Tryptophan-Depletion Challenge in Depressed Patients Treated with Desipramine or Fluoxetine: Implications for the Role of Serotonin in the Mechanism of Antidepressant Action Pedro L. Delgado, Helen L. Miller, Ronald M. Salomon, Julio Licinio, John H. Krystal, Francisco A. Moreno, George R. Heninger, and Dennis S. Charney Background: Brain serotonin (5-HT) content is depen- dent on plasma levels of the essential amino acid, trypto- phan (TRP). We have previously reported that rapid TRP depletion more frequently reversed the antidepressant response to monoamine oxidase inhibitors and 5-HT reuptake inhibitors than to desipramine (DMI). This study further investigates the relationship of relapse during TRP depletion to antidepressant type in nonrefractory, de- pressed patients randomly assigned to treatment with either DMI or fluoxetine (FLU). Methods: Fifty-five drug-free depressed (DSM-III-R) pa- tients were randomly assigned to antidepressant treatment with either DMI or FLU. All patients were either treatment naive (n = 34) or had previously received successful antidepressant treatment (n = 21). During the treatment phase, 35 patients had therapeutic responses by predeter- mined criteria (DMI 18/25; FLU 17/23) and 30 of these (15 DMI responders and 15 FLU responders) went on to TRP depletion testing. Patients received two 2-day test sessions involving administration of similar amino acid drinks. One session led to rapid TRP depletion 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 in HDRS with total  17. Results: Total and free TRP decreased 70% to 80% 5 hours after the TRP-free drink. While 8/15 FLU respond- ers 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 but not DMI. Depressive relapse during TRP deple- tion appears to be more related to antidepressant type than to patient variables since patients were randomly assigned to the two treatments. Antidepressant response to FLU appears to be more dependent on 5-HT availability than that of DMI, suggesting that antidepressants mediate their therapeutic effects through different mechanisms. Biol Psychiatry 1999;46:212–220 © 1999 Society of Bio- logical Psychiatry Key Words: Norepinephrine, monoamines, major depres- sion Introduction T hough many of the pharmacologic effects of antide- pressant drugs have been well characterized, the specific properties that underlie their therapeutic effects remain poorly understood. Of the hypotheses that have been proposed concerning the neurochemical systems through which antidepressant medications mediate their therapeutic effects in depression, most support exists for those theories postulating effects on the serotonergic (5-HT) (Coppen 1967; Lapin and Oxenkrug 1969; Murphy et al 1978; Blier and de Montigny 1990) or noradrenergic (NA) systems (Schildkraut 1965; Bunney and Davis 1965; Siever and Davis 1985). These hypotheses generally propose that administration of antidepressant drugs lead to increased neurotransmission through the NA and/or 5-HT systems because of a time-dependent process of neuronal adaptation (Blier and de Montigny 1990). These theories have, for the most part, made the assumption that antide- pressant drugs are acting on the brain systems that are abnormal in depressed patients, and are working to nor- malize their function. Over the past 15 years, many investigators have tried to test these hypotheses in depressed patients by administer- ing drugs that act as either direct or indirect NA or 5-HT agonists (see Delgado and Charney 1991 for review). From the Departments of Psychiatry, West Haven Department of Veterans Affairs Medical Center, Yale University School of Medicine, New Haven, CT (HLM, RMS, JL, JHK, GRH, DSC); and the Department of Psychiatry, University of Arizona College of Medicine, Tucson, AZ (PLD, FAM). Address reprint requests to Pedro L. Delgado, MD, Department of Psychiatry, University of Arizona College of Medicine, 7303 AHSC, 1501 N. Campbell Avenue, Tucson, AZ 85724. Received August 26, 1998; revised January 4, 1999; accepted January 11, 1999. © 1999 Society of Biological Psychiatry 0006-3223/99/$20.00 PII S0006-3223(99)00014-1