A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression.
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.
Ising
Marcus
M
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).
Lucae
Susanne
S
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).
Binder
Elisabeth B
EB
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).
Bettecken
Thomas
T
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).
Uhr
Manfred
M
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).
Ripke
Stephan
S
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).
Kohli
Martin A
MA
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).
Hennings
Johannes M
JM
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).
Horstmann
Sonja
S
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).
Kloiber
Stefan
S
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).
Menke
Andreas
A
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).
Bondy
Brigitta
B
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).
Rupprecht
Rainer
R
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).
Domschke
Katharina
K
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).
Baune
Bernhard T
BT
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).
Arolt
Volker
V
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).
Rush
A John
AJ
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).
Holsboer
Florian
F
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).
Müller-Myhsok
Bertram
B
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).
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
D000928:Antidepressive Agents; D005819:Genetic Markers