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:
Fall 2005:
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:
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.AbstractApproximately 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
- Neuropsychopharmacology. 2008 33(10):2546-7; author reply 2548.[full text on-line]
August 2006:
November 2006:
May 2007:
November 2007:
-
Neuropsychopharmacology. 2008 33, 2546–2547. [Carroll’s letter on-line]
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Neuropsychopharmacology. 2008 33, 2548. [Rapaport’s response on-line]
January 2008:
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.
For the record, Emory just hired this same Mark Rapaport to replace Charles Nemeroff as chairman of its psychiatry department. What were they thinking?
So goes Miami, so goes Emory.
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.