finding…."

January 2008:

Dr. Carroll wrote his narrative of this story on the Healthcare Renewal blog [ANTIPSYCHOTIC DRUGS FOR DEPRESSION?] on January 16, 2008 – the main resource used for constructing this timeline. His conclusions couldn’t be clearer and I link his post here. As usual, he speaks best for himself.

If you’ve made it this far, good for you. I’m sure I missed some spots along the way and just caught the high points in this tawdry Saga. And I know for many, this is old news, at least pieces of the story. But it’s time to put some action along with the story other than just the fact that this is obviously conduct unbecoming scientists, physicians, responsible medical industries.

After the initial review in the 2005 article which says, "Risperidone augmentation resulted in symptomatic remission in a substantial number of patients with chronic resistant depression who were nonresponsive to standard antidepressant therapy," everything else that I’ve listed here happened in the pages of the Neuropsychopharmacology, the Journal of the American College of Neuropharmacology for the next two and a half years until Carroll’s blog post. That journal is very important to the few neuroscientists that read it, but is hardly on the news-stands or even available to most practicing psychiatrists. Likewise, Healthcare Renewal isn’t exactly daily reading for practitioners. Yet the message about augmenting antidepressants with atypical antipsychotics traveled far and wide, quoted extensively. It’s still traveling. So, although this is a fine example of a few people’s persistence in finally debunking a negative and misrepresented study, the desired impact was still profound and came at a lucrative time in Risperdal’s life cycle [when it was still in patent]. In other words, the gambit worked.

And on the subject of articles being ghostwritten by people under contract to pharmaceutical companies, this study is a prime candidate. The trial itself was conducted by Janssen, not directed by any non-company investigator. Of the three authors, Nemeroff had a long-time association with ghost-writer Sally Laden at Scientific Therapeutics Information both through GSK and Cyberonics as had Martin Keller through GSK. Their "guest authorship" is legend. We know from the Rothman Report filed by an investigator with access to primary discovery documents that Excerptia Medica, a medical ghost-writing firm around the corner from Janssen, was churning out articles favorable to Risperdal and soliciting authors during this period. We know that Dr, Nemeroff was editor of Neuropsychopharmacology and had used it as a conduit for promoting Cyberonics and apparently Janssen, companies with which he was financially involved. There’s a hell of a lot more evidence of criminal misbehavior on this page than evidence that Risperdal helps depressed people. And yet the gambit worked.

Racketeering. It is what it is…
  1.  
    Ivan
    September 17, 2011 | 9:16 PM
     

    For the record, Emory just hired this same Mark Rapaport to replace Charles Nemeroff as chairman of its psychiatry department. What were they thinking?

  2.  
    Tom
    September 17, 2011 | 11:06 PM
     

    So goes Miami, so goes Emory.

  3.  
    Ivan
    September 18, 2011 | 2:48 AM
     

    Well, so I did some checking and found a Press Release from Dr. Mark Rapaport and Cedars Sinai dating to August 2006, just after the Neuropsychopharmacology report appeared on line. It is a model of wishful thinking and obfuscation.

    It makes me think Dr. Rapaport is being disingenuous if not hypocritical in his published reply to Dr. Carroll. What he says in the journal does not jibe with the Press Release from August 2006. Here is a url: http://tinyurl.com/3cnpmoe

    For instance, he says in his Press Release “people suffering from resistant major depressive disorder who don’t respond to standard antidepressants can benefit when the drug therapy is augmented by a broad spectrum psychotropic agent, even when treated for a brief period of time. That doesn’t sound like a “negative finding.” The observed remission rate was 63% but that was with open label treatment. As Dr. Carroll pointed out, this is the weakest level of evidence.

    In the Press Release, Dr. Rapaport went on to say, “…those characterized as less severely ill only needed to stay on the broad spectrum psychotropic agent Risperidone for a brief period of time to experience lasting benefits; making their antidepressant medication work effectively. Those depressed patients who were characterized as more severely ill, however, needed to continue Risperidone on an ongoing basis to experience the same level of effectiveness.” These statements are nothing but wishful thinking. With continuation treatment, the relapse rate in the less severely ill patients was 38% on placebo and 49% on Risperdal – no benefit there. In more severely ill patients the relapse rate was 64% on placebo and 56% on Risperdal – no significant difference there, either.

    The Press Release continues, “The implications of our research shows that a certain subset of individuals with chronic depression who don’t respond to standard treatment with antidepressant medication could benefit from a brief period of supplementary therapy,” said Dr. Rapaport, the study’s principal investigator. Huh? That was never one of the stated objectives of the study, and the question was never addressed with an appropriate controlled design. Dr. Rapaport was blowing smoke that day in August 2006.

    And notice the branding language, calling Risperdal “a broad spectrum psychotropic agent.” This is the worst kind of shilling for the corporate sponsor.

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