title: Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Outpatient clinic.
  
  
  METHODS
  Twenty-seven medication-free patients with rMDD (18 women and 9 men) and 26 controls (17 women and 9 men).
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Molecular Imaging Program of the Clinical Neuroscience Division, Department of Psychiatry, Yale University School of Medicine, 950 Campbell Avenue, West Haven, CT 06516, USA. alexander.neumeister@yale.edu
authors.forename: Alexander
authors.initials: A
authors.lastname: Neumeister
authors.forename: Xian-Zhang
authors.initials: XZ
authors.lastname: Hu
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: Markus
authors.initials: M
authors.lastname: Schwarz
authors.forename: Allison C
authors.initials: AC
authors.lastname: Nugent
authors.forename: Omer
authors.initials: O
authors.lastname: Bonne
authors.forename: Peter
authors.initials: P
authors.lastname: Herscovitch
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Drevets
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Charney
mesh_terms: D000328:Adult; D000553:Ambulatory Care; D000596:Amino Acids / Q000008:administration & dosage / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D004311:Double-Blind Method; D005260:Female; D019788:Fluorodeoxyglucose F18; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D010919:Placebos; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D012701:Serotonin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology*; D014018:Tissue Distribution; D014364:Tryptophan / Q000097:blood / Q000172:deficiency* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D010919:Placebos; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D019788:Fluorodeoxyglucose F18; D012701:Serotonin; D014364:Tryptophan; D005947:Glucose