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Meta-Analysis
. 2021 Nov;144(5):422-432.
doi: 10.1111/acps.13361. Epub 2021 Aug 25.

Clozapine levels as a predictor for therapeutic response: A systematic review and meta-analysis

Dan Siskind  1   2   3 , Meghna Sharma  2   4 , Mrinal Pawar  2   5 , Ella Pearson  6 , Elias Wagner  7 , Nicola Warren  1   2   3 , Steve Kisely  1   2   3   8
Affiliations
Meta-Analysis

Clozapine levels as a predictor for therapeutic response: A systematic review and meta-analysis

Dan Siskind et al. Acta Psychiatr Scand. 2021 Nov.

Abstract

Objectives: Clozapine levels may be a more useful predictor of therapeutic response than the dose, given the variability in clozapine metabolism between individuals. We therefore systematically reviewed and meta-analysed the impact of clozapine levels on response and/or relapse to provide guidance on optimal clozapine levels.

Methods: We systematically searched PubMed, PsycInfo and Embase for studies exploring clozapine levels and response and/or relapse. Our primary meta-analysis was rates of response above and below clozapine level thresholds of 350 ng/ml and 600 ng/ml. Secondary analyses were undertaken of mean clozapine levels, dose and concentration/dose (C/D) ratio and response and/or relapse. A meta-regression by study duration was conducted.

Results: Twenty studies met inclusion criteria. Clozapine levels above 350 ng/ml were associated with statistically significantly higher rates of response (OR 2.27 95% CI 1.40-3.67, p < 0.001), but not above 600 ng/ml (OR 1.40 95% CI 0.85-2.31, p = 0.19). Higher mean clozapine levels were associated with better rates of response (SMD 0.24, 95% CI 0.00-0.49, p = 0.05), and lower rates of relapse (SMD -0.72, 95% CI -1.26 to -0.19, p = 0.008). By contrast, neither clozapine dose nor C/D ratio was associated with differing rates of response. Similarly, study duration did not affect outcome.

Conclusions: Our findings are in keeping with current guidelines that recommend targeting clozapine levels above 350 ng/ml before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600 ng/ml may have an unfavourable risk-benefit ratio.

Keywords: clozapine; levels; meta-analysis; relapse; response.

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