AIMS: Both inflammation and smoking are known to affect clozapine metabolism. However, the impact of inflammation on clozapine metabolism in relation to smoking status is unclear. Therefore, we investigated correlations between C-reactive protein (CRP) and clozapine levels in smokers and non-smokers separately. METHODS: Patients were included retrospectively from a therapeutic drug monitoring (TDM) service in Oslo, Norway, during January 2005-April 2022. Inclusion criteria were known smoking status and CRP measurements no longer than 7 days before or after clozapine TDM. Exclusion criteria were confirmed blood sampling for TDM outside 10-30 h after the last clozapine intake. Information about clozapine dosing was retrieved from the requisition forms. RESULTS: In 126 patients fulfilling the criteria (47% smokers), dose-adjusted serum concentration (CD) of clozapine correlated significantly with CRP in non-smokers (R = 0.492
p <
001) but not in smokers (R = 0.191
p = 0.166). When subgrouping non-smoking patients into low CRP (<
5 mg/L
reference [51% of the population]), mid CRP (5-50 [37%]) and high CRP (>
50 [12%]), clozapine CD gradually increased in mid- (+48%, p = 0.004) and high-CRP groups (+204%, p <
0.001) compared with the low-CRP group. No significant differences in clozapine CD were found between CRP groups among smokers (p >
0.15). CONCLUSIONS: We report a significant correlation between CD of clozapine and CRP levels in non-smoking patients only. In these patients, clozapine CD is more than 3-fold higher at CRP >
50 versus CRP <
5. This suggests that non-smokers are most susceptible to clozapine side effects during inflammation or infection and represent patients where TDM analyses are especially important for guiding clozapine dosing.