OBJECTIVE To investigate the potential drug-drug interaction between lamotrigine, an antiepileptic agent used to treat bipolar disorders, and olanzapine, an atypical antipsychotic drug also used to treat bipolar disorders, both of which are metabolized by the uridine diphosphate glucuronosyltransferase system. METHODS Prospective cohort study. METHODS University center for clinical research. METHODS Fourteen nonsmoking, healthy volunteers. METHODS Subjects received lamotrigine 25 mg/day for 5 days, then 50 mg/day for 10 days to achieve steady-state concentrations. On day 15, blood samples were obtained before and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after the dose. Lamotrigine 50 mg/day was then given for an additional 3 days. On the next day, lamotrigine 50 mg and olanzapine 5 mg were coadministered. Blood samples were obtained at the same times as before and at 48, 72, and 96 hours after dosing. RESULTS Blood samples were assayed for lamotrigine and olanzapine concentrations by means of high-performance liquid chromatography. Olanzapine did not significantly affect lamotrigine disposition, as we observed no differences in the area under the concentration-time curve from 0-24 hours or in lamotrigine plasma concentrations at baseline or at 24 hours. For lamotrigine, the mean time to reach maximum concentration was significantly prolonged during olanzapine coadministration (mean +/- SD 1.9 +/- 1.3 vs 4.0 +/- 3.0 hrs, p = 0.025), possibly because of the anticholinergic properties associated with olanzapine. Mild sedation was the only adverse effect that occurred during lamotrigine and olanzapine coadministration. CONCLUSIONS Lamotrigine and olanzapine can safely be combined in healthy volunteers at the low doses studied, without a clinically significant interaction. When prescribing high doses of olanzapine and lamotrigine for bipolar disorder, patients must be carefully monitored.