We investigated the effects of add-on lamotrigine treatment on plasma glutamate (Glu) levels, in 29 epileptic patients. Plasma Glu levels were determined by high-performance liquid chromatography at baseline and at 1 and 3 months post-treatment. In patients with a seizure reduction of > or = 66% a decrease of Glu at month 1 was noted, followed by return to baseline levels at month 3. In the remaining patients a gradual increase of Glu was noted throughout the 3 months of the study. The above findings indicate that an excellent clinical response to add-on lamotrigine may be characterized by a statistically significant, yet transient decrease of plasma Glu levels, while increasing Glu levels may accompany a response that is moderate at best. The combination of lamotrigine with valproate was more frequent in patients with excellent clinical response and tended to result in glutamate decrease.