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The genetics of severe depression

Molecular Psychiatry volume 30, pages 1117–1126 (2025)Cite this article

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Abstract

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.

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References

  1. Zhdanava M, Pilon D, Ghelerter I, Chow W, Joshi K, Lefebvre P, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82:e1–7.

    Google Scholar 

  2. Shih RA, Belmonte PL, Zandi PP. A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry. 2004;16:260–83.

    PubMed  Google Scholar 

  3. Wray NR, Gottesman II. Using summary data from the Danish national registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder. Front Genet. 2012;3:118.

    PubMed  PubMed Central  Google Scholar 

  4. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: Review and meta-analysis. Am J Psychiatry. 2000;157:1552–62.

    CAS  PubMed  Google Scholar 

  5. Pettersson E, Lichtenstein P, Larsson H, Song J, Agrawal A, Børglum AD, et al. Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls. Psychological Med. 2019;49:1166–73.

    CAS  Google Scholar 

  6. Levinson DF, Mostafavi S, Milaneschi Y, Rivera M, Ripke S, Wray NR, et al. Genetic studies of major depressive disorder: Why are there no genome-wide association study findings and what can we do about it? Biol Psychiatry. 2014;76:510–2.

    PubMed  PubMed Central  Google Scholar 

  7. Hyde CL, Nagle MW, Tian C, Chen X, Paciga SA, Wendland JR, et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat Genet. 2016;48:1031–6.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Howard DM, Adams MJ, Clarke T, Hafferty JD, Gibson J, Shirali M, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci. 2019;22:343–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mitchell AJ, Coyne JC. Do ultra-short screening instruments accurately detect depression in primary care? A pooled analysis and meta-analysis of 22 studies. Br J Gen Pract. 2007;57:144–51.

    PubMed  PubMed Central  Google Scholar 

  11. Flint J. The genetic basis of major depressive disorder. Mol Psychiatry. 2023;28:2254–65.

    PubMed  PubMed Central  Google Scholar 

  12. Zeggini E, Panoutsopoulou K, Southam L, Rayner NW, Day-Williams AG, Lopes MC, et al. Identification of new susceptibility loci for osteoarthritis (arcOGEN): A genome-wide association study. Lancet. 2012;380:815–23.

    PubMed  Google Scholar 

  13. Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B, Bossini-Castillo L, et al. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets. Nature Genet. 2017;49:416–25.

    CAS  PubMed  Google Scholar 

  14. Soda T, McLoughlin DM, Clark SR, Oltedal L, Kessler U, Haavik J, et al. International consortium on the genetics of electroconvulsive therapy and severe depressive disorders (gen-ECT-ic). Eur Arch Psychiatry Clin Neurosci. 2020;270:921–32.

    PubMed  Google Scholar 

  15. Mathew SJ, Wilkinson ST, Altinay M, Asghar-Ali A, Chang LC, Collins KA, et al. Electroconvulsive therapy (ECT) vs. ketamine in patients with treatment-resistant depression: The ELEKT-D study protocol. Contemp Clin Trials. 2019;77:19–26.

    PubMed  Google Scholar 

  16. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association Publishing; 2022.

  17. World Health Organization. International statistical classification of diseases and related health problems. Geneva: World Health Organization; 2019.

  18. Zimmerman M, Martinez JH, Young D, Chelminski I, Dalrymple K. Severity classification on the Hamilton depression rating scale. J Affect Disord. 2013;150:384–8.

    PubMed  Google Scholar 

  19. Zimmerman M, Balling C, Chelminski I, Dalrymple K. Understanding the severity of depression: Which symptoms of depression are the best indicators of depression severity? Compr Psychiatry. 2018;87:84–8.

    PubMed  Google Scholar 

  20. Roose SP, Glassman AH, Walsh BT, Woodring S, Vital-herne J. Depression, delusions, and suicide. Am J Psychiatry. 1983;140:1159–62.

    CAS  PubMed  Google Scholar 

  21. Rush AJ, Weissenburger JE. Melancholic symptom features and DSM-IV. Am J Psychiatry. 1994;151:489–98.

    CAS  PubMed  Google Scholar 

  22. Zisook S, Lesser I, Stewart JW, Wisniewski SR, Balasubramani GK, Fava M, et al. Effect of age at onset on the course of major depressive disorder. Am J Psychiatry. 2007;164:1539–46.

    PubMed  Google Scholar 

  23. Zimmerman M, Morgan TA, Stanton K. The severity of psychiatric disorders. World Psychiatry. 2018;17:258–75.

    PubMed  PubMed Central  Google Scholar 

  24. Miller CH, Sacchet MD, Gotlib IH. Support vector machines and affective science. Emotion Rev. 2020;12:297–308.

    Google Scholar 

  25. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649–59.

    PubMed  Google Scholar 

  26. McIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, et al. Treatment‐resistant depression: Definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22:394–412.

    PubMed  PubMed Central  Google Scholar 

  27. National Institute for Health and Care Excellence. Depression in adults: Treatment and management, NICE guideline NG222. London, UK: NICE; 2022. Accessed 9 June 2024.

  28. Food and Drug Administration. Neurological devices; reclassification of electroconvulsive therapy devices; effective date of requirement for premarket approval for electroconvulsive therapy devices for certain specified intended uses. final order. Federal register. 2018;83:66103–24.

    Google Scholar 

  29. Kaster TS, Blumberger DM, Gomes T, Sutradhar R, Dasklakis ZJ, Wijeysundera DN, et al. Patient-level characteristics and inequitable access to inpatient electroconvulsive therapy for depression: A population-based cross-sectional study: Caractéristiques au niveau du patient et accès inéquitable à la thérapie électroconvulsive pour patients hospitalisés. Can J Psychiatry. 2021;66:147–58.

    PubMed  Google Scholar 

  30. Jørgensen MB, Rozing MP, Kellner CH, Osler M. Electroconvulsive therapy, depression severity and mortality: Data from the Danish national patient registry. J Psychopharmacol. 2020;34:273–9.

    PubMed  Google Scholar 

  31. Kellner C, Kaicher D, Banerjee H, Knapp R, Shapiro R, Briggs M, et al. Depression severity in electroconvulsive therapy (ECT) versus pharmacotherapy trials. J ECT. 2015;31:31–3.

    PubMed  Google Scholar 

  32. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. The clinical characteristics of major depression as indices of the familial risk to illness. Br J Psychiatry. 1994;165:66–72.

    CAS  PubMed  Google Scholar 

  33. Torgersen S. Genetic factors in moderately severe and mild affective disorders. Arch Gen Psychiatry. 1986;43:222–6.

    CAS  PubMed  Google Scholar 

  34. Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, et al. A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry. 1982;39:1157–67.

    CAS  PubMed  Google Scholar 

  35. Weissman MM, Kidd KK, Prusoff BA. Variability in rates of affective disorders in relatives of depressed and normal probands. Arch Gen Psychiatry. 1982;39:1397–403.

    CAS  PubMed  Google Scholar 

  36. Cadoret RJ, Woolson R, Winokur G. The relationship of age of onset in unipolar affective disorder to risk of alcoholism and depression in parents. J Psychiatr Res. 1977;13:137–42.

    CAS  PubMed  Google Scholar 

  37. Mendlewicz J, Baron M. Morbidity risks in subtypes of unipolar depressive illness: Differences between early and late onset forms. Br J Psychiatry. 1981;139:463–6.

    CAS  PubMed  Google Scholar 

  38. Weissman MM, Wickramaratne P, Merikangas KR, Leckman JF, Prusoff BA, Caruso KA, et al. Onset of major depression in early adulthood: Increased familial loading and specificity. Arch Gen Psychiatry. 1984;41:1136–43.

    CAS  PubMed  Google Scholar 

  39. Price RA, Kidd KK, Weissman MM. Early onset (under age 30 years) and panic disorder as markers for etiologic homogeneity in major depression. Arch Gen Psychiatry. 1987;44:434–40.

    CAS  PubMed  Google Scholar 

  40. Kupfer DJ, Frank E, Carpenter LL, Neiswanger K. Family history in recurrent depression. J Affect Disord. 1989;17:113–9.

    CAS  PubMed  Google Scholar 

  41. Lieb R, Isensee B, Ho¨fler M, Wittchen H. Parental depression and depression in offspring: Evidence for familial characteristics and subtypes? J Psychiatr Res. 2002;36:237–46.

    PubMed  Google Scholar 

  42. Bland RC, Newman SC, Orn H. Recurrent and nonrecurrent depression: A family study. Arch Gen Psychiatry. 1986;43:1085–9.

    CAS  PubMed  Google Scholar 

  43. Guffanti G, Gameroff MJ, Warner V, Talati A, Glatt CE, Wickramaratne P, et al. Heritability of major depressive and comorbid anxiety disorders in multi‐generational families at high risk for depression. Am J Med Genet B Neuropsychiatr Genet. 2016;171:1072–9.

    PubMed  Google Scholar 

  44. Weissman MM, Gershon ES, Kidd KK, Prusoff BA, Leckman JF, Dibble E, et al. Psychiatric disorders in the relatives of probands with affective disorders: The Yale University—National institute of mental health collaborative study. Arch Gen Psychiatry. 1984;41:13–21.

    CAS  PubMed  Google Scholar 

  45. Lyons MJ, Eisen SA, Goldberg J, True W, Lin N, Meyer JM, et al. A registry-based twin study of depression in men. Arch Gen Psychiatry. 1998;55:468–72.

    CAS  PubMed  Google Scholar 

  46. Kendler KS, Gatz M, Gardner CO, Pedersen NL. Age at onset and familial risk for major depression in a Swedish national twin sample. Psychol Med. 2005;35:1573–9.

    PubMed  Google Scholar 

  47. Kendler KS, Gatz M, Gardner CO, Pedersen NL. Clinical indices of familial depression in the Swedish twin registry. Acta Psychiatr Scand. 2007;115:214–20.

    CAS  PubMed  Google Scholar 

  48. Kendler KS, Gardner CO, Prescott CA. Clinical characteristics of major depression that predict risk of depression in relatives. Arch Gen Psychiatry. 1999;56:322–7.

    CAS  PubMed  Google Scholar 

  49. Kendler KS, Ohlsson H, Lichtenstein P, Sundquist J, Sundquist K. The genetic epidemiology of treated major depression in Sweden. Am J Psychiatry. 2018;175:1137–44.

    PubMed  Google Scholar 

  50. von Knorring A, Cloninger CR, Bohman M, Sigvardsson S. An adoption study of depressive disorders and substance abuse. Arch Gen Psychiatry. 1983;40:943–50.

    Google Scholar 

  51. Kendler KS, Ohlsson H, Sundquist J, Sundquist K. Family genetic risk scores and the genetic architecture of major affective and psychotic disorders in a Swedish national sample. JAMA Psychiatry. 2021;78:735–43.

    PubMed  Google Scholar 

  52. Levinson DF. The genetics of depression: A review. Biol Psychiatry. 2006;60:84–92.

    CAS  PubMed  Google Scholar 

  53. Holmans P, Weissman MM, Zubenko GS, Scheftner WA, Crowe RR, DePaulo JR, et al. Genetics of recurrent early-onset major depression (GenRED): Final genome scan report. Am J Psychiatry. 2007;164:248–58.

    PubMed  Google Scholar 

  54. Lohoff FW. Overview of the genetics of major depressive disorder. Curr Psychiatry Rep. 2010;12:539–46.

    PubMed  PubMed Central  Google Scholar 

  55. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516–7.

    CAS  PubMed  Google Scholar 

  56. Levey DF, Stein MB, Wendt FR, Pathak GA, Zhou H, Aslan M, et al. Bi-ancestral depression GWAS in the million veteran program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat Neurosci. 2021;24:954–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Harder A, Nguyen T, Pasman JA, Mosing MA, Hägg S, Lu Y. Genetics of age-at-onset in major depression. Transl Psychiatry. 2022;12:124.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Nguyen T, Harder A, Xiong Y, Kowalec K, Hägg S, Cai N, et al. Genetic heterogeneity and subtypes of major depression. Mol Psychiatry. 2022;27:1667–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Mitchell BL, Campos AI, Whiteman DC, Olsen CM, Gordon SD, Walker AJ, et al. The Australian genetics of depression study: New risk loci and dissecting heterogeneity between subtypes. Biol Psychiatry. 2022;92:227–35.

    CAS  PubMed  Google Scholar 

  60. Als TD, Kurki MI, Grove J, Voloudakis G, Therrien K, Tasanko E, et al. Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses. Nat Med. 2023;29:1832–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Musliner KL, Agerbo E, Vilhjálmsson BJ, Albiñana C, Als TD, Østergaard SD, et al. Polygenic liability and recurrence of depression in patients with first-onset depression treated in hospital-based settings. JAMA Psychiatry. 2021;78:792–5.

    PubMed  PubMed Central  Google Scholar 

  62. Docherty AR, Edwards AC, Yang F, Peterson RE, Sawyers C, Adkins DE, et al. Age of onset and family history as indicators of polygenic risk for major depression. Depress Anxiety. 2017;34:446–52.

    PubMed  PubMed Central  Google Scholar 

  63. Shi J, Potash JB, Johnson JK, Adams P, Chaudhury S, Jancic D, et al. Genome-wide association study of recurrent early-onset major depressive disorder. Mol Psychiatry. 2011;16:193–201.

    CAS  PubMed  Google Scholar 

  64. Peterson RE, Cai N, Bigdeli TB, Li Y, Reimers M, Nikulova A, et al. The genetic architecture of major depressive disorder in Han Chinese women. JAMA Psychiatry. 2017;74:162–8.

    PubMed  PubMed Central  Google Scholar 

  65. Cai N, Bigdeli TB, Kretzschmar W, Li Y, Liang J, Song L, et al. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature. 2015;523:588–91.

    CAS  Google Scholar 

  66. Docherty AR, Moscati A, Bigdeli TB, Edwards AC, Peterson RE, Adkins DE, et al. Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE. Psychol Med. 2020;50:793–8.

    PubMed  Google Scholar 

  67. Rahman S, Islam R. Mammalian Sirt1: Insights on its biological functions. Cell Commun Signal. 2011;9:9–11.

    Google Scholar 

  68. Lin D, Li L, Chen W, Chen J, Ren D, Zheng Z, et al. LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity. Mol Psychiatry. 2023;28:908–18.

    CAS  PubMed  Google Scholar 

  69. Dang R, Cai H, Zhang L, Liang D, Lv C, Guo Y, et al. Dysregulation of neuregulin-1/ErbB signaling in the prefrontal cortex and hippocampus of rats exposed to chronic unpredictable mild stress. Physiol Behav. 2016;154:145–50.

    CAS  PubMed  Google Scholar 

  70. Fiori LM, Kos A, Lin R, Théroux J, Lopez JP, Kühne C, et al. miR-323a regulates ERBB4 and is involved in depression. Mol Psychiatry. 2021;26:4191–204.

    CAS  PubMed  Google Scholar 

  71. Pasman JA, Chen Z, Smit DJA, Vink JM, van den Oever MC, Pattij T, et al. The CADM2 gene and behavior: A phenome-wide scan in UK-biobank. Behav Genet. 2022;52:306–14.

    PubMed  PubMed Central  Google Scholar 

  72. Andreadou M, Ingelfinger F, De Feo D, Cramer TLM, Tuzlak S, Friebel E, et al. IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice. Nat Neurosci. 2023;26:1701–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kang H, Kim K, Park Y, Yoo K, Kim J, Lee J, et al. Genetic markers for depressive disorders with earlier age at onset. Prog Neuropsychopharmacol Biol Psychiatry. 2021;108:110176.

    CAS  PubMed  Google Scholar 

  74. Nivard MG, Mbarek H, Hottenga JJ, Smit JH, Jansen R, Penninx BW, et al. Further confirmation of the association between anxiety and CTNND2: Replication in humans. Genes Brain Behav. 2014;13:195–201.

    CAS  PubMed  Google Scholar 

  75. 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.

  76. McClain LL, Shaw P, Sabol R, Chedia AM, Segretti AM, Rengasamy MM, et al. Rare variants and biological pathways identified in treatment‐refractory depression. J Neurosci Res. 2020;98:1322–34.

    CAS  PubMed  Google Scholar 

  77. Hupalo D, Forsberg CW, Goldberg J, Kremen WS, Lyons MJ, Soltis AR, et al. Rare variant association study of veteran twin whole-genomes links severe depression with a nonsynonymous change in the neuronal gene BHLHE22. World J Biol Psychiatry. 2022;23:295–306.

    CAS  PubMed  Google Scholar 

  78. Subaran RL, Odgerel Z, Swaminathan R, Glatt CE, Weissman MM. Novel variants in ZNF34 and other brain-expressed transcription factors are shared among early-onset MDD relatives. Am J Med Genet B Neuropsychiatr Genet. 2016;171B:333–41.

    PubMed  PubMed Central  Google Scholar 

  79. 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.

    PubMed  Google Scholar 

  80. 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.

    PubMed  PubMed Central  Google Scholar 

  81. Clements CC, Karlsson R, Lu Y, Juréus A, Rück C, Andersson E, et al. Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy. Mol Psychiatry. 2021;26:2429–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Power RA, Tansey KE, Buttenschøn HN, Cohen-Woods S, Bigdeli T, Hall LS, et al. Genome-wide association for major depression through age at onset stratification: Major depressive disorder working group of the psychiatric genomics consortium. Biol Psychiatry. 2017;81:325–35.

    PubMed  PubMed Central  Google Scholar 

  83. Lan N, Lu Y, Zhang Y, Pu S, Xi H, Nie X, et al. FTO – A common genetic basis for obesity and cancer. Front Genet. 2020;11:559138.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Al-Massadi O, Dieguez C, Schneeberger M, López M, Schwaninger M, Prevot V, et al. Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis. Nat Rev Endocrinol. 2021;17:745–55.

    CAS  PubMed  Google Scholar 

  85. Mullins N, Forstner AJ, Coleman JRI, Qiao Z, Kim M, Panagiotaropoulou G, et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nature Genet. 2021;53:817–29.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 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.

    PubMed  PubMed Central  Google Scholar 

  88. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Rudberg I, Hermann M, Refsum H, Molden E. Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients. Eur J Clin Pharmacol. 2008;64:1181–8.

    CAS  PubMed  Google Scholar 

  90. Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E. Impact of the ultrarapid CYP2C1917 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther. 2008;83:322–7.

    CAS  PubMed  Google Scholar 

  91. Kim YN, Jung HY, Eum WS, Kim DW, Shin MJ, Ahn EH, et al. Neuroprotective effects of PEP-1-carbonyl reductase 1 against oxidative-stress-induced ischemic neuronal cell damage. Free Radic Biol Med. 2014;69:181–96.

    CAS  PubMed  Google Scholar 

  92. Jermy BS, Glanville KP, Coleman JRI, Lewis CM, Vassos E. Exploring the genetic heterogeneity in major depression across diagnostic criteria. Mol Psychiatry. 2021;26:7337.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Baune BT, Soda T, Sullivan PF, Zandi P. The genomics of electroconvulsive therapy international consortium (GenECT-ic). Lancet Psychiatry. 2019;6:e23.

    PubMed  PubMed Central  Google Scholar 

  94. Zandi PP, Morreale M, Reti IM, Maixner DF, McDonald WM, Patel PD, et al. National Network of Depression Centers’ recommendations on harmonizing clinical documentation of electroconvulsive therapy. J ECT. 2022;38:159–64.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was funded by the National Institute of Mental Health grants R01MH121542 and R01MH121545. BV is funded by a DBT/Wellcome Trust India Alliance Intermediate (Clinical and Public Health) Research Fellowship (IA/CPHI/20/1/505266)

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Clio E. Franklin, Irving M. Reti, Peter P. Zandi & James B. Potash

  2. Department of Psychiatry, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA

    Eric Achtyes

  3. Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, USA

    Murat Altinay

  4. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Kala Bailey & Mustafa M. Husain

  5. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Mahendra T. Bhati

  6. Department of Psychiatry, University of Florida Health, Gainsville, FL, USA

    Brent R. Carr

  7. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    Susan K. Conroy

  8. Department of Psychiatry, University of Massachusetts Memorial Health, Worchester, MA, USA

    Khurshid A. Khurshid

  9. Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Glen Oaks, NY, USA

    Todd Lencz

  10. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    William M. McDonald

  11. Department of Psychiatry, Huntsman Mental Health Institute, University of Utah Health School of Medicine, Salt Lake City, UT, USA

    Brian J. Mickey

  12. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    James Murrough

  13. VISN 2 Mental Illness Research, Education, and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA

    James Murrough

  14. Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Sean Nestor

  15. Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany

    Thomas Nickl-Jockschat

  16. German Center for Mental Health (DZPG), partner site Halle-Jena-Magdeburg, Magdeburg, Germany

    Thomas Nickl-Jockschat

  17. Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Halle-Jena-Magdeburg, Magdeburg, Germany

    Thomas Nickl-Jockschat

  18. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Sina Nikayin & Gerard Sanacora

  19. Department of Psychiatry and Behavioral Health, Ohio State University College of Medicine, Columbus, OH, USA

    Kevin Reeves

  20. Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Care Center at Houston, Houston, TX, USA

    Salih Selek

  21. Department of Psychiatry, Carver College of Medicine, and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA

    Nicholas T. Trapp

  22. Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India

    Biju Viswanath

  23. Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, USA

    Jesse H. Wright

  24. Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Patrick Sullivan

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  1. Clio E. Franklin
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  2. Eric Achtyes
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Contributions

CEF and JBP drafted the manuscript. CEF drafted the tables. PPZ conceptualized the project and was lead editor. EA, MA, KB, MTB, BRC, SKC, MMH, KAK, TL, WMM, BJM, JM, SN, TN, SN, KR, IMR, SS, GS, NTT, BV, JHW and PS contributed further to the tables and manuscript and approved the final version.

Corresponding authors

Correspondence to Peter P. Zandi or James B. Potash.

Ethics declarations

Competing interests

PFS is a consultant and shareholder for Neumora Therapeutics. In the past 2 years GS has served as consultant to Abbvie, Ancora/Embark, Aptinyx, Atai, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Clexio, Cowen, Denovo Biopharma, Daiichi Sankyo, ECR1, EMA Wellness, Freedom Biosciences, Gilgamesh, Intra-Cellular Therapies, Janssen, KOA Health, Levo therapeutics, Lundbeck, Merck, MiCure, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Perception Neuroscience, Praxis Therapeutics, Relmada Therapeutics, Sage Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Usona Insititute, Valeant, Vistagen Therapeutics, and XW Labs; and received research contracts from Johnson & Johnson/Janssen, Merck, and the Usona Institute over the past 36 months. Dr. Sanacora holds equity in Biohaven Pharmaceuticals, Freedom Biosciences, Gilead Relmada, and Tetricus and is a co-inventor on a US patent (#8,778,979) held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018, by Yale University Office of Cooperative Research. Yale University has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship. Dr. Sanacora does not receive any direct payments through this relationship and the University has put multiple measures in place to mitigate this institutional conflict of interest. Questions about the details of these measures should be directed to Yale University’s Conflict of Interest office. All other authors have no conflicting interests to declare.

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Franklin, C.E., Achtyes, E., Altinay, M. et al. The genetics of severe depression. Mol Psychiatry 30, 1117–1126 (2025). https://doi.org/10.1038/s41380-024-02731-1

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