Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression

Background Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania.

Methods In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined.

Results Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups.

Conclusions The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov] .)

Bipolar disorder, the sixth-leading cause of disability worldwide, is a chronic and recurrent psychiatric illness with a lifetime prevalence of just under 4% and annual costs that exceed those of diabetes or recurrent (unipolar) major depressive disorder. Although abnormal mood elevation is the cardinal diagnostic feature that distinguishes bipolar disorder from recurrent major depressive disorder, depression that alternates with manic episodes (bipolar depression) is the leading cause of impairment and death among patients with bipolar disorders.

Two main limitations related to standard antidepressant medications hamper their use in the treatment of bipolar depression. First, though these agents have proved to be efficacious in treating unipolar depression, the data providing support for their use in treating bipolar depression are minimal and are not considered to be sufficient to guide clinical practice. Second, the widely held belief that antidepressants can induce new episodes of abnormal mood elevation or accelerate the rate of cycling has been neither confirmed nor refuted by placebo-controlled studies.

Adequately powered, well-controlled studies are needed to show the effectiveness of treatments for bipolar depression under conditions of routine clinical practice. Pivotal studies sponsored by pharmaceutical companies are designed primarily to demonstrate efficacy for purposes of regulatory approval. These studies typically involve narrow eligibility requirements and short-term cross-sectional outcomes, which limit the generalizability of the results to routine clinical practice.

The Food and Drug Administration (FDA) has not approved any of the more than 25 standard antidepressants for the treatment of bipolar depression. However, standard antidepressants are commonly used as adjuncts to mood-stabilizing medication for the treatment of bipolar depression, despite limited evidence of the short-term and long-term efficacies and the putative risk of treatment-emergent mania or hypomania. Furthermore, in a placebo-controlled study in which subjects using therapeutic doses of the mood stabilizer lithium were randomly assigned to receive concurrent treatment with a standard antidepressant (paroxetine or imipramine) or placebo, those receiving lithium plus an antidepressant did not have a significant advantage over those receiving lithium plus placebo. Indeed, the only large positive trial of standard antidepressant treatment for bipolar depression published to date involved combination treatment with an atypical antipsychotic drug, rather than a traditional (non–dopamine blocking) mood stabilizer. In that study, the combination of olanzapine and fluoxetine was superior to placebo as well as to olanzapine alone. However, the study did not address the effectiveness of standard antidepressants used in conjunction with lithium or valproate; thus, its results may not be generalizable to the treatment of patients with bipolar depression who typically seek treatment.

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is a collaboration sponsored by the National Institute of Mental Health designed to evaluate the effectiveness of treatments for bipolar disorder and to provide results that are generalizable to routine clinical practice. STEP-BD recruited a representative group of patients with bipolar disorder who were seeking treatment and used clinically meaningful outcomes. We report results from a controlled trial within STEP-BD evaluating the effectiveness of standard antidepressants for the short-term treatment of major depressive episodes in patients with bipolar disorder.

Methods

The STEP-BD collaborators conducted this multicenter, double-blind, randomized, placebo-controlled, parallel-group study of standard antidepressants (either bupropion or paroxetine) as adjuncts to treatment with mood stabilizers (lithium, valproate, carbamazepine, or other FDA-approved antimanic agents) at 22 centers in the United States between November 1999 and July 2005. Subjects with bipolar I or bipolar II disorder were treated for up to 26 weeks to evaluate the effectiveness, safety, and tolerability of the adjunctive use of antidepressant medication. The study was approved by the institutional review board at each site and was overseen by a data and safety monitoring board.

The rationale for the design and methods of the STEP-BD trials has been described previously. The STEP-BD protocol was critiqued by a committee of external experts and consumer advocates and was posted for public review.

Selection of Subjects

Study subjects were at least 18 years old and met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), for a major depressive episode associated with bipolar I or bipolar II disorder. The diagnosis of bipolar disorder was confirmed at entry into STEP-BD by using an affective disorder evaluation form adapted from the Structured Clinical Interview for DSM-IV14 and by the independent administration of the Mini-International Neuropsychiatric Interview. We excluded subjects with a history of intolerance or nonresponse to both bupropion and paroxetine, as well as those requiring current short-term treatment for a coexisting substance-abuse disorder or requiring the addition of antipsychotic medication or a change in the dose of a long-term antipsychotic medication. Subjects enrolled in STEP-BD provided additional written informed consent for our study. At the time of randomization, all subjects agreed to receive a concomitant mood stabilizer.

Source Information

From Massachusetts General Hospital, Harvard Medical School (G.S.S., A.A.N., M.J.O.), and Boston University (M.W.O.) — all in Boston; Case Western Reserve University–University Hospitals Case Medical Center, Cleveland (J.R.C.); Baylor College of Medicine and South Central Mental Illness Research Education and Clinical Core — both in Houston (L.B.M., J.M.M.); the University of Pittsburgh (S.R.W.) and University of Pittsburgh School of Medicine (E.S.F., M.E.T.) — both in Pittsburgh; the University of Pennsylvania, Philadelphia (L.G.); the University of Texas Health Science Center, San Antonio (C.L.B.); the University of Oklahoma College of Medicine–Tulsa, Tulsa (M.D.F.); Stanford University School of Medicine, Stanford, CA (T.A.K.); the University of Massachusetts Medical School, Worcester (J.P.); the Portland Veterans Affairs Medical Center and Oregon Health and Sciences University — both in Portland (P.H.); the University of Toledo College of Medicine, Toledo, OH (D.R.); the University of Colorado Health Sciences Center, Denver (M.H.A.); the University of Colorado, Boulder, and University of Colorado Health Sciences Center, Boulder (D.J.M.); and Purdue University, West Lafayette, IN (E.B.D.).

This article (10.1056/NEJMoa064135) was published at http://www.nejm.org on March 28, 2007.

Address reprint requests to Dr. Sachs at the Bipolar Clinic and Research Program, Massachusetts General Hospital, 50 Staniford St., Suite 580, Boston, MA 02114, or at .(JavaScript must be enabled to view this email address).

Authors:  Gary S. Sachs, M.D., Andrew A. Nierenberg, M.D., Joseph R. Calabrese, M.D., Lauren B. Marangell, M.D., Stephen R. Wisniewski, Ph.D., Laszlo Gyulai, M.D., Edward S. Friedman, M.D., Charles L. Bowden, M.D., Mark D. Fossey, M.D., Michael J. Ostacher, M.D., M.P.H., Terence A. Ketter, M.D., Jayendra Patel, M.D., Peter Hauser, M.D., Daniel Rapport, M.D., James M. Martinez, M.D., Michael H. Allen, M.D., David J. Miklowitz, Ph.D., Michael W. Otto, Ph.D., Ellen B. Dennehy, Ph.D., and Michael E. Thase, M.D.

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