Psychotic Symptoms Associated With Topiramate

Sir: Approximately 70% of clozapine metabolism is explained by the cytochrome P450 1A2 (CYP1A2). 1 The CYP1A2 can be inhibited by respiratory infections. Decreased theophylline (a CYP1A2 substrate) clearance during upper respiratory infections has been described in asthmatic children 2,3 and in adults with chronic bronchitis. 4 Cytokines released during infection decrease CYP1A2 activity and synthesis. 5 Expert pediatricians recommend decreasing theophylline doses by half during severe respiratory infections. 3 Two cases of increased plasma clozapine concentrations during respiratory infection were recently published. 6,7 The English-language literature was reviewed in October 2003 with a PubMed search using all searchable years and several term combinations including clozapine and CYP3A, clozapine and macrolide, and clozapine and fluoroquinolone. All the references listed in the newly found articles and in those gathered over the course of my more than 7 years of interest in the subject were also reviewed to obtain all relevant articles. This critical review of the literature suggests that 3 prior clozapine toxicity cases attributed to drug interactions with erythromycin 8,9 or ampicillin 10 are better explained by 1 pharyngitis case 8 and 2 sinusitis cases. 9,10 Ampicillin does not inhibit the CYPs. 11 Erythromycin inhibits CYP3A, but a study of a single clozapine dose in 12 healthy males failed to show any effects of erythromycin. 12 Similarly, itraconazole, another potent CYP3A inhibitor, did not influence clozapine metabolism. Therefore, in 2 patients taking erythromycin, 8,9 CYP1A2 inhibition associated with a respiratory infection was probably the major factor contributing to clozapine toxicity, although some small effects of erythromycin cannot be ruled out. Assuming that clozapine follows linear pharmacokinetics, 14 clozapine concentration-todose ratio associated with the respiratory infection decreased by a factor of 2 to 3 times (3.3, 6 2.0, 7 1.9, 8 and 3.0 9 ).