Clozapine Levels as a Predictor for Therapeutic Response: A Systematic Review and Meta-Analysis

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 350ng/mL and 600ng/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 350ng/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 600ng/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 were 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 350ng/mL before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600ng/mL may have an unfavourable risk- benefit ratio.