Background
Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.
Methods and Findings
We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.
Conclusions
A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature.
Authors
Alexander C. Tsai1#*, Nicholas Z. Rosenlicht2#, Jon N. Jureidini3, Peter I. Parry4, Glen I. Spielmans5, David Healy6
1 Robert Wood Johnson Health and Society Scholars Program, Harvard University, Cambridge, Massachusetts, United States of America, 2 Department of Psychiatry, University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, California, United States of America, 3 Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia, 4 Child and Adolescent Mental Health Service, Division of Mental Health, Flinders University, Adelaide, South Australia, Australia, 5 Department of Psychology, Metropolitan State University, St. Paul, Minnesota, United States of America, 6 Department of Psychological Medicine, Cardiff University, Cardiff, Wales, United Kingdom
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