Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report

Clozapine is mainly metabolized by the cytochrome P450 1A2 (CYP1A2), which may be inhibited by serious respiratory infections. This case report supports that a serious respiratory infection may increase clozapine levels and contribute to side effects. Plasma clozapine and norclozapine levels were monitored 17 times during 1 year. The concentration-to-dose ratio (C/D), an index of metabolic activity, was obtained by dividing the sum of plasma clozapine and norclozapine concentration (total clozapine concentration) by clozapine dose. The coefficient of variation (CV) of the total clozapine concentrations was calculated at different doses to provide a measure of the noise associated with determining clozapine concentrations in clinical practice. During a respiratory infection, the patient was taking 600 mg/day of clozapine. Clozapine levels were 1245 ng/ml (norclozapine 472 ng/ml), reflecting a decrease in clozapine metabolism by approximately a factor of 2. The high clozapine levels were associated with side effects (myoclonus and increased sedation). The C/D during the infection was 2.9, while the rest of C/Ds ranged between 1.0 and 1.6. CVs before and after the infection, at different doses, were always lower than 20%. When the level during the infection was included to calculate the CV on 600 mg/day, the CV increased to 54%. The theophylline literature, a prior case report and this case all suggest that if a clozapine patient develops a severe respiratory infection with fever, the psychiatrist must pay particular attention to any signs suggestive of major clozapine toxicity associated to a decrease in clozapine metabolism. If any of these signs appear, the psychiatrist may need to consider cutting the clozapine dose in half until the patient has recovered from the infection.