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. 2025 Feb 26;82(5):505-513.
doi: 10.1001/jamapsychiatry.2024.4825. Online ahead of print.

Genetic Correlates of Treatment-Resistant Depression

Bohan Xu  1   2 , Katherine L Forthman  2 , Rayus Kuplicki  2 , Jonathan Ahern  1   3 , Robert Loughnan  1   3 , Firas Naber  1   2 , Wesley K Thompson  1   2   4 , Charles B Nemeroff  5 , Martin P Paulus  2   6 , Chun Chieh Fan  1   2   7
Affiliations

Genetic Correlates of Treatment-Resistant Depression

Bohan Xu et al. JAMA Psychiatry. .

Abstract

Importance: Treatment-resistant depression (TRD) is a major challenge in mental health, affecting a significant number of patients and leading to considerable burdens. The etiological factors contributing to TRD are complex and not fully understood.

Objective: To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits and explore their potential role in the etiology of TRD using large-scale genomic data from the All of Us (AoU) Research Program.

Design, setting, and participants: This study was a cohort design with observational data from participants in the AoU Research Program who have both electronic health records and genomic data. Data analysis was performed from March 27 to October 24, 2024.

Exposures: PGS for 61 unique traits from 7 domains.

Main outcomes and measures: Logistic regressions to test if PGS was associated with treatment-resistant depression (TRD) compared with treatment-responsive major depressive disorder (trMDD). Cox proportional hazard model was used to determine if the progressions from MDD to TRD were associated with PGS.

Results: A total of 292 663 participants (median [IQR] age, 57 (41-69) years; 175 981 female [60.1%]) from the AoU Research Program were included in this analysis. In the discovery set (124 945 participants), 11 of the selected PGS were found to have stronger associations with TRD than with trMDD, encompassing PGS from domains in education, cognition, personality, sleep, and temperament. Genetic predisposition for insomnia (odds ratio [OR], 1.11; 95% CI, 1.07-1.15) and specific neuroticism (OR, 1.11; 95% CI, 1.07-1.16) traits were associated with increased TRD risk, whereas higher education (OR, 0.88; 95% CI, 0.85-0.91) and intelligence (OR, 0.91; 95% CI, 0.88-0.94) scores were protective. The associations held across different TRD definitions (meta-analytic R2 >83%) and were consistent across 2 other independent sets within AoU (the whole-genome sequencing Diversity dataset, 104 388, and Microarray dataset, 63 330). Among 28 964 individuals followed up over time, 3854 developed TRD within a mean of 944 days (95% CI, 883-992 days). All 11 previously identified and replicated PGS were found to be modulating the conversion rate from MDD to TRD.

Conclusions and relevance: Results of this cohort study suggest that genetic predisposition related to neuroticism, cognitive function, and sleep patterns had a significant association with the development of TRD. These findings underscore the importance of considering psychosocial factors in managing and treating TRD. Future research should focus on integrating genetic data with clinical outcomes to enhance understanding of pathways leading to treatment resistance.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Nemeroff reported receiving personal fees from ANeuroTech, Signant Health, Janssen Research and Development, BioXcel Therapeutics, Silo Pharma, Engrail Therapeutics, Clexio Biosciences, EcoR1 Capital, EmbarkNeuro, Galen Mental Health, Goodcap Pharmaceuticals, ITI Inc, LUCY Scientific Discovery, Relmada Therapeutics, Sage Therapeutics, Senseye Inc, Precisement Health, EMA Wellness, Heading Health, Synapsebio, Ninnion, Pasithea, Skyland Trails, Corcept Therapeutics Company, and Laureate Institute for Brain Research outside the submitted work; having a patent for method and devices for transdermal delivery of lithium, a patent for method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay, and a patent for compounds, compositions, methods of synthesis, and methods of treatment issued. Dr Paulus reported receiving grants from National Institute for General Medical Services during the conduct of the study, advisory fees from Spring Care Inc, royalties from UpToDate Royalties for an article on methamphetamine, and consulting fees from Boehringer Ingelheim International GmbH outside the submitted work. No other disclosures were reported.

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