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| PMID |
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| TITLE |
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| Genome-wide meta-analyses of non-response to antidepressants provide insights into underlying molecular genetics and suggest potential pharmacotherapies. |
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| ABSTRACT |
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| Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants (25,255 non-responders and 110,216 responders). We performed genome-wide association meta-analyses, genetic correlation analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified one novel locus (rs1106260) associated with non-response to selective serotonin reuptake inhibitors (SSRIs), and one novel locus (rs60847828) associated with non-response to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) and showed significant polygenic prediction in independent samples. Genetic correlation analyses show positive associations between non-response to antidepressants and most psychiatric traits, and negative associations with cognitive traits and subjective well-being. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants. |
| © 2025. The Author(s), under exclusive licence to Springer Nature Limited. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2024/11/08 |
| accepted |
2025/11/06 |
| revised |
2025/10/06 |
| medline |
2025/11/20 00:30 |
| pubmed |
2025/11/20 00:30 |
| entrez |
2025/11/19 23:15 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Koch E |
|
Koch |
Elise |
E |
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Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. e.m.koch@medisin.uio.no. |
| Puusepp T |
|
Puusepp |
Tuuli |
T |
|
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. |
| Einarsson G |
|
Einarsson |
Guðmundur |
G |
|
deCODE Genetics/Amgen, Reykjavík, Iceland. |
| Mitchell BL |
|
Mitchell |
Brittany L |
BL |
|
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. |
| Harder A |
|
Harder |
Arvid |
A |
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Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden. |
| Lin Y |
|
Lin |
Yuhao |
Y |
|
Institute of Psychiatry, Psychology & Neuroscience; Social, Genetic & Developmental Psychiatry Centre; King's College London, London, UK. |
| García-Marín LM |
|
García-Marín |
Luis M |
LM |
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School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. |
| Krebs K |
|
Krebs |
Kristi |
K |
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Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. |
| Shadrin AA |
|
Shadrin |
Alexey A |
AA |
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KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway. |
| Xiong Y |
|
Xiong |
Ying |
Y |
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Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden. |
|
Estonian Biobank Research Team |
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| Frei O |
|
Frei |
Oleksandr |
O |
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Center for Bioinformatics, Department of Informatics, University of Oslo, 0316, Oslo, Norway. |
| Lu Y |
|
Lu |
Yi |
Y |
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Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden. |
| Hägg S |
|
Hägg |
Sara |
S |
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Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden. |
| Rentería ME |
|
Rentería |
Miguel E |
ME |
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Brain & Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Medland SE |
|
Medland |
Sarah E |
SE |
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Brain & Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Wray NR |
|
Wray |
Naomi R |
NR |
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Department of Psychiatry, The University of Oxford, Oxford, UK. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
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Brain & Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Hübel C |
|
Hübel |
Christopher |
C |
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National Centre for Register-based Research, Aarhus Business and Social Sciences, Aarhus University, Aarhus, Denmark. |
| Breen G |
|
Breen |
Gerome |
G |
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Institute of Psychiatry, Psychology & Neuroscience; Social, Genetic & Developmental Psychiatry Centre; King's College London, London, UK. |
| Thorgeirsson T |
|
Thorgeirsson |
Thorgeir |
T |
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deCODE Genetics/Amgen, Reykjavík, Iceland. |
| Stefánsson H |
|
Stefánsson |
Hreinn |
H |
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deCODE Genetics/Amgen, Reykjavík, Iceland. |
| Stefánsson K |
|
Stefánsson |
Kári |
K |
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Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. |
| Lehto K |
|
Lehto |
Kelli |
K |
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Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. |
| Milani L |
|
Milani |
Lili |
L |
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Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. |
| Andreassen OA |
|
Andreassen |
Ole A |
OA |
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KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway. ole.andreassen@medisin.uio.no. |
| O'Connell KS |
|
O'Connell |
Kevin S |
KS |
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Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. k.s.oconnell@medisin.uio.no. |
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| INVESTIGATORS |
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| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Metspalu |
Andres |
A |
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| Esko |
Tõnu |
T |
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| Mägi |
Reedik |
R |
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| Nelis |
Mari |
M |
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| Hudjashov |
Georgi |
G |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: Molecular psychiatry |
| ISOABBREVIATION: Mol Psychiatry |
| YEAR: 2025 |
| MONTH: Nov |
| DAY: 19 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1476-5578 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Mol Psychiatry |
| COUNTRY: England |
| ISSNLINKING: 1359-4184 |
| NLMUNIQUEID: 9607835 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
| UpdateOf |
Res Sq. 2024 Dec 23:rs.3.rs-5418279. doi: 10.21203/rs.3.rs-5418279/v1. |
39764137 |
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| GRANTS |
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| GRANTID |
AGENCY |
COUNTRY |
| 2021-02615_VR |
Vetenskapsrådet (Swedish Research Council) |
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| 2021-02732 |
Vetenskapsrådet (Swedish Research Council) |
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| 964874 |
EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020) |
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| 296030 |
Norges Forskningsråd (Research Council of Norway) |
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| 223273 |
Norges Forskningsråd (Research Council of Norway) |
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