title: Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.
abstract: 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.
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: L N
authors.initials: LN
authors.lastname: Yatham
authors.affiliation: Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Beaulieu
authors.affiliation: Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Schaffer
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Kauer-Sant'Anna
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Kapczinski
authors.affiliation: Bipolar Research Program, Department and Institute of Psychiatry, University of São Paulo Medical School, Sao Paulo, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Lafer
authors.affiliation: Department of Psychiatry, Western University, London, ON, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Psychiatry, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: S V
authors.initials: SV
authors.lastname: Parikh
authors.affiliation: Department of Psychiatry, Université de Montréal, Montreal, QC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Daigneault
authors.affiliation: Centre for Health Evaluation & Outcome Sciences, St. Paul's Hospital, Vancouver, BC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: D J
authors.initials: DJ
authors.lastname: Bond
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.
authors.forename: P H
authors.initials: PH
authors.lastname: Silverstone
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Walji
authors.affiliation: Department of Psychiatry, Providence Care, Queen's University, Kingston, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Milev
authors.affiliation: Institut universitaire en santé mentale de Québec, Quebec, QC, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Baruch
authors.affiliation: Hospital Universitario de Santa Maria, Santa Maria, Brazil.
authors.forename: A
authors.initials: A
authors.lastname: da Cunha
authors.affiliation: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Quevedo
authors.affiliation: Bipolar Research Program, Department and Institute of Psychiatry, University of São Paulo Medical School, Sao Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Dias
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Kunz
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: L T
authors.initials: LT
authors.lastname: Young
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: R W
authors.initials: RW
authors.lastname: Lam
authors.affiliation: School of Population & Public Health, University of British Columbia, Vancouver, BC, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Wong
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001569:Benzodiazepines / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D003131:Combined Modality Therapy / Q000379:methods; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008094:Lithium / Q000627:therapeutic use; D008297:Male; D000077152:Olanzapine; D018967:Risperidone / Q000627:therapeutic use*; D013997:Time Factors; D015430:Weight Gain
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D008094:Lithium; D018967:Risperidone; D000077152:Olanzapine