Rapid clozapine titration in treatment-refractory bipolar disorder

Abstract Background Clozapine is effective in treatment-refractory bipolar disorder (BD). Guidelines recommend slow titration to prevent seizures, hypotension and myocarditis, but this stance is not supported by comparative data. Objective To evaluate the safety and effectiveness of rapid clozapine titration in BD. Methods Analysis of a consecutive cohort of treatment-refractory BD patients with mixed/manic episode admitted on alternate days to one of two units of a psychiatric hospital. On one unit, clozapine was started at 25 mg followed by 25–50 mg as needed every 6 h (maximum=100 mg/day) on day 1, followed by increases of 25–100 mg/day. On the other unit, clozapine was initiated with 25 mg in day 1, followed by increases of 25–50 mg/day. The primary outcome was the number of days from starting clozapine until readiness for discharge, adjusted in logistic regression for the number of antipsychotics tried during the hospitalization, psychotropic co-treatments and presence of psychotic features. Results Patients subject to rapid ( N =44) and standard ( N =23) titration were similar in age, gender, smoking status, body mass index, illness severity at baseline and discharge, and highest clozapine dose. Clozapine was discontinued due to hypotension ( N =1) and pneumonia ( N =1) during rapid titration, and for excessive sedation ( N =1) in each titration group. The number of hospital days from starting clozapine until readiness for discharge was 3.8 days shorter in the rapid titration group (12.7±6.3 vs. 16.5±5.8, p =0.0077). Conclusion Rapid clozapine titration appeared safe and effective for treatment-refractory BD. The potential for shorter hospital stays justifies prospective trials of this method.