Carbamazepine but not valproate induces CYP2A6 activity in smokers with mental illness.

Background: Antiepileptic drugs (AED) are being increasingly used in the management of serious mental illness, but their effects on nicotine metabolism have not been studied.

Methods: This study investigated the effects of three AEDs (carbamazepine, oxcarbazepine, and valproic acid) on nicotine and nicotine metabolite levels in 149 smokers with schizophrenia and bipolar disorder who participated in an afternoon blood draw for nicotine, cotinine, and 3'-hydroxycotinine (3HC). The ratio of 3HC to cotinine was calculated as a marker of CYP2A6 metabolic activity. Among the participants, 8 smokers were taking carbamazepine, 6 were taking oxcarbazepine, and 40 were taking valproic acid.

Results: The 3HC/cotinine ratio was significantly higher in individuals taking carbamazepine or oxcarbazepine (combined, n = 14) versus those not taking either (mean 0.993 versus 0.503; P < 0.001). The cotinine/cigarette per day ratio was significantly lower in individuals taking carbamazepine or oxcarbazepine. The 3HC/cotinine ratios were also significantly higher in the subgroup of individuals taking carbamazepine (n = 8) versus those not taking it. There were no significant differences in nicotine or cotinine levels or 3HC/cotinine ratios in individuals taking valproic acid versus those not taking it. We conducted backward stepwise linear regression models to identify predictors of the log transformed 3HC/cotinine ratios. Taking carbamazepine and number of cigarettes smoked per day were significant determinants of log 3HC/cotinine.

Conclusions: Carbamazepine likely induces hepatic metabolism via CYP2A6 and is associated with increased 3HC/cotinine ratios.

Impact: Increased nicotine metabolism in individuals using AED has implications for increased smoking behavior and exposure to more tobacco toxins, which warrants further study.