Relationship Between Clozapine Levels and Adverse Effects Evaluated by the GASS‐C in Treatment‐Resistant Schizophrenia

OBJECTIVE: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. However, evidence regarding whether adverse effects are related to the clozapine concentration is insufficient. METHODS: Patients treated with clozapine for at least 6 weeks and maintained on a fixed dose for > 1 week were included (n = 47). Adverse effects were assessed using the self-rated Glasgow Antipsychotic Side-effects Scale for Clozapine (GASS-C). Plasma concentrations of clozapine and norclozapine were measured, and the relationship between the GASS-C score and clozapine concentration was analyzed. RESULTS: Clozapine concentration was significantly associated with both the GASS-C score (rs = 0.435, p = 0.002) and norclozapine concentration (rs = 0.363 p = 0.012). In addition, significant correlations with large effect sizes were found for GASS-C sub-items such as hypersalivation and anticholinergic symptoms. Multiple regression indicated that the GASS-C total score was associated with both clozapine (β = 0.374, p = 0.012) and norclozapine (β = 0.404, p = 0.005) concentrations. CONCLUSIONS: Adverse effects, including subjective ones, of clozapine may be concentration-related and clinically important. However, monitoring clozapine levels may only have a supplementary role in managing its subjective adverse effects because subjective GASS-C scores could be influenced by psychological factors and patient perception, which may not always correlate linearly with pharmacokinetic data.