Effects of Caffeine Withdrawal From the Diet on the Metabolism of Clozapine in Schizophrenic Patients

Abstract

Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity.

Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia

“…It has been shown previously that the N-desmethylclozapine to clozapine ratio gives an estimate of CYP1A2 activity [23]. It is possible that the cause for increased serum clozapine concentrations in the two drop-out patients could have been the infection itself.…”

Therapeutic drug monitoring of atypical antipsychotic drugs

“…Thus, patients requiring these higher dosages should probably be titrated more cautiously to avoid the adverse effects associated with higher dosages, such as seizures and confusion (14). Changes in the habitual caffeine intake alter the metabolism of clozapine in schizophrenic patients (35). Thus, a patient's intake of caffeine should be medically supervized and the monitoring of clozapine and metabolite levels may be warranted.…”

Augmentative Effects of Fluvoxamine on Duloxetine Plasma Levels in Depressed Patients

“…Caff eine intake (caff eine as a weak inhibitor of CYP 1A2) was stable throughout the study but was not monitored systematically. Although not previously described for a possible pharmacokinetic interaction between caff eine and DLX it must be taken into account that due to its weak inhibiting properties on 1A2, caff eine can possibly infl uence CYP 1A2 metabolized drugs as is described, e. g., for clozapine [ 16 ] . Regarding a possible pharmacokinetic drug-drug interaction between fl uvoxamine and caff eine it must also be taken into account, that fl uvoxamine may lead to enhanced caff eine levels as previously described [ 17 ] .…”