title: A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression.
abstract: BACKGROUND
  The efficacy of antidepressant drug treatment in depression is unsatisfactory; 1 in 3 patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome.
  
  
  OBJECTIVE
  To identify genetic and clinical determinants of antidepressant drug treatment outcome in depression.
  
  
  METHODS
  Genomewide pharmacogenetic association study with 2 independent replication samples.
  
  
  METHODS
  We performed a genomewide association study in patients from the Munich Antidepressant Response Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single-nucleotide polymorphisms highly related to outcome in both genomewide association studies was genotyped in a sample of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.
  
  
  METHODS
  A total of 339 inpatients with a depressive episode (MARS sample), a further 361 inpatients with depression (German replication sample), and 832 outpatients with major depression (STAR*D sample).
  
  
  METHODS
  We generated a multilocus genetic variable that described the individual number of alleles of the selected single nucleotide polymorphisms associated with beneficial treatment outcome in the MARS sample ("response" alleles) to evaluate additive genetic effects on antidepressant drug treatment outcome.
  
  
  RESULTS
  Multilocus analysis revealed a significant contribution of a binary variable that categorized patients as carriers of a high vs low number of response alleles in the prediction of antidepressant drug treatment outcome in both samples (MARS and STAR*D). In addition, we observed that patients with a comorbid anxiety disorder combined with a low number of response alleles showed the least favorable outcome.
  
  
  CONCLUSIONS
  These results demonstrate the importance of multiple genetic factors combined with clinical features in the prediction of antidepressant drug treatment outcome, which underscores the multifactorial nature of this trait.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Hennings
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Sonja
authors.initials: S
authors.lastname: Horstmann
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Stefan
authors.initials: S
authors.lastname: Kloiber
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Andreas
authors.initials: A
authors.lastname: Menke
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Brigitta
authors.initials: B
authors.lastname: Bondy
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Rainer
authors.initials: R
authors.lastname: Rupprecht
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: A John
authors.initials: AJ
authors.lastname: Rush
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany (Drs Ising, Lucae, Binder, Bettecken, Uhr, Ripke, Kohli, Hennings, Horstmann, Kloiber, Menke, Holsboer, and Müller-Myhsok), Department of Psychiatry, Ludwig Maximilians University, Munich, Germany (Drs Bondy and Rupprecht), Department of Psychiatry, Westfalian Wilhelms University Muenster, Muenster, Germany (Drs Domschke, Baune, and Arolt), Department of Psychiatry, James Cook University, Townsville, Australia (Dr Baune), Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA, and Department of Clinical Sciences, Duke-NUS, Singapore (Dr Rush).
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002874:Chromosome Mapping; D003866:Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D005838:Genotype; D005858:Germany; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D005819:Genetic Markers