title: Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment.
abstract: Depressive disorders account for a large and increasing global burden of disease. Although the condition of many patients improves with medication, only a minority experience full remission, and patients whose condition responds to one medication may not have a response to others. Individual variation in antidepressant treatment outcome is, at present, unpredictable but may have a partial genetic basis. We searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives for Depression (STAR*D) study and were prospectively assessed. In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. We detected significant and reproducible association between treatment outcome and a marker in HTR2A (P range 1 x 10(-6) to 3.7 x 10(-5) in the total sample). Other markers in HTR2A also showed evidence of association with treatment outcome in the total sample. HTR2A encodes the serotonin 2A receptor, which is downregulated by citalopram. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele. The A allele was over six times more frequent in white than in black participants, and treatment was less effective among black participants. The A allele may contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.
authors.affiliation: Genetic Basis of Mood and Anxiety Disorders, Department of Health and Human Services (DHHS), Bethesda. Electronic address: mcmahonf@intra.nimh.nih.gov.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
authors.affiliation: Genetic Basis of Mood and Anxiety Disorders, Department of Health and Human Services (DHHS), Bethesda.
authors.forename: Silvia
authors.initials: S
authors.lastname: Buervenich
authors.affiliation: Departments of Psychiatry, Neuroscience, and Pharmacology & Biological Chemistry, Mount Sinai School of Medicine, New York.
authors.forename: Dennis
authors.initials: D
authors.lastname: Charney
authors.affiliation: Section of Molecular Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, DHHS, Rockville, MD.
authors.forename: Robert
authors.initials: R
authors.lastname: Lipsky
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
authors.forename: A John
authors.initials: AJ
authors.lastname: Rush
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, NIH, DHHS, Baltimore.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, NIH, DHHS, Baltimore.
authors.forename: Alexa J M
authors.initials: AJM
authors.lastname: Sorant
authors.affiliation: Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, NIH, DHHS, Baltimore.
authors.forename: George J
authors.initials: GJ
authors.lastname: Papanicolaou
authors.affiliation: Genetic Basis of Mood and Anxiety Disorders, Department of Health and Human Services (DHHS), Bethesda.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Laje
authors.affiliation: Massachusetts General Hospital, Boston.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Madhukar H
authors.initials: MH
authors.lastname: Trivedi
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wisniewski
authors.affiliation: Laboratory of Molecular Pathophysiology, Mood and Anxiety Program, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda.
authors.forename: Husseini
authors.initials: H
authors.lastname: Manji
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D044402:Receptor, Serotonin, 5-HT2A; D015283:Citalopram