The mechanisms underlying the acute and prophylactic antimanic properties of valproate have remained elusive. There are some reports that treatment with valproic acid may increase brain serotonergic neurotransmission in the rodent. This study was carried out in order to investigate the effects of subchronic therapy with valproate on central serotonin metabolism in manic patients. Toward this end, the authors examined plasma cortisol responses to 200 mg (orally) L-5-hydroxy-tryptophan (L-5-HTP) in 10 manic patients both before and after subchronic treatment with valproate. Administration of L-5-HTP resulted in significantly increased cortisol responses both before and after treatment with valproate. The L-5-HTP-induced cortisol responses were significantly higher after treatment with valproate than before treatment. It is suggested that valproate may increase central serotonergic neurotransmission and that this stimulation may play a role in the antimanic effects of valproate.