Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: Implications for the role of serotonin in the mechanism of antidepressant action

Background: Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). Ne hale previously reported th at rapid TRP depletion more frequently reversed the antidepressant response to monoamine oxidase inhibitors and 5-HT I reuptake inhibitors than to des ipramine (DMI), This study further investigates the relationship of relapse during TRP depletion to antidepressant type in nonrefractory, depressed pa tients randomly assigned to treatment with either DMI or fluoxetine (FLU). Methods: Fifty-five drug-free depressed (DSM-III-R) patients were randomly assigned to antidepressant treatment with either DMI or FLU. All patients,w ere either treatment naive (n = 34) or had previously received successful a ntidepressant treatment (n = 21), During the treatment phase, 35 patients h ad therapeutic responses by predetermined criteria (DMI 18/25; FLU 17/23) a nd 30 of these (15 DMI responders and 15 FLU responders) went ent on to TRP depletion resting. Patients received two 2-day test sessions involving adm inistration of similar amino acid drinks. One session led to rapid TRP depl etion and the other did not. Behavioral ratings [Hamilton Depression Scale (HDRS)] and plasma for TRP levels were obtained prior to, during, and after testing. Relapse,was defined as a 50% increase ill HDRS with total less th an or equal to 17 Results: Total and free TRP decreased 70% to 80% 5 hours after the TRP-free drink. While 8/15 FLU responders relapsed, only, 1/15 of the DMI responders relapsed No patient experienced significant depressive symptoms during control testing, Conclusions: Rapid depletion of plasma TRP transiently reverses the antidepressant response in many patients on FLU b ut not DMI. Depressive relapse during;TRP depletion appears to be more rela ted to antidepressant type than to patient variables since patients were ra ndomly assigned to the two treatments, Antidepressant response to FLU appea rs to be more dependent on 5-HT availability than that of DMI, suggesting t hat antidepressants mediate their therapeutic effects through different mec hanisms. (C) 1999 Society of Biological Psychiatry.