Clinical and Physiological Consequences of Rapid Tryptophan Depletion

Abstract

We review here the rapid tryptophan depletion (RTD) methodology and its controversial association with depressive relapse. RTD has been used over the past decade to deplete serotonin (5-hydroxy-tryptamine, or 5-HT) in humans and to probe the role of the central serotonin system in a variety of psychiatric conditions. Its current popularity was stimulated by reports that RTD reversed the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) KEY WORDS : 5-HT; Serotonin; Tryptophan-free drink; Major depressionSerotonin (5-hydroxy-tryptamine, or 5-HT) is involved in many physiologic and behavioral systems and clinical disease states. Much of the information available on the function of serotonin comes from pharmacological agents which mimic or amplify endogenous serotonergic neurotransmission, such as serotonin agonists or SSRIs. Historically, methods to functionally deplete serotonin have been problematic. Even previous approaches that have been moderately successful in experimental animals -such as the 5-HT synthesis inhibitor, parachloro-phenylalanine (PCPA); the neurotoxin 5-6-dihydroxy-tryptamine; or various lesions to the serotonergic raphe nuclei of the brainstem -have been non-specific, rife with secondary effects, or clearly inapplicable to humans (e.g., Engelman et al. 1967;Koella et al. 1968;Jouvet et al. 1967). The advent of rapid tryptophan depletion (RTD) as a method to deplete central serotonin has been met with enthusiasm because of its reversibil- NO . 6 ity, its relative lack of side effects, and its merit in elucidating the pathophysiology of various psychiatric conditions. This paper reviews the RTD methodology and its reported ability to induce a depressive relapse in euthymic patients, and other physiological and clinical effects. RAPID TRYPTOPHAN DEPLETION Availability of Tryptophan and Serotonin SynthesisRTD is based on the current understanding of the 5-HT biosynthetic pathway, in which the first step is generally considered to be the rate-limiting one. The first step entails the hydroxylation of the amino acid TRP (by the enzyme TRP hydroxylase, or TRP-H) into the intermediate product 5-hydroxy-tryptophan, or 5-HTP. 5-HTP is then decarboxylated into 5-HT. Under normal conditions, TRP-H is about 50% saturated with TRP. Increasing or decreasing the availability of TRP correlates highly with the amount of 5-HT produced (e.g., Lin et al. 1969;Schaechter and Wurtman 1990). Because the body cannot synthesize TRP, reducing dietary intake of TRP reduces TRP levels in plasma and diminishes its transport from plasma into the brain.In humans, TRP depletion is accomplished by consuming a TRP-free amino acid drink (e.g., Delgado et al. 1990;Biggio et al. 1974). This drink contains 15 amino acids in the same proportion as in human milk, except that TRP, aspartic acid, and glutamic acid are omitted (see Table 1). Within a matter of hours (4 to 12), plasma TRP declines to 10-50% of baseline levels (Delgado et al. 1990(Delgado et al. , 199...

Predictors of Mood Response to Acute Tryptophan Depletion A Reanalysis

“…For instance, although Delgado et al (1990) reported a relapse in 14 of 21 subjects (67%), converting their scores provided in Table 1 to standardized scores, shows that 3 of 21 patients had a full relapse (14%). This suggests that, even in recently remitted patients, a clinical relapse is uncommon (Moore et al 2000). The general image seems to be that ATD causes a complete or near return of depression.…”

Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer

“…Studies in non-cancer patients with depression suggest that rapid tryptophan depletion to roughly 20% of normal plasma levels (Delgado et al, 1990;Smith et al, 1999) can induce a relapse of depression (Moore et al, 2000). Acute tryptophan depletion of a similar magnitude in healthy volunteers has been associated with impairment of long-term memory (Riedel et al, 1999).…”

Effects of Rapid Tryptophan Depletion on Sleep Electroencephalogram and Mood in Subjects with Partially Remitted Depression on Bupropion

“…The Moore et al (1998) study used subjects in full remission with HRSD-17 scores of below 7 for at least two months with a total treatment time of two to 13 months, while the Delgado et al (1990Delgado et al ( , 1999) studies used patients who were only partially remitted with scores of less than 18 on the 25-item HRSD for two weeks with a total treatment time of four to 10 weeks. (Further discussions of discrepancies in TFD studies can be found in Moore et al 1998Moore et al , 2000Moore et al , 2001.) Our current study uses partially remitted patients with two weeks of HRSD-17 scores below 11 and a total of five to 11 weeks of treatment, yet we find no "depressive relapse" in response to tryptophan depletion.…”

“…Rapid depletion of plasma tryptophan levels by administration of a tryptophan-free amino acid drink (TFD) depletes central 5-HT levels (Biggio et al 1974;Moja et al 1988). See Moore et al (2000) for a recent review of the TFD literature.…”