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Mol Psychiatry. 2016 Aug;21(8):1050-6. doi: 10.1038/mp.2015.158. Epub 2015 Oct 13.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

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Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Douglas Hospital, McGill University, Montreal, QC, Canada.
Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON, Canada.
Bipolar Disorder Program and Laboratory of Molecular Psychiatry, National Institute for Translational Medicine, INCT-TM, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Bipolar Research Program, Department and Institute of Psychiatry, University of São Paulo Medical School, Sao Paulo, Brazil.
Department of Psychiatry, Western University, London, ON, Canada.
Department of Psychiatry, University Health Network, University of Toronto, Toronto, ON, Canada.
Department of Psychiatry, Université de Montréal, Montreal, QC, Canada.
Centre for Health Evaluation & Outcome Sciences, St. Paul's Hospital, Vancouver, BC, Canada.
Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.
Department of Psychiatry, Providence Care, Queen's University, Kingston, ON, Canada.
Institut universitaire en santé mentale de Québec, Quebec, QC, Canada.
Hospital Universitario de Santa Maria, Santa Maria, Brazil.
Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil.
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
School of Population & Public Health, University of British Columbia, Vancouver, BC, Canada.


Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

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