Efficacy and Safety Outcomes of Different Plasma Clozapine and Norclozapine Levels in Schizophrenia Spectrum Disorder: A Dose-Response Meta-Analysis Exploring "critical" Levels.

BACKGROUND: A dose-response meta-analysis (DRMA) exploring serum/plasma clozapine and norclozapine concentrations in relation to efficacy and safety outcomes in schizophrenia spectrum disorders is warranted. METHODS: PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched through February 16th, 2026. Cohort studies and clinical trials of clozapine-exposed participants were eligible. Linear models were first fitted, followed by exploratory quadratic models estimating population-level concentration-response turning points. RESULTS: Thirty-four studies including 134,111 participants were included. Quadratic models yielded the following exploratory clozapine turning points: Brief Psychiatric Rating Scale change (535 ng/mL), Positive and Negative Syndrome Scale total change (898 ng/mL), tolerability (707 ng/mL), blood dyscrasia (357 ng/mL), electroencephalogram abnormalities/seizures (452 ng/mL), salivary hypersecretion (225 ng/mL), and tachycardia (503 ng/mL). Certainty was moderate for 11/21 and low for 10/21 outcomes. CONCLUSIONS: These values should not be interpreted as universal therapeutic or toxic thresholds, nor as targets for dose escalation. Rather, they are exploratory vertices derived from heterogeneous studies. Overall, findings support individualized therapeutic drug monitoring and caution against pursuing unduly high clozapine concentrations when additional benefit is uncertain and adverse-event risk may increase.