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Combination treatment in bipolar disorder: a review of controlled trials


Corresponding author: Dr Carlos A. Zarate Jr Mood and Anxiety Disorders Program, National Institute of Mental Health, 9000 Rockville Pike, Building 10, Room 3s250, Bethesda, MD 20892, USA. Fax: +1 301 402-9360; e-mail:


Objectives:  Monotherapy is often inadequate and combination drug regimens have become the norm for the treatment of bipolar disorder. Virtually all classes of psychotropic drugs have been used in bipolar disorder in combination for a variety of indications. This article reviews the available published data from controlled, blinded studies regarding combination treatments in the different treatment phases of bipolar disorder.

Methods:  Articles for this review were obtained from a search of the Medline database (1966–2002), using the following keywords and phrases: add-on, antipsychotic, anticonvulsant, antidepressant, combination treatment, lithium, neuroleptic, and polypharmacy. The search was augmented by data presented at scientific meetings. Data included in this article were only from controlled studies that evaluated combinations of two or more agents.

Results:  For acute mania, the most useful combination treatments as determined by controlled studies, appear to be an antipsychotic drug with a mood-stabilizer. The combination of lithium and valproate, even though widely used for acute mania, is lacking in controlled data. For acute bipolar depression, the controlled combination studies reviewed fail to show clear advantages in efficacy of an antidepressant with a mood-stabilizer versus two stabilizers or a mood-stabilizer alone. Large, controlled, randomized, long-term studies with modern antidepressants are not available. Controlled combination studies of mood-stabilizers suggest gains in efficacy over monotherapy in the long-term treatment of bipolar disorder.

Conclusions:  Controlled combination studies in bipolar disorder are uncommon. Increased attention should be given to study combination treatments in all phases of bipolar illness to determine the most efficacious and safest combinations.