To assess the status of the brain serotonergic system in relation to ongoing behavior, agents with predominant actions on serotonin synthesis, release, uptake, and receptor mechanisms are being evaluated. Abnormalities in the neuroendocrine responses to tryptophan, 5-hydroxytryptophan, fenfluramine, and m-chlorophenylpiperazine are under exploration in depressed patients. These agents are also being used to assess postulated changes in serotonin metabolism and serotonin receptor adaptation during longer term treatment with antidepressant drugs, lithium, and other psychoactive agents. Concurrent studies in rodent and nonhuman primate models are helping to validate these approaches to the exploration of the role of serotonin in psychiatric and neurologic disorders.