Observations in humans and animals have indicated that chronic, but not acute, antidepressant treatment (ADT) can desensitize 5-HT1A receptor-mediated responses, such as hypothermia. We hypothesized that 5-HT1A desensitization would be necessary for an antidepressant response (ADR) to occur. To test this hypothesis, we examined 5HT1A-agonist ipsapirone (IPS)-induced hypothermia in 28 depressed patients being treated with fixed doses of nortriptyline (75 mg) at 3-day and 3-week treatment points. Decreases in 24-item Hamilton scores (412) were used to dichotomize the response data into ADR groups of 13 responders (ADR + ) and 15 nonresponders (ADRÀ). A two-way repeated measures analysis of variance indicated significant temperature differences in the area under the curve between response groups across time from 3-day to 3-week intervals (df ¼ 1, 26, F ¼ 6.6, po0.02). In comparison to 3 days treatment, at 3 weeks, the ADR + patients showed blunted hypothermic responses to IPS. ADRÀ did not show this effect, implicating ADR + patients to be less responsive to 5HT1A-receptor stimulation after 3 weeks treatment. Similar effects were not found for 5HT1A postsynaptically mediated ACTH and cortisol responses. These results indicate that to achieve ADR, serotonergic neurotransmission needs to be altered as reflected by the change in 5-HT1a receptor responsiveness documented herein.