To evaluate the efficacy and safety of clozapine for treatment-resistant bipolar disorder (TRBD).


A systematic review of randomized controlled studies, open-label prospective studies, and retrospective studies of patients with TRBD was carried out. Interventions included clozapine monotherapy or clozapine combined with other medications. Outcome measures were efficacy and adverse drug reactions (ADRs).


Fifteen clinical trials with a total sample of 1,044 patients met the inclusion criteria. Clozapine monotherapy or clozapine combined with other treatments for TRBD was associated with improvement in: (i) symptoms of mania, depression, rapid cycling, and psychotic symptoms, with many patients with TRBD achieving a remission or response; (ii) the number and duration of hospitalizations, the number of psychotropic co-medications, and the number of hospital visits for somatic reasons for intentional self-harm/overdose; (iii) suicidal ideation and aggressive behavior; and (iv) social functioning. In addition, patients with TRBD showed greater clinical improvement in long-term follow-up when compared with published schizophrenia data. Sedation (12%), constipation (5.0%), sialorrhea (5.2%), weight gain (4%), and body ache/pain (2%) were the commonly reported ADRs; however, these symptoms but did not usually require drug discontinuation. The percentage of severe ADRs reported, such as leukopenia (2%), agranulocytosis (0.3%), and seizure (0.5%), appeared to be lower than those reported in the published schizophrenia literature.


The limited current evidence supports the concept that clozapine may be both an effective and a relatively safe medication for TRBD.

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Published in Bipolar Disorders, v. 17, issue 3, p. 235-247.

© 2014 John Wiley & Sons A/S.

This is the peer reviewed version of the following article: Li X-B, Tang Y-L, Wang C-Y, de Leon J. Clozapine for treatment-resistant bipolar disorders: a systematic review. Bipolar Disorders 17(3):235-247, 2015., which has been published in final form at http://dx.doi.org/10.1111/bdi.12272. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

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