Pharmacogenetics of antidepressant response: A polygenic approach.
Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.



Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).



No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.



We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Judit
J
García-González
College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.
Katherine E
KE
Tansey
Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Joanna
J
Hauser
Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia.
Neven
N
Henigsberg
Department of Psychiatry, University of Bonn, Bonn, Germany.
Wolfgang
W
Maier
Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
Ole
O
Mors
Biological Psychiatry Unit and Dual Diagnosis Ward, Istituto Di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
Anna
A
Placentino
Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
Marcella
M
Rietschel
Laboratoire de Psychologie Médicale, Université Libre de Bruxelles and Psy Pluriel-Centre Européen de Psychologie Médicale, Brussels, Belgium.
Daniel
D
Souery
Institute of Public Health of the Republic of Slovenia, Ljubljana, Slovenia.
Tina
T
Žagar
Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poland.
Piotr M
PM
Czerski
Institute of Public Health of the Republic of Slovenia, Ljubljana, Slovenia; Department of Molecular and Biomedical Sciences, Jozef Stefan Institute, Ljubljana, Slovenia.
Borut
B
Jerman
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark.
Henriette N
HN
Buttenschøn
Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
Thomas G
TG
Schulze
Department of Psychiatry, University of Bonn, Bonn, Germany.
Astrid
A
Zobel
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Anne
A
Farmer
Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.
Katherine J
KJ
Aitchison
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Ian
I
Craig
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Peter
P
McGuffin
Department of Genetic Medicine and Laboratories, University Hospitals of Geneva, Geneva, Switzerland.
Michel
M
Giupponi
Department of Psychiatry, University of Geneva, Geneva, Switzerland.
Nader
N
Perroud
Center of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Medicines Research Centre, Verona, Italy.
Guido
G
Bondolfi
Medical Research Council CAiTE Centre, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
David
D
Evans
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Michael
M
O'Donovan
School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
Tim J
TJ
Peters
Pharma Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland.
Jens R
JR
Wendland
Division of Psychiatry, University College London, London, UK.
Glyn
G
Lewis
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Shitij
S
Kapur
Department of Psychiatry, Center for Experimental Drugs and Diagnostics, Massachusetts General Hospital, Boston, USA.
Roy
R
Perlis
Department of Psychiatry, University of Münster, Münster, Germany.
Volker
V
Arolt
Department of Psychiatry Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
Katharina
K
Domschke
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Gerome
G
Breen
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Charles
C
Curtis
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Lee
L
Sang-Hyuk
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Carol
C
Kan
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Stephen
S
Newhouse
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Hamel
H
Patel
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia.
Bernhard T
BT
Baune
Department of Psychiatry, Dalhousie University, Halifax, Canada.
Rudolf
R
Uher
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom. Electronic address: Cathryn.lewis@kcl.ac.uk.
Cathryn M
CM
Lewis
Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Chiara
C
Fabbri
D000928:Antidepressive Agents / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D010597:Pharmacogenetics; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics
D000928:Antidepressive Agents
Antidepressant; Major depressive disorder; Pharmacogenomics; Polygenic risk scores; Schizophrenia