Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment.
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.
McMahon
Francis J
FJ
Genetic Basis of Mood and Anxiety Disorders, Department of Health and Human Services (DHHS), Bethesda. Electronic address: mcmahonf@intra.nimh.nih.gov.
Buervenich
Silvia
S
Genetic Basis of Mood and Anxiety Disorders, Department of Health and Human Services (DHHS), Bethesda.
Charney
Dennis
D
Departments of Psychiatry, Neuroscience, and Pharmacology & Biological Chemistry, Mount Sinai School of Medicine, New York.
Lipsky
Robert
R
Section of Molecular Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, DHHS, Rockville, MD.
Rush
A John
AJ
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
Wilson
Alexander F
AF
Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, NIH, DHHS, Baltimore.
Sorant
Alexa J M
AJM
Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, NIH, DHHS, Baltimore.
Papanicolaou
George J
GJ
Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, NIH, DHHS, Baltimore.
Laje
Gonzalo
G
Genetic Basis of Mood and Anxiety Disorders, Department of Health and Human Services (DHHS), Bethesda.
Fava
Maurizio
M
Massachusetts General Hospital, Boston.
Trivedi
Madhukar H
MH
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
Wisniewski
Stephen R
SR
Department of Epidemiology, University of Pittsburgh, Pittsburgh.
Manji
Husseini
H
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.
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
D000928:Antidepressive Agents; D044402:Receptor, Serotonin, 5-HT2A; D015283:Citalopram