Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression

Background: Evidence suggests that serotonin transporter gene promoter polymorphism (5HTTLPR)-dependent low transcriptional activity of the human serotonin transporter gene may be a genetic susceptibility factor for depression. We studied the behavioral responses to tryptophan depletion (TD) in healthy women with and without a first-degree family history of depression and examined the relationship to 5HTTLPR alleles. Methods: Twenty-four healthy women with a negative family history of depression and 21 women with a positive family history of depression were genotyped for the polymorphism of the 5HTTLPR and then entered a double-blind, placebo-con trolled, randomized crossover TD study. The effects of these interventions were assessed with measures of depression and plasma tryptophan levels. Results: The TD induced a robust decrease of plasma tryptophan levels in all women irrespective of family history of depression or 5HTTLPR genotypes. The s/s genotype of the 5HTTLPR was associated with an increased risk of developing depressive symptoms during TD irrespective of family history. In contrast, individuals with the l/l genotype did not develop depressive symptoms, irrespective of family history. Finally, s/l subjects without family history showed a mood response that was intermedia e between the s/s and l/l subjects, while s/l subjects with a family history of depression showed the same depressiogenic effect of TD as seen in the s/s subjects. Conclusions: The results of the present study suggest that the s-allele of the 5HTTLPR and a positive family history of depression are additive risk factors for the development of depression during TD.