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Augmentation With a Second Antipsychotic in Patients With Schizophrenia Who Partially Respond to Clozapine: A Meta-Analysis

Paton, Carol BSc, DipClinPharm*; Whittington, Craig PhD; Barnes, Thomas R. MD, DSc*

Journal of Clinical Psychopharmacology: April 2007 - Volume 27 - Issue 2 - p 198-204
doi: 10.1097/JCP.0b013e318036bfbb
Brief Reports

Objectives: To conduct a meta-analysis of randomized placebo-controlled trials (RCTs) of clozapine augmentation with another antipsychotic drug in patient with schizophrenia who partially respond to clozapine and compare the results with the findings of relevant open studies.

Methods: A systematic literature search was conducted to identify eligible RCTs. All baseline, posttreatment, and change scores in these trials were included in the meta-analysis. For change in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale total scores, the effect size was calculated, and for the proportion of patients with a reduction in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale scores of 20% or more, the relative risk was calculated.

Results: There was a total of 166 participants in the 4 eligible RCTs. Pooling effect sizes across these studies revealed clinically important heterogeneity (I2 = 63.5%). Analyzing by duration accounted for the heterogeneity (I2 = 0%), whereas analyzing by drug did not (I2 = 57.5%). The 2 RCTs lasting 10 weeks or more gave an odds ratio of response to treatment of 4.41 (95% confidence interval, 1.38 to 14.07). In 8 open studies identified, the same pattern of response was seen. The main treatment-emergent side effects reported were extrapyramidal side effects and raised serum prolactin.

Conclusions: Augmentation of clozapine with another antipsychotic drug in patients with schizophrenic illness that has partially responded to clozapine is worthy of an individual clinical trial. This trial may need to be longer than the 4 to 6 weeks usually recommended for acute antipsychotic monotherapy.

*Department of Psychological Medicine, Imperial College, and †Centre for Outcomes Research and Effectiveness, Subdepartment of Clinical Health Psychology, University College, London, UK.

Received May 11, 2006; accepted after revision January 15, 2007.

Address correspondence and reprint requests to Carol Paton, BSc, DipClinPharm, Department of Psychological Medicine, Imperial College, Charing Cross Campus, Reynold's Bldg, St Dunstan's Rd, London W6 8RP, UK. E-mail:

© 2007 Lippincott Williams & Wilkins, Inc.