title: Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies.
abstract: OBJECTIVE
  Indirect evidence suggests that common genetic variation contributes to individual differences in antidepressant efficacy among individuals with major depressive disorder, but previous studies may have been underpowered to detect these effects.
  
  
  METHODS
  A meta-analysis was performed on data from three genome-wide pharmacogenetic studies (the Genome-Based Therapeutic Drugs for Depression [GENDEP] project, the Munich Antidepressant Response Signature [MARS] project, and the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study), which included 2,256 individuals of Northern European descent with major depressive disorder, and antidepressant treatment outcomes were prospectively collected. After imputation, 1.2 million single-nucleotide polymorphisms were tested, capturing common variation for association with symptomatic improvement and remission after up to 12 weeks of antidepressant treatment.
  
  
  RESULTS
  No individual association met a genome-wide threshold for statistical significance in the primary analyses. A polygenic score derived from a meta-analysis of GENDEP and MARS participants accounted for up to approximately 1.2% of the variance in outcomes in STAR*D, suggesting a weakly concordant signal distributed over many polymorphisms. An analysis restricted to 1,354 individuals treated with citalopram (STAR*D) or escitalopram (GENDEP) identified an intergenic region on chromosome 5 associated with early improvement after 2 weeks of treatment.
  
  
  CONCLUSIONS
  Despite increased statistical power accorded by meta-analysis, the authors identified no reliable predictors of antidepressant treatment outcome, although they did identify modest, direct evidence that common genetic variation contributes to individual differences in antidepressant response.
authors: Rudolf.Uher@kcl.ac.uk
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000493:pharmacokinetics; D002895:Chromosomes, Human, Pair 5; D015283:Citalopram / Q000008:administration & dosage / Q000493:pharmacokinetics; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram
references: JAMA. 2010 Jan 6;303(1):47-53
references: 20051569
references: Biol Psychiatry. 1994 Oct 1;36(7):467-71
references: 7811843
references: J Neural Transm Gen Sect. 1992;88(2):157-60
references: 1632943
references: Nat Genet. 2011 Mar;43(3):246-52
references: 21297633
references: Arch Gen Psychiatry. 1981 Jan;38(1):98-103
references: 7458574
references: Clin Pharmacol Ther. 2010 Nov;88(5):634-42
references: 20861834
references: Biol Psychiatry. 2006 Mar 15;59(6):493-501
references: 16199008
references: J Clin Psychiatry. 2011 Feb;72(2):156-67
references: 21034686
references: Bioinformatics. 2010 Sep 1;26(17):2190-1
references: 20616382
references: Nature. 2009 Aug 6;460(7256):748-52
references: 19571811
references: Stat Med. 2006 Jan 15;25(1):127-41
references: 16217841
references: Am J Psychiatry. 2006 Nov;163(11):1905-17
references: 17074942
references: Biol Psychiatry. 2010 Sep 15;68(6):e25-7
references: 20619826
references: J Psychiatr Res. 1998 Sep-Oct;32(5):255-9
references: 9789202
references: Arch Gen Psychiatry. 2009 Sep;66(9):966-975
references: 19736353
references: Genet Epidemiol. 2010 Jan;34(1):60-6
references: 19847795
references: J Cardiovasc Transl Res. 2010 Jun;3(3):173-82
references: 20560037
references: Mol Psychiatry. 2011 Nov;16(11):1076-87
references: 21709685
references: Psychol Med. 2012 May;42(5):967-80
references: 21929846
references: Schizophr Res. 2009 Jan;107(1):13-21
references: 18930379
references: Arch Gen Psychiatry. 2008 Aug;65(8):870-80
references: 18678792
references: Control Clin Trials. 2004 Feb;25(1):119-42
references: 15061154
references: Genet Epidemiol. 2008 Apr;32(3):227-34
references: 18300295
references: Psychol Med. 2010 Aug;40(8):1367-77
references: 19863842
references: Psychol Med. 2008 Feb;38(2):289-300
references: 17922940
references: Br J Psychiatry. 1982 Jul;141:45-9
references: 7116071
references: Int J Neuropsychopharmacol. 2011 Apr;14(3):405-12
references: 20800012
references: JAMA. 2002 Apr 10;287(14):1840-7
references: 11939870
references: Biol Psychiatry. 2010 Jan 15;67(2):133-8
references: 19846067
references: Am J Hum Genet. 2009 Feb;84(2):210-23
references: 19200528
references: J Psychiatr Res. 2009 Jan;43(3):215-29
references: 18586274
references: Am J Psychiatry. 2006 Jan;163(1):28-40
references: 16390886
references: Neuropsychopharmacology. 2006 Nov;31(11):2433-42
references: 16554742
references: Stat Med. 2009 Nov 30;28(27):3363-85
references: 19731223
references: Arzneimittelforschung. 1964 Jun;14:SUPPL:496-500
references: 14253947
references: Am J Psychiatry. 2010 May;167(5):555-64
references: 20360315
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Psychopharmacology (Berl). 2005 Dec;183(2):257-64
references: 16220334
references: Arch Gen Psychiatry. 1991 Sep;48(9):796-800
references: 1929769
references: Br J Psychiatry. 2009 Mar;194(3):252-9
references: 19252156
references: J Am Coll Cardiol. 2009 Oct 20;54(17):1609-16
references: 19833260
references: J Biopharm Stat. 1998 May;8(2):337-52
references: 9598427
references: Pharmacogenomics. 2012 Jan;13(2):233-40
references: 22256872
references: J Mol Med (Berl). 2007 Jul;85(7):777-82
references: 17476472
references: Nat Genet. 2008 Sep;40(9):1056-8
references: 18711365