Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression
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.
Background Episodes of depression are the most frequent causeof disability among patients with bipolar disorder. The effectivenessand safety of standard antidepressant agents for depressiveepisodes associated with bipolar disorder (bipolar depression)have not been well studied. Our study was designed to determinewhether adjunctive antidepressant therapy reduces symptoms ofbipolar depression without increasing the risk of mania.
Methods In this double-blind, placebo-controlled study, we randomlyassigned subjects with bipolar depression to receive up to 26weeks of treatment with a mood stabilizer plus adjunctive antidepressanttherapy or a mood stabilizer plus a matching placebo, underconditions generalizable to routine clinical care. A standardizedclinical monitoring form adapted from the mood-disorder modulesof the Structured Clinical Interview for the Diagnostic andStatistical Manual of Mental Disorders, fourth edition, wasused at all follow-up visits. The primary outcome was the percentageof subjects in each treatment group meeting the criterion fora durable recovery (8 consecutive weeks of euthymia). Secondaryeffectiveness outcomes and rates of treatment-emergent affectiveswitch (a switch to mania or hypomania early in the course oftreatment) were also examined.
Results Forty-two of the 179 subjects (23.5%) receiving a moodstabilizer plus adjunctive antidepressant therapy had a durablerecovery, as did 51 of the 187 subjects (27.3%) receiving amood stabilizer plus a matching placebo (P=0.40). Modest nonsignificanttrends favoring the group receiving a mood stabilizer plus placebowere observed across the secondary outcomes. Rates of treatment-emergentaffective 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 associatedwith increased efficacy or with increased risk of treatment-emergentaffective switch. Longer-term outcome studies are needed tofully assess the benefits and risks of antidepressant therapyfor bipolar disorder. (ClinicalTrials.gov number, NCT00012558
[ClinicalTrials.gov]
.)
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 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 gsachs{at}partners.org.
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