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Efficacy of antimanic treatments in mixed states


  • Roger S McIntyre,

    1. Department of Psychiatry
    2. Department of Pharmacology, University of Toronto
    3. Mood Disorders Psychopharmacology Unit, University Health Network
    4. Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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  • Jinju Yoon

    1. Mood Disorders Psychopharmacology Unit, University Health Network
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Corresponding author:
Roger S. McIntyre, MD, FRCPC
University of Toronto
University Health Network
399 Bathurst Street
Toronto, ON, Canada, M5T 2S8
Fax: 416-603-5368


McIntyre RS, Yoon J. Efficacy of antimanic treatments in mixed states. Bipolar Disord 2012: 14 (Suppl. 2): 22–36. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.

Objective:  To review the efficacy of pharmacological agents in bipolar mixed states.

Methods:  We conducted a PubMed search of all English-language articles involving Food and Drug Administration (FDA)-approved agents for manic/mixed states in adults with bipolar I disorder. We also included names of agents established as efficacious in acute mania/mixed states that have not received FDA approval for bipolar disorder. Bibliographies from relevant articles were also searched. The efficacy of each agent in the mixed state subpopulation was reviewed, as evidenced by change from baseline on total scores of mania [e.g., Young Mania Rating Scale (YMRS)] and depression [e.g., Montgomery–Åsberg Depression Rating Scale (MADRS)] measures.

Results:  No available study is dedicated exclusively to the evaluation of mixed state populations. Although key inclusion and exclusion criteria are similar across treatment studies, mixed states have been variably defined and measured. The use of conventional manic and depressive metrics in bipolar mixed states perpetuates the unproven notion that mixed states are the consequence of coexisting depression and mania. Notwithstanding the methodological limitations, there are numerically more studies that exist for atypical antipsychotic agents than for any other class. On the basis of symptomatic improvement, recommendations for and/or strong admonishments against any established antimanic agents (e.g., lithium) cannot be made. An emergent signal supports combination treatment strategies (e.g., atypical antipsychotic plus divalproex) over mood stabilizer monotherapy (e.g., divalproex). Available evidence does not empirically support the hypothesis that conventional antipsychotics engender and/or amplify depressive symptoms in bipolar mixed states.

Conclusions:  All proven antimanic agents (including lithium), can be recommended in the treatment of mixed/dysphoric states. The totality of evidence with attention paid to the therapeutic index of each agent would suggest that atypical antipsychotics and divalproex be considered as first-line treatment, with lithium and carbamazepine as second-line. Most individuals will require combination therapy for the treatment of mixed states; variable combinations of atypical antipsychotics and conventional mood stabilizers have the most replicated evidence.