Four adult men with resistant partial seizures underwent an intensive open-label protocol designed to evaluate long-term add-on lamotrigine (LTG) therapy. Following an 8-week baseline, LTG was added to their background medication(s) (carbamazepine in three; carbamazepine and phenytoin in one). Incremental LTG doses of 50, 100, 150, and 200 mg every 12 h were given on days 58-60, 61-63, 64-127, and 128-176, respectively. The patients were hospitalized during and after each of the dose increases for a total of 25 days. Frequent outpatient visits were performed biweekly, weekly, or monthly, depending on the phase of the protocol. Frequent clinical, electrocardiographic (ECG), and laboratory evaluations were performed. Serial blood levels and 24-h urine collections were performed sequentially. In patients 1, 2, and 3, LTG was well tolerated at 200 mg b.i.d. Patient 4 did not tolerate 150 mg, b.i.d., but tolerated and maintained complete seizure control on 100 b.i.d. All four patients tolerated LTG and continued to receive it for 39, 46, 105, and 104 weeks, respectively. Serial 12-h plasma LTG levels were obtained on days 63, 70, and 133. On these days, the mean (+/- SD) LTG clearances (dose/AUC) were 0.0436 +/- 0.0171, 0.0468 +/- 0.0093, and 0.0575 +/- 0.0160 L/h/kg, respectively. Some 43-87% of the LTG was recovered in the urine, predominantly as the glucuronide metabolite. In the four patients, the mean weekly seizure frequency per patient was 6.5 in baseline, 5.0 on submaximal LTG doses, and 3.5 on the maximum administered doses. Three of the four patients eventually experienced a greater than 50% decrease in seizure frequency. In conclusion, when given for long periods of time (9.5 months to 2 years), LTG was well tolerated in doses up to 400 mg/day and mean trough levels of 3.0 +/- 0.6 microgram/ml; LTG has a favorable pharmacokinetic profile and appears to exhibit first-order linear kinetics during long-term chronic dosing; LTG shows preliminary evidence of efficacy during long-term administration; and to date, our patients represent the longest reported experience of continuous and closely monitored LTG therapy in the literature.