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 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.