This project builds on the investigator's previous work on serotonergic differences between depressed patients who are antidepressant responders vs. those not responding. This study proposes to extend data from the PI's laboratory to date suggesting that chronic, but not acute, 5-HTlA partial agonist administration may have antidepressant effects and desensitize human 5-HT1A receptor-stimulated responses in depressed patients. This proposal seeks to test the hypothesis that standard antidepressant treatment is associated with 5-HT1A receptor-mediated adaptations which will be discriminative of a treatment response to nortriptyline. The project utilizes a standard nortriptyline treatment protocol designed by the investigator to test for biological differences between antidepressant responders vs. antidepressant nonresponders. The nortriptyline treatment design has been used successfully to date to test response groups at different time points during treatment, yielding different response cohorts sufficient to test for biological differences between groups. The present study builds on the investigator's IND# to utilize the 5-HT1A agonist properties of ipsapirone in a challenge paradigm designed to test the ACTH, cortisol, and hypothermic responses of 5-HTlA pre- and postsynaptic receptor subtypes, in a new approach designed to explore the possibility that a 5-HTlA receptor adaptation may underlie a component of the response mechanism to standard antidepressant treatment. lpsapirone and placebo challenges are done at baseline, with repeat challenges performed during acute and chronic treatment, using a fixed dose nortriptyline treatment paradigm designed to yield approximately equal sized groups of responding vs. nonresponding patients in which the differences in 5-HT1A receptor adaptations can be tested.
