GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22.

Article  Google Scholar 

Lee SL, Pearce E, Ajnakina O, Johnson S, Lewis G, Mann F, et al. The association between loneliness and depressive symptoms among adults aged 50 years and older: a 12-year population-based cohort study. Lancet Psychiatry. 2021;8:48–57.

Article  PubMed  PubMed Central  Google Scholar 

Fabbri C, Hagenaars SP, John C, Williams AT, Shrine N, Moles L, et al. Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts. Mol Psychiatry. 2021;26:3363–73.

Article  PubMed  PubMed Central  Google Scholar 

Pain O, Hodgson K, Trubetskoy V, Ripke S, Marshe VS, Adams MJ, et al. Identifying the common genetic basis of antidepressant response. Biol Psychiatry Glob Open Sci. 2022;2:115–26.

23andMe Research Team, Li QS, Tian C, Hinds D. Genome-wide association studies of antidepressant class response and treatment-resistant depression. Transl Psychiatry. 2020;10:360.

Article  Google Scholar 

Zhang Y, Qi G, Park J-H, Chatterjee N. Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits. Nat Genet. 2018;50:1318–26.

Article  PubMed  CAS  Google Scholar 

Maranville JC, Cox NJ. Pharmacogenomic variants have larger effect sizes than genetic variants associated with other dichotomous complex traits. Pharmacogenomics J. 2016;16:388–92.

Article  PubMed  CAS  Google Scholar 

Grzenda A, Widge AS. Electronic health records and stratified psychiatry: bridge to precision treatment? Neuropsychopharmacology. 2024;49:285–90.

Article  PubMed  Google Scholar 

Ostergaard SD, Jensen SOW, Bech P. The heterogeneity of the depressive syndrome: when numbers get serious. Acta Psychiatr Scand. 2011;124:495–6.

Article  PubMed  CAS  Google Scholar 

Milaneschi Y, Lamers F, Berk M, Penninx BWJH. Depression heterogeneity and its biological underpinnings: toward immunometabolic depression. Biol Psychiatry. 2020;88:369–80.

Article  PubMed  CAS  Google Scholar 

Badini I, Coleman JRI, Hagenaars SP, Hotopf M, Breen G, Lewis CM, et al. Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption. Psychol Med. 2022;52:726–36.

Article  PubMed  Google Scholar 

de Kluiver H, Jansen R, Penninx BWJH, Giltay EJ, Schoevers RA, Milaneschi Y. Metabolomics signatures of depression: the role of symptom profiles. Transl Psychiatry. 2023;13:198.

Article  PubMed  PubMed Central  Google Scholar 

Beijers L, Wardenaar KJ, van Loo HM, Schoevers RA. Data-driven biological subtypes of depression: systematic review of biological approaches to depression subtyping. Mol Psychiatry. 2019;24:888–900.

Article  PubMed  Google Scholar 

Beijers L, van Loo HM, Romeijn J-W, Lamers F, Schoevers RA, Wardenaar KJ. Investigating data-driven biological subtypes of psychiatric disorders using specification-curve analysis. Psychol Med. 2022;52:1089–1100.

Article  PubMed  Google Scholar 

Fabbri C, Kasper S, Kautzky A, Zohar J, Souery D, Montgomery S, et al. A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping. Transl Psychiatry. 2020;10:50.

Article  PubMed  PubMed Central  Google Scholar 

Shah SB, Peddada TN, Song C, Mensah M, Sung H, Yavi M, et al. Exome-wide association study of treatment-resistant depression suggests novel treatment targets. Sci Rep. 2023;13:12467.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kang J, Castro VM, Ripperger M, Venkatesh S, Burstein D, Linnér RK, et al. Genome-wide association study of treatment-resistant depression: shared biology with metabolic traits. Am J Psychiatry. 2024;181:608–19.

Wigmore EM, Hafferty JD, Hall LS, Howard DM, Clarke T-K, Fabbri C, et al. Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP. Pharmacogenomics J. 2020;20:329–41.

Article  PubMed  CAS  Google Scholar 

Xia C, Amador C, Huffman J, Trochet H, Campbell A, Porteous D, et al. Pedigree- and SNP-associated genetics and recent environment are the major contributors to anthropometric and cardiometabolic trait variation. PLoS Genet. 2016;12:e1005804.

Article  PubMed  PubMed Central  Google Scholar 

Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50:668–81.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Fabbri C, Tansey KE, Perlis RH, Hauser J, Henigsberg N, Maier W, et al. New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation. Pharmacogenomics J. 2018;18:413–21.

Article  PubMed  CAS  Google Scholar 

Fabbri C, Kasper S, Kautzky A, Bartova L, Dold M, Zohar J, et al. Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples. Br J Psychiatry. 2019;214:36–41.

Article  PubMed  Google Scholar 

Li QS, Tian C, Seabrook GR, Drevets WC, Narayan VA. Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response. Transl Psychiatry. 2016;6:e889.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Choi SW, Mak TS-H, O’Reilly PF. Tutorial: a guide to performing polygenic risk score analyses. Nat Protoc. 2020;15:2759–72.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sternat T, Fotinos K, Fine A, Epstein I, Katzman MA. Low hedonic tone and attention-deficit hyperactivity disorder: risk factors for treatment resistance in depressed adults. Neuropsychiatr Dis Treat. 2018;14:2379–87.

Article  PubMed  PubMed Central  Google Scholar 

Chen M-H, Pan T-L, Hsu J-W, Huang K-L, Su T-P, Li C-T, et al. Attention-deficit hyperactivity disorder comorbidity and antidepressant resistance among patients with major depression: a nationwide longitudinal study. Eur Neuropsychopharmacology. 2016;26:1760–7.

Article  CAS  Google Scholar 

Bron TI, Bijlenga D, Verduijn J, Penninx BWJH, Beekman ATF, Kooij JJS. Prevalence of ADHD symptoms across clinical stages of major depressive disorder. J Affect Disord. 2016;197:29–35.

Article  PubMed  Google Scholar 

Vannucchi G, Medda P, Pallucchini A, Bertelli M, Angst J, Azorin J-M, et al. The relationship between attention deficit hyperactivity disorder, bipolarity and mixed features in major depressive patients: evidence from the BRIDGE-II-Mix study. J Affect Disord. 2019;246:346–54.

Article  PubMed  CAS  Google Scholar 

Correa R, Akiskal H, Gilmer W, Nierenberg AA, Trivedi M, Zisook S. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord. 2010;127:10–18.

Article  PubMed  CAS  Google Scholar 

Sternat T, Katzman MA. Neurobiology of hedonic tone: the relationship between treatment-resistant depression, attention-deficit hyperactivity disorder, and substance abuse. Neuropsychiatr Dis Treat. 2016;12:2149–64.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Vanderbilt University Hospitals and Clinics. Community Health Needs Assessment. 2013. https://www.vumc.org/communityhealthimprovement/sites/default/files/VU_CHNA_Report_2013_FINAL_COMBINED_060713_330_1.doc_1.pdf. Accessed 28 June 2024.

Mass General Brigham. 2025. https://www.massgeneralbrigham.org/en. Accessed 16 January 2025.

Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007;357:1939–45.

Article  PubMed  CAS  Google Scholar 

Medicare. Does Medicare Cover ECT? 2024. https://www.medicare.org/articles/does-medicare-cover-ect/. Accessed 28 June 2024.

Cai N, Revez JA, Adams MJ, Andlauer TFM, Breen G, Byrne EM, et al. Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat Genet. 2020;52:437–47.

Article  PubMed