Slim Evidence Supporting Drug as Bipolar Maintenance Therapy
May 9, 2011 — The evidence base for prescribing the second-generation antipsychotic medication aripiprazole (Abilify, Bristol-Myers Squibb) for maintenance treatment of bipolar disorder is limited to a single company-sponsored trial, according to results of a critical literature review published May 3 in PLoS Medicine.
"I think the take-home message is that despite US FDA [Food and Drug Administration] approval for maintenance treatment of bipolar disorder and the subsequent widespread marketing and use of Abilify for this indication, there really is no solid evidence that it is effective in controlling symptoms or preventing relapse in the long run," Nicholas Rosenlicht, MD, from the Department of Psychiatry, University of California, San Francisco, who worked on the review, told Medscape Medical News.
"This does not necessarily mean the drug doesn't work; it just means that we don't have evidence it does in this context," Dr. Rosenlicht emphasized. "We would not advocate anyone stopping the medication on the basis of our findings; that is something that should only be determined in collaboration with one's doctor, and for some people it may turn out to be an effective medication."
"Still, one should approach the use of Abilify for maintenance treatment of bipolar disorder with caution, at least until there is better evidence that it works since there are other drugs with more established track records," Dr. Rosenlicht added.
Erick Turner, MD, from the Department of Psychiatry, Oregon Health & Science University in Portland was a peer reviewer on the study but was not involved in the review itself. He told Medscape Medical News that what he finds "interesting" about this paper is how such a small amount of evidence can be amplified.
"One piece of evidence can enter an 'echo chamber' and get covered in multiple other papers and then get ratified in treatment recommendations. The average consumer of this information, the prescriber, could easily believe that he or she is practicing evidence-based medicine at its finest," Dr. Turner said.
Using multiple databases, Dr. Rosenlicht and colleagues systematically reviewed the literature to identify double-blind, randomized, controlled trials regarding the use of aripiprazole for maintenance therapy of bipolar disorder.
The investigators found only 2 reports (J Clin Psychiatry. 2006;67:626-637 and J Clin Psychiatry. 2007;68:1480-1491), both describing the results of a single trial on the use of aripiprazole monotherapy during the maintenance phase of bipolar disorder.
In addition, the researchers say they identified 4 "critical limitations to the trial's interpretation and overall utility":
- Insufficient duration to demonstrate maintenance efficacy;
- Limited generalizability due to its enriched sample;
- Possible conflation of iatrogenic adverse effects of abrupt medication
- Low overall completion rate
"We were quite surprised at how thin the supposed evidence in support of its use was, and when we scratched the surface and critically examined what little evidence there was, it essentially evaporated," Dr. Rosenlicht told Medscape Medical News.
"A thoughtful look" at the study, he added, "shows that in the true maintenance phase of the study the drug was not significantly better than placebo. And this was in subjects who had been specially selected because they seemed to have an acute positive response to the drug."
Despite these shortcomings, a citation search by the authors found that this single trial was subsequently cited in 80 publications that discussed the use of aripiprazole for bipolar maintenance treatment. Of these, only 24 (30%) mentioned adverse events reported and only 4 (5%) mentioned study limitations.
"Perhaps the most surprising finding," Dr. Rosenlicht said, "was how positively the study's findings were spun and how a whole raft of subsequent papers and review articles uncritically cited these supposedly positive findings."
According to Dr. Turner, "it's good that the average prescriber is alerted to this phenomenon in general and specifically with aripiprazole. However, he or she should consider that the evidence might be similarly sparse on other drugs approved for long-term maintenance treatment, and not just bipolar disorder."
"Also, even if the drug were completely devoid of any efficacy for preventing manias and depressions, the prescriber could be somewhat reassured knowing that this drug is FDA-approved for acute treatment of bipolar mania and also that it appears to have some antidepressant activity, as evidenced by its approval as an add-on for unipolar depression," he added.
Drug Company Responds
Asked to comment on the PLoS Medicine paper, Sonia Choi, director of public affairs for the drug's manufacturer, Bristol-Myers Squibb, told Medscape Medical News in an email:
"Bristol-Myers Squibb and Otsuka are committed to making clinical data available to physicians that enable informed treatment decisions. A total of 5 long-term studies of Abilify (aripiprazole) in a maintenance setting for Bipolar I Disorder were conducted and have been either published in peer-reviewed journals or presented during medical meetings, including the American Psychiatric Association annual meeting."
“These studies were conducted in accordance with good clinical practice and represent designs that were endorsed by leading researchers in Bipolar I Disorder. Two of these studies led to FDA approval of aripiprazole as maintenance treatment for Bipolar I Disorder as monotherapy and adjunctive therapy to either lithium or valproate."
"We are confident in the Abilify clinical development program and will continue to make available information about the efficacy and safety of Abilify from our studies in this and other indicated uses."
Dr. Rosenlicht concludes that on the basis of his group's literature review, "we need a lot more study on the usefulness of Abilify in the long-term treatment bipolar disorder."
Dr. Turner doesn't think prescribers should "radically alter their practices," but they should "temper any enthusiasm" they might have about the drug.
In an email to Medscape Medical News, Lisa Kubaska, PharmD, from the FDA's Center for Drug Evaluation and Research, said the FDA approved the aripiprazole supplement in 2005, "based on a pretty typical randomized withdrawal maintenance study. Our standard for a maintenance claim for a drug already shown in shorter-term trials to have benefit in a disorder is a single study. We carefully reviewed this trial and considered it positive, and sufficient to support the claim."
The authors received no specific funding for this study. A complete list of author disclosures can be found with the original article. Dr. Turner has disclosed no relevant financial relationships.
PLoS Med. Published online May 3, 2011.