• Evidence suggests that lithium treatment alters serotoninergic (5-HT) function in laboratory animals and humans. Since 5-HT function may be abnormal in patients with affective disorders, we studied 23 such patients by measuring responses to intravenous infusion of the 5-HT precursor tryptophan before and during short-term (less than one week) or long-term (greater than three weeks) lithium treatment. The prolactin response to tryptophan was significantly enhanced after short-term lithium treatment; long-term lithium treatment had no effect. Other studies have shown that the prolactin response to tryptophan is also enhanced after long-term tricyclic antidepressant treatment in depressed patients and after short- and long-term lithium treatment in healthy subjects. The present findings suggest that lithium treatment enhances 5-HT function, but that homeostatic responses of the 5-HT system to long-term lithium treatment may differ in patients with affective disorder and healthy subjects.