Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature
A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use.
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
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.
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.
Please see later in the article for the Editors' Summary
Citation: Tsai AC, Rosenlicht NZ, Jureidini JN, Parry PI, Spielmans GI, et al. (2011) Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature. PLoS Med 8(5): e1000434. doi:10.1371/journal.pmed.1000434
Academic Editor: Phillipa J. Hay, University of Western Sydney, Australia
Received: August 3, 2010; Accepted: March 23, 2011; Published: May 3, 2011
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: The authors received no specific funding for this study. ACT received salary support as a Robert Wood Johnson Health and Society Scholar at Harvard University. No funding bodies had any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: ACT receives salary support through the Robert Wood Johnson Foundation Health and Society Scholars Program. The Robert Wood Johnson Foundation's stated mission is to improve the health and health care of all Americans. NZR is a member of the National Physicians Alliance, a not-for-profit organisation whose stated primary goal is to restore physicians' primary emphasis on the core values of service, integrity, and advocacy. The National Physicians Alliance rejects funding from commercial health care interests and encourages its members to do the same. NZR, JNJ, and PIP are members of Healthy Skepticism, an international not-for-profit organisation whose stated aim is to improve health by reducing harm from misleading drug promotion; GIS joined Healthy Skepticism after this article was accepted for publication. GIS is a current shareholder (<$10,000) in a mutual fund, Vanguard Healthcare, that invests heavily in pharmaceutical companies. DH reports no links to pharmaceutical companies in the past 5 years. ACT is a former board member of the ethics committee, and former member, of the National Physicians Alliance. ACT and NZR are former members of No Free Lunch, a not-for-profit organisation whose stated mission was to encourage health care providers to practice medicine on the basis of scientific evidence rather than on the basis of pharmaceutical promotion. JNJ was engaged by the law firm of Baum, Hedlund, Aristei & Goldman to provide an independent analysis of the data in Glaxo SmithKline's Study 329 of paroxetine in adolescents. DH has been an expert witness in ten legal cases involving antidepressant medications and one case involving the patent on olanzapine (Zyprexa).
Abbreviations: CI, confidence interval; NDA, new drug application
* E-mail: firstname.lastname@example.org
# These authors contributed equally to this work.
Editors' Summary Top
Bipolar disorder (manic depression) is a serious, long-term mental illness that affects about 1% of adults at some time during their life. It usually develops in late adolescence or early adulthood and affects men and women from all backgrounds. People with bipolar disorder experience wild mood swings that interfere with daily life and damage relationships. During ¡°manic¡± episodes, which can last several months if untreated, they may feel euphoric (¡°high¡±), energetic, or irritable. They may be full of ambitious plans, feel creative, and spend money recklessly. They can also have psychotic symptoms¡ªthey may see or hear things that are not there. During depressive episodes, affected individuals may feel helpless, worthless, and suicidal. Treatments for bipolar disorder include drugs to stabilize mood swings (for example, lithium and anticonvulsant medications), antidepressants to treat depressive episodes, and antipsychotic drugs to treat manic episodes. Psychotherapy can also help and patients can be taught to recognize the signs of approaching manic or depressive episodes and the triggers for these episodes.
Why Was This Study Done?
Treatment of bipolar disorder is divided into three phases: acute treatment lasting about 2 months to achieve remission, continuance treatment lasting from months 2 through 6 to prevent relapse, and long-term maintenance treatment to prevent recurrence. Second-generation (atypical) antipsychotics are widely used for acute treatment of manic episodes but are also used for maintenance treatment. For example, the atypical antipsychotic aripiprazole, which gained US approval for this indication in 2005, is now a popular choice among clinicians for treating bipolar disorder. But how much evidence is there to support aripiprazole's use in the maintenance treatment of bipolar disorder? Here, the researchers systematically search the published literature for double-blind randomized controlled trials of aripiprazole for this indication, critically analyze the quality of these trials, and undertake a citation search to investigate how the results of these trials have been disseminated in the scientific literature. In double-blind randomized controlled trials, patients are randomly assigned to receive a test drug or a control (generally, placebo), and the effects of these drugs compared; patients in the trial, and physicians administering treatments, would not know who is receiving the test drug or control until the trial is completed.
What Did the Researchers Do and Find?
The researchers' search for reports of double-blind randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder using predefined criteria identified only two publications, both describing a single trial¡ªthe Keck trial. Critical review of this trial identified four issues that limit its interpretation for supporting aripiprazole as a maintenance therapy: the trial was too short to demonstrate maintenance efficacy; all the trial participants had responded well to aripiprazole as an acute treatment so the generalizability of the trial's results was limited; the trial design meant that some of the apparent beneficial treatment results could have reflected the adverse effects of abrupt medication discontinuation in the control group; and the trial had a low completion rate. The researchers' citation search identified 80 publications that cited the Keck trial in discussions of the use of aripiprazole for maintenance treatment of bipolar disorder. Only a quarter of these papers presented any numerical data from the trial, only a third mentioned any of the reported adverse events, and only four papers mentioned the trial's limitations.
What Do These Findings Mean?
This evaluation of the evidence base supporting the use of aripiprazole for the maintenance treatment of bipolar disorder shows that the justification for this practice relies on the results of one published trial. Moreover, the methodology and reporting of this trial mean that its results cannot easily be generalized to inform the treatment of most patients with bipolar disorder. Worryingly, the researchers' citation search indicates that the Keck trial has been cited uncritically in the ensuing scientific literature. Although the unique features of bipolar disorder make it hard to undertake controlled studies of treatment options, the researchers express concern that ¡°the publication and apparently uncritical acceptance of this trial may be diverting patients away from more effective treatments¡±.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000434.
First-generation antipsychotic medications have been used for many decades in the short-term treatment of acute manic episodes associated with bipolar disorder . Second-generation antipsychotic medications have increasingly gained popularity for this use as well . However, their promotion for the maintenance treatment of bipolar disorder is a more recent phenomenon ¨C. In one recently published nationally representative survey of physicians, mood disorders accounted for the majority of antipsychotic medication prescriptions , and a recent shift to prescription of antipsychotic medications was observed in a sample of San Diego county Medicaid beneficiaries with bipolar disorder .
Traditionally, the clinical care of patients diagnosed with bipolar disorder has been divided into three phases (borrowed from clinical consensus about the phases of treatment for major depressive disorder ,): treatment of acute episodes to symptomatic remission, continuation treatment to prevent relapse, and maintenance treatment to prevent recurrence. The 2 mo following recovery from the acute episode is commonly described as acute phase recovery, and the continuation phase of treatment (during which the natural course of the episode is considered still active even though the patient may be asymptomatic) is defined as lasting from months 2 through 6