Antidepressant medications are prescribed to millions of Americans, many of whom receive the drug for months to years. Despite increasingly sophisticated studies in animals and the development of more biochemically specific antidepressants, the therapeutic mechanism of action in man remains unknown. Comparison of biochemical effects in CSF, plasma and urine in the same patients is now feasible with new, efficient high performance liquid chromatography assays, and, when coupled with physiologic, behavioral and neuroendocrine measures, allows for clearer systems interpretations of changes. Findings of particular interest include the following: 1. We previously found that five different antidepressant treatments shared the property of decreasing norepinephrine (NE) turnover; we add to that a similar finding after bupropion in patients of particular interest since: 2. Non-response after the atypical new putative antidepressant bupropion is associated with elevated plasma homovanillic acid, the major dopamine (DA) metabolite, and induction of transient psychosis. These findings support the hypothesis that increased efficiency of the NE distinct from the DA system is a prerequisite for antidepressant effect. Moreover, they support the association of excess stimulation of DA with psychosis. 3. ECT tratment appears to normalize the exaggerated plasma NE response to an orthostatic challenge seen in depressed patients as well as decreasing NE turnover. 4. A rat model for studying neuroendocrine response in man has been developed and implicates interactions of serotonin and DA in prolactin increases after drugs.