It has been reported that low pretreatment cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels may correlate with better clinical response to selective serotonin reuptake inhibitors (SSRI) compared to non-serotonergic antidepressant drugs. We examined the hypothesis that serotonergic system status, as measured by the prolactin (PRL) response to fenfluramine (FEN), may predict outcome in a heterogenous sample treated with various types of antidepressant treatment. Higher PRL response predicted a favorable outcome for males and females treated with either pharmacotherapy, psychotherapy [milieu therapy with or without cognitive behavior therapy (CBT)], or electroconvulsive therapy (ECT). All patients in the high PRL response group responded to antidepressant therapies. Patients receiving ECT had the highest proportion of treatment responders, the highest degree of treatment response, and, unlike drug or psychotherapy treatment, improved significantly whether in the high or low PRL response group. PRL response to a single dose fenfluramine challenge may be a useful predictor of response to pharmacological or psychotherapeutic treatments in major depression. By contrast, ECT is an effective short-term treatment independent of pretreatment serotonergic responsivity.