The addition of lithium to the tricyclic antidepressant medication of 23 patients with major depression resulted in an increase in the prolactin response to intravenous L-tryptophan after both four days and four weeks of treatment. The extent of this increase did not distinguish the ten patients who were classified as clinical responders (greater than 50% reduction in score on the HRSD). Among the responders there was a modestly significant correlation between the decrease in score on the HRSD and the enhancement of tryptophan-induced prolactin release. Some responders, however, showed very little change in this endocrine response over the four weeks of lithium treatment. Lithium may increase brain 5-HT function in tricyclic-resistant depression but there is only limited support for the hypothesis that changes in brain 5-HT function are involved in the antidepressant effect of this treatment combination.