A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions

Rationale Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile. Objective This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs. Methods Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded. Results A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025). Conclusions Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.