When you happen onto a really long blog post with lots of quotes, you can usually count on the fact that the blogger is out to prove something and getting his/her facts in a row. I usually skip to the end [or move on], being an impatient scanner myself. So I thought I’d start with the conclusion. Drs. Robert Gibbons and J. John Mann are making a career of attacking the FDA’s Black Box Warnings of potential suicidality from certain medications. Their articles generally rely on special access to datasets made available by pharmaceutical connections, yet they list their research support as coming from public grants. It smells like three day old fish to me, and I wonder why the journals keep publishing them.
There are three examples – two are Pfizer Drugs [Chantix® and Neurontin®], and one is about Lilly and Wyeth/Pfizer drugs [Prozac® and Effexor®]. I’m not going to comment on the content of their articles. The post would reach to the floor. I’m just going to document what I said in the last paragraph and let you come to your own conclusions about the Conflict of Interest problems and the special treatment by industry on NIMH funded research. First, the most recent example.
Chantix® [Varenicline] was introduced as a smoking cessation aid in 2006. In 2009, the FDA issued a black box warning of possible side effects including depression, suicidal thoughts, and suicidal actions. Moore, Glemullen et al reported on their analysis of the FDA records in several subsequent articles in PLoS ONE:
by Thomas J. Moore, Joseph Glenmullen, and Curt D. FurbergPLoS ONE. 2010 5[12]: e15337. doi:10.1371/journal.pone.0015337.
Context: Violence towards others is a seldom-studied adverse drug event and an atypical one because the risk of injury extends to others.Objective: To identify the primary suspects in adverse drug event reports describing thoughts or acts of violence towards others, and assess the strength of the association.Conclusions: Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs. Prospective studies to evaluate systematically this side effect are needed to establish the incidence, confirm differences among drugs and identify additional common features.
by Thomas J. Moore, Curt D. Furberg, Joseph Glenmullen, John T. Maltsberger, and Sonal Singh.PLoS ONE. 2011 6[11]: e27016. doi:10.1371/journal.pone.0027016.
Background: Two treatments for smoking cessation — varenicline and bupropion — carry Boxed Warnings from the U.S. Food and Drug Administration [FDA] about suicidal/self-injurious behavior and depression. However, some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown.Conclusions: Varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation.
Now this published on-line in the American Journal of Psychiatry:
by Robert D. Gibbons and J. John MannAmerican Journal of Psychiatry. 2013 Sep 13. [Epub ahead of print]
Objective: In 2009, the U.S. Food and Drug Administration issued a black box warning for varenicline regarding neuropsychiatric events. The authors used data from randomized controlled trials and from a large Department of Defense [DOD] observational study to assess the efficacy and safety of varenicline.Conclusions: This analysis revealed no evidence that varenicline is associated with adverse neuropsychiatric events. The evidence supports the superior efficacy of varenicline relative to both placebo and bupropion, indicating considerable benefit without evidence of risk of serious neuropsychiatric adverse events, in individuals with and without a recent history of a psychiatric disorder.
Like I said, it looks familiar. We have been here before with Drs. Gibbons and Mann:
by Robert D. Gibbons, Kwan Hur, C. Hendricks Brown, and J. John MannPharmacoepidemiologic Drug Safety. 2010 19[12]:1241–1247.
Purpose: On December 16, 2008 FDA issued a class warning for antiepileptic drugs and suicidal thoughts and behavior. The purpose of this study was to determine if the antiepileptic drug gabapentin increases risk of suicide attempt in patients to which it was prescribed for various indications.Conclusions: This study finds that gabapentin does not increase risk of suicide attempts in non-psychiatric populations and is associated with a reduction in suicide attempt risk in patients with psychiatric disorders.
by Robert D. Gibbons, C. Hendricks Brown, Kwan Hur, John M. Davis, and J. John MannArchives of General Psychiatry. Published online February 6, 2012.
Context: The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults.Conclusions: Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication…
It would appear that Dr. Gibbons and Dr. Mann never met an FDA Black Box Warning they really cared much for. And as I said, there’s more in common with these three articles than just the shared authorship of Drs. Gibbons and Mann and their monotonous opinion of FDA warnings. They had special access to datasets to analyze, unavailable to the rest of us:
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Chantix® [Varenicline]:"Dr. Gibbons has served as an expert witness for Pfizer in a case related to varenicline and neuropsychiatric adverse events, for the U.S. Department of Justice and for Wyeth on cases related to antidepressants and suicide, and for Pfizer on cases related to gabapentin and suicide… Data for the randomized controlled trials were supplied by Pfizer. Pfizer had no involvement in the analysis of these data or the writing of the paper. Pfizer reviewed the final manuscript to ensure accuracy of the study descriptions and ensure against inadvertent disclosure of confidential information or unprotected inventions. Pfizer did not provide any comments except minor corrections in Table 1." from Varenicline, Smoking Cessation, and Neuropsychiatric Adverse Events.
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Neurontin® [Gabapentin]:"Dr. Gibbons has served or is currently serving as an expert witness for the U.S. Department of Justice, Wyeth and Pfizer Pharmaceuticals, the latter involving gabapentin, the drug considered in this paper… The data were obtained from PHARMetrics and purchased as a part of the above listed litigation by Pfizer for $15,000. Pfizer was not involved in any of the research related to this manuscript or the data used in this study and did not review the results or the manuscript prior to submission for publication. The data use agreement stipulated that Dr. Gibbons could publish the results of the analyses regardless of outcome. Dr. Gibbons relied upon the results of a preliminary analysis of these data in his expert testimony in the matter of Bulger v. Pfizer Inc. and was paid by Pfizer for the time that he and Dr. Hur spent performing those analyses…" from Gabapentin and Suicide Attempts.
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Suicidal Thoughts and Behavior With Antidepressant Treatment:"To help determine what impact antidepressants have on the course of depression and suicidal thoughts and behavior in different age groups, we obtained complete longitudinal data for RCTs of fluoxetine hydrochloride conducted by Eli Lilly and Co, the Treatment for Adolescents With Depression Study of fluoxetine in children by the National Institute of Mental Health,3 and adult studies for venlafaxine hydrochloride conducted by Wyeth." from Suicidal Thoughts and Behavior With Antidepressant Treatment: Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine. NOTE: Wyeth was purchased by Pfizer in 2009.
There’s something else in common. They are all listed as being grant supported:
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Chantix® [Varenicline]:"Supported by NIMH grants MH062185 [to Dr. Mann] and MH8012201 [to Dr. Gibbons]." from Varenicline, Smoking Cessation, and Neuropsychiatric Adverse Events.
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Neurontin® [Gabapentin]:"This work was supported by NIMH grants MH062185 [JJM] and R56 MH078580 [RDG and CHB], and MH40859 [CHB] and AHRQ grant 1U18HS016973 [RDG]." from Gabapentin and Suicide Attempts.
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Suicidal Thoughts and Behavior With Antidepressant Treatment:"This work was supported by grants MH062185 [Dr Mann], R56 MH078580 [Drs Gibbons and Brown], MH8012201 [Drs Gibbons and Brown], and MH040859 [Dr Brown] from the National Institute of Mental Health and grant 1U18HS016973 from the Agency for Healthcare Research and Quality [Dr Gibbons]." from Suicidal Thoughts and Behavior With Antidepressant Treatment: Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine.
If Pfizer [or Lilly] wants to argue with the FDA, I’m sure the FDA would be glad to talk to them. If they want to argue in public and encourage doctors to ignore the FDA, they could buy ads in the journals. I object, however, to their releasing information the rest of us can’t see to Drs. Gibbons and Mann to publish with the COI burden they have and absolutely no way for practicing or dissenting physicians to look into things for ourselves. It’s just not right. And, by the way, do our public granting institutions keep up with where their our money is being spent?
sidenote Chantix-why are so many patients drawn to smoking to begin with?
Nicotine is one of the most effective anti-inflamatories known:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC404586/
Good to see Joseph Glenmullen is still interested in adverse effects of psychiatric drugs. He wrote the best (but badly named) book on tapering antidepressants, The Antidepressant Solution.
One must keep in mind FDA black box warnings represent actual, not theoretical, injuries to humans, as the FDA doesn’t act unless legal action or patient lobbying embarrasses it into publishing such warnings.
This is interesting, It includes Prozac. Checking the FDA’s work usually doesn’t reveal good things.
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050045
“We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available.”
“Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance.”