Elsevier

Biological Psychiatry

Volume 46, Issue 4, 15 August 1999, Pages 498-505
Biological Psychiatry

Original Articles
Tryptophan depletion and depressive vulnerability

https://doi.org/10.1016/S0006-3223(99)00095-5Get rights and content

Abstract

Background: Rapid and transient depletion of tryptophan (TRP) causes a brief depressive relapse in most patients successfully treated with and taking selective serotonin reuptake inhibitors, but little change in drug-free, symptomatic depressed patients. This study investigates the effects of TRP depletion in drug-free subjects in clinical remission from a prior major depressive episode (MDE).

Methods: Twelve subjects with a prior MDE, currently in clinical remission and drug-free for at least 3 months (patients), and 12 healthy subjects without personal or family history of Axis I disorder (controls), received TRP depletion. The study was conducted in a double-blind, controlled [full (102-g) and quarter-strength (25 g) 15-amino acid drinks], crossover fashion. Behavioral ratings and plasma TRP levels were obtained prior to, during, and after testing.

Results: All subjects experienced significant depletion of plasma TRP on both test-drinks, showing a significant dose–response relation. Healthy control subjects had minimal mood changes, but patients had a depressive response of greater magnitude.

Conclusions: In the context of prior TRP depletion studies with antidepressant-treated, and drug-free symptomatic depressed patients, these results suggest that depression may be caused not by an abnormality of 5-HT function, but by dysfunction of other systems or brain regions modulated by 5-HT.

Introduction

Alarge body of experimental data supports a central role for enhanced serotonin (5-HT) neurotransmission in the therapeutic mechanism of action of some antidepressant drugs (Blier et al 1990), although the primary role of diminished 5-HT neurotransmission in the pathophysiology of depression is less clear Delgado et al 1994a, Murphy et al 1978. Some of the most provocative data in this regard come from studies utilizing the tryptophan (TRP) depletion paradigm Delgado et al 1990, Ellenbogen et al 1996, Delgado et al 1991, Delgado et al 1994a. Plasma TRP levels are dependent on dietary intake of TRP (Rose et al 1954), and brain 5-HT levels are, in turn, dependent on plasma levels of TRP Curzon 1979, Curzon 1981, Fernstrom 1977, Moja et al 1989. A rapid but transient depletion of 80% to 90% of TRP plasma levels can be accomplished in less than 5 hours by oral administration of a 15-amino acid, TRP-free drink (Young et al 1989). This drink induces hepatic protein synthesis and causes rapid depletion of plasma TRP in the anabolic process (Moja et al 1991), which causes a significant decrease in the rate of 5-HT synthesis (Nishizawa et al 1997). A drink proportionally identical in composition to that used in humans attenuates the release of 5-HT by about 50% in the frontal cortexes of rats treated with fluvoxamine for 2 weeks (Bell and Artigas et al 1996).

TRP depletion causes a rapid but transient relapse of clinical depression in 50% to 70% of recently remitted depressed patients treated with selective 5-HT reuptake inhibitors (SSRIs), but in only 20% of those treated with the norepinephrine reuptake inhibitor desipramine (Delgado et al 1998). Similarly, TRP depletion transiently reverses the antidepressant effect of a standard course of bright light therapy in 80% of patients with seasonal affective disorder (Lam et al 1996).

Benkelfat and co-workers (1994) found that TRP depletion induced mild depressive symptoms in 30% of young male subjects with family histories of mood disorder but did not affect healthy male control subjects without personal or family histories of mood disorder. The authors suggest that the mood response to TRP depletion might be a marker for genetic vulnerability for major affective disorders. If this is true, then TRP depletion could be used to identify these individuals before they become ill, ensuring early intervention, decreasing suffering, minimizing social and occupational dysfunction, and lowering health care expenditures (Wells et al 1989).

If a depressive response to TRP depletion is primarily seen in those individuals at risk for depression, then TRP depletion should lead to clinically meaningful depressive symptoms in clinically remitted subjects with an established past history of a major depressive episode (history-positive subjects). The present study was designed to test this hypothesis by comparing the mood response to TRP depletion of 12 history-positive subjects with that of 12 age- and gender-matched control subjects with no personal or family history of mental disorders.

Section snippets

Subjects

Twenty-eight subjects were recruited through local newspaper advertisements and word of mouth, and they provided written informed consent to participate in this study. Twenty-four subjects completed the entire protocol; 4 dropped out prior to completion. One history-positive subject was discontinued for using prescription opiates prior to testing. Another history-positive subject and 1 control subject discontinued the study due to nausea and vomiting during the first TRP depletion test. The

Demographic characteristics

The clinical characteristics of history-positive subjects and relevant demographic characteristics of control subjects are listed in Table 1. While the two groups differ in clinical history relevant to a prior MDE, there are no significant differences in age or gender distribution.

Somatic effects

The amino acid drinks and capsules were generally well tolerated. No serious adverse effects were reported. Based on the symptom checklist scores, the most common side effects of the amino acid drink were nausea (80%)

Discussion

TRP depletion caused clinically significant depressive symptoms in history-positive but not in age- and gender-matched control subjects. The differences between the two groups of subjects in mood response to TRP depletion cannot be accounted for by differences in demographic characteristics or TRP levels before or during depletion, but appear to be related to the presence of a past history of depression. As will be discussed, these findings are most consistent with the hypothesis that mood may

Acknowledgements

Supported by National Institute of Mental Health Grant R01 MH48977 to Dr. Delgado, and by National Research Service Award 5 T32 MH19126-07 to Dr. Moreno.

Portions of these data have been presented in abstract from at the following meetings: 148th and 149th Annual Meeting of the American Psychiatric Association, New Research Abstract #97, May 1995, and Abstract #346, May 1996. 25th Annual Meeting of the Society for Neuroscience, Abstract #81.17, November 1995. 34th Annual Meeting of the American

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