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Alexander Neumeister, MD; Anastasios Konstantinidis, MD; Juergen Stastny, MD; Markus J. Schwarz, MD; Oliver Vitouch, PhD; Matthaus Willeit, MD; Nicole Praschak-Rieder, MD; Johanna Zach, CTA; Martina de Zwaan, MD; Brigitta Bondy, MD; Manfred Ackenheil, MD; Siegfried Kasper, MD

Arch Gen Psychiatry. 2002;59:613-620.

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-controlled, 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 intermediate 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.

From the National Institute of Mental Health, Mood and Anxiety Disorders Program, Bethesda, Md (Dr Neumeister); Department of General Psychiatry, University of Vienna, Vienna, Austria (Drs Neumeister, Konstantinidis, Stastny, Willeit, Praschak-Rieder, de Zwaan, and Kasper); Department of Neurochemistry, University Hospital of Psychiatry, Munich, Germany (Drs Schwarz, Bondy, and Ackenheil and Ms Zach); and the Max Planck Institute for Human Development, Berlin, Germany (Dr Vitouch).

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