Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls.

Context Tryptophan depletion (TD) is a model used to study the contribution of reduced serotonin transmission to the pathogenesis of major depressive disorder (MDD). Recent studies have not sufficiently addressed the relative contribution of a functional-length triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, to the behavioral and neural responses to TD in individuals with remitted MDD (rMDD) and controls. Objective To determine the role of 5-HTTLPR on the behavioral and neural responses to TD in medication-free patients with rMDD and individually matched controls. Design Participants were stratified according to diagnosis and 5-HTTLPR genotypes and underwent TD on one test day and sham depletion on the other test day in a prospective, double-blind, randomized order. Setting Outpatient clinic. Participants Twenty-seven medication-free patients with rMDD (18 women and 9 men) and 26 controls (17 women and 9 men). Interventions Tryptophan depletion was induced by administration of capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing lactose. Fludeoxyglucose F 18 positron emission tomography was performed 6 hours after TD. Magnetic resonance images were obtained for each participant. Main Outcome Measures Quantitative positron emission tomography of regional cerebral metabolic rates for glucose and measures of depression using the Hamilton Depression Rating Scale. Results Behavioral responses to TD are affected by 5-HTTLPR in patients with rMDD and controls. A direct effect of 5-HTTLPR on the regulation of regional cerebral metabolic rates for glucose was identified in patients with rMDD for the amygdala, hippocampus, and subgenual anterior cingulate cortex. Conclusions Variations in 5-HTTLPR modulate the sensitivity of patients with rMDD and controls to the behavioral effects of TD. In patients with rMDD, variations in triallelic 5-HTTLPR have a direct effect on regulation of regional cerebral metabolic rates for glucose in a corticolimbic circuit that has been implicated in rMDD.