Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls.
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.
Neumeister
Alexander
A
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
Hu
Xian-Zhang
XZ
Luckenbaugh
David A
DA
Schwarz
Markus
M
Nugent
Allison C
AC
Bonne
Omer
O
Herscovitch
Peter
P
Goldman
David
D
Drevets
Wayne C
WC
Charney
Dennis S
DS
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
D000596:Amino Acids; D010919:Placebos; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D019788:Fluorodeoxyglucose F18; D012701:Serotonin; D014364:Tryptophan; D005947:Glucose