Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion

Abstract

This study investigated the relationship between depressive symptom response during tryptophan (TRP) depletion and a functional polymorphism of the promoter region of the serotonin (5-HT) transporter gene (SLC6A4). 1 Forty-three subjects in remission from a major depressive episode who underwent TRP depletion were genotyped. DNA was extracted from blood lymphocytes or from cheek cells. 2 The two common alleles are designated long (l) and short (s). Depressive symptoms were measured with the 25-item Hamilton Depression Rating Scale (HDRS). 3 There was a significant association between the l homozygous genotype and the depressive response to TRP depletion, with a significant main effect of time (F = 8.763, df = 3, 38, P = Ͻ0.001), and time × l homozygous allele interaction (F = 3.676, df = 3, 38, P = 0.02). Individuals whose genotype predicted increased 5-HT transporter activity may be more susceptible to depressive changes in response to transient 5-HT perturbations. The use of endophenotypic markers for affective disorders such as the mood response to TRP depletion may facilitate studies of complex genetic traits such as depression by decreasing its heterogeneity. Molecular Psychiatry ( Although the TRP-free amino acid drink utilized in this project rapidly and consistently depletes plasma levels of this 5-HT precursor, 4,5 reduces 5-HT synthesis, 6,7 and lowers cerebrospinal fluid levels of the 5-HT metabolite 5HIAA, 8,9 the behavioral responses observed in subjects with similar clinical and treatment history vary dramatically. Delgado et al 10 reported that individuals recently achieving remission from major depression during treatment with a serotonin reuptake inhibitor experienced a transient return of depressive symptoms, but not all subjects experienced a similarly dramatic response. Others have replicated these findings, also noticing differing rates of mood response. 11,12 Benkelfat et al 13 and Klaassen et al 14 showed that healthy subjects with a family history of affective disorders were more likely than healthy controls to experience mood changes in response to TRP depletion. Although the effect for group was statistically significant, the degree of mood response within each group was also varied. Smith et al 15 and Moreno et al 5 reported that medication-free remitted depressed patients also experience transient depressive changes in response to TRP depletion. In these studies, the response was also varied with about two thirds of the subjects accounting for most of the mood changes observed. Furthermore, Leyton et al, 16 while studying a similar population, reported that only a small portion of their subjects experienced mood response during TRP depletion. An important and unanswered question remains: What determines which subjects will experience a mood response to TRP depletion and which ones will not?A number of potential explanations have been proposed including the possibility that individuals having depressive mood responses to TRP depletion are doing so because their brain 5-HT has depleted ...

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

“…In addition to not having many clinical relapse predictors, our subjects may not be genetically predisposed to a depressive response after tryptophan depletion. A recent study by Moreno et al (2002) showed an association between a particular genotype in the promoter region of the serotonin trans- Figure 2. Mean free plasma tryptophan levels at 2:30 P.M., 10:30 P.M., and 7 A.M. on the control and experimental days (values given are means Ϯ SEM, n ϭ 8) with a significant interaction effect between the factors of day and time (F 2,14 ϭ 19.32, p ϭ .00009) porter gene and a depressive response to tryptophan depletion.…”

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

“…These mice show reduced 5-HT tissue concentrations and increased extracellular concentrations of 5-HT in the striatum and probably other structures (for review see Murphy et al 51 ). The l-allele of the 5-HTTLPR polymorphism is associated with better SSRI antidepressive effects than the s-allele 49,52,53 and with faster response to several SSRI's. 54,55 Combined treatment with a 5-HT 1A blocker to prevent negative feedback at the somatodendritic level compensated for the worse antidepressant effect of SSRIs in s/s and s/l genotypes, 56 suggesting higher 5-HT 1A negative feedback in s-allele genotypes.…”

“…Some studies reported no association, 39,43,44 others found an association between the s-allele and depression, 26,[45][46][47][48] while others conclude that the l-allele is associated with depression. 49 However, most evidence seems to suggest an association between the s-allele of 5-HTTLPR and depression. The lower 5-HT uptake activity caused by the s-allele may result in increased levels of 5-HT in the vicinity of the 5-HTergic cell bodies and dendrites in the raphe complex.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…Among individuals with a history of depression, the ll phenotype is consistently associated with more severe mood deterioration during tryptophan depletion. 89,90 On the other hand, among individuals without personal history of depression, the effect of TD is smaller, includes changes in anxiety, punishment sensitivity and motivation rather than mood and is more pronounced among ss homozygotes. [91][92][93][94] Neumeister and colleagues 90 proposed a model explaining this apparent interaction of 5-HTTLPR with personal history of depression by differential activity of pre-and postsynaptic 5-HT1A and 5-HT1B receptors.…”