Rapid clozapine titration in treatment-refractory bipolar disorder

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 25mg followed by 25-50mg as needed every 6h (maximum=100mg/day) on day 1, followed by increases of 25-100mg/day. On the other unit, clozapine was initiated with 25mg in day 1, followed by increases of 25-50mg/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.