GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2018;392:1789–858.
Proudman D, Greenberg P, Nellesen D. The growing burden of major depressive disorders (MDD): Implications for researchers and policy makers. Pharmacoeconomics. 2021;39:619–25.
Bains N, Abdijadid S. Major depressive disorder. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
Ekman M, Granström O, Omérov S, Jacob J, Landén M. The societal cost of depression: evidence from 10,000 Swedish patients in psychiatric care. J Affect Disord. 2013;150:790–7.
Saez E, Erkoreka L, Moreno-Calle T, Berjano B, Gonzalez-Pinto A, Basterreche N, et al. Genetic variables of the glutamatergic system associated with treatment-resistant depression: a review of the literature. World J Psychiatry. 2022;12:884–96.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.
Amos TB, Tandon N, Lefebvre P, Pilon D, Kamstra RL, Pivneva I, et al. Direct and indirect cost burden and change of employment status in treatment-resistant depression: a matched-cohort study using a US commercial claims database. J Clin Psychiatry. 2018;79:17m11725.
Brenner P, Nygren A, Hägg D, Tiger M, O’Hara M, Brandt L, et al. Health care utilisation in treatment-resistant depression: a Swedish population-based cohort study. Int J Psychiatry Clin Pract. 2022;26:251–8.
Lundberg J, Cars T, Lööv S-Å, Söderling J, Sundström J, Tiihonen J, et al. Association of treatment-resistant depression with patient outcomes and health care resource utilization in a population-wide study. JAMA Psychiatry. 2023;80:167–75.
Reutfors J, Andersson TM-L, Brenner P, Brandt L, DiBernardo A, Li G, et al. Mortality in treatment-resistant unipolar depression: a register-based cohort study in Sweden. J Affect Disord. 2018;238:674–9.
Fabbri C, Corponi F, Souery D, Kasper S, Montgomery S, Zohar J, et al. The genetics of treatment-resistant depression: a critical review and future perspectives. Int J Neuropsychopharmacol. 2019;22:93–104.
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.
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.
Li QS, Tian C, Hinds D, 23andMe Research Team. Genome-wide association studies of antidepressant class response and treatment-resistant depression. Transl Psychiatry. 2020;10:360.
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.
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.
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.
Degenhardt F, Priebe L, Herms S, Mattheisen M, Mühleisen TW, Meier S, et al. Association between copy number variants in 16p11.2 and major depressive disorder in a German case-control sample. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:263–73.
Cook EH Jr, Scherer SW. Copy-number variations associated with neuropsychiatric conditions. Nature. 2008;455:919–23.
Williams NM, Franke B, Mick E, Anney RJL, Freitag CM, Gill M, et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry. 2012;169:195–204.
Zhang X, Abdellaoui A, Rucker J, de Jong S, Potash JB, Weissman MM, et al. Genome-wide burden of rare short deletions is enriched in major depressive disorder in four cohorts. Biol Psychiatry. 2019;85:1065–73.
Rasmussen HB, Dahmcke CM. Genome-wide identification of structural variants in genes encoding drug targets: possible implications for individualized drug therapy. Pharmacogenet Genomics. 2012;22:471–83.
O’Dushlaine C, Ripke S, Ruderfer DM, Hamilton SP, Fava M, Iosifescu DV, et al. Rare copy number variation in treatment-resistant major depressive disorder. Biol Psychiatry. 2014;76:536–41.
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.
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.
Howes OD, Thase ME, Pillinger T. Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry. 2022;27:58–72.
Gaynes BN, Lux L, Gartlehner G, Asher G, Forman-Hoffman V, Green J, et al. Defining treatment-resistant depression. Depress Anxiety. 2020;37:134–45.
Conway CR, George MS, Sackeim HA. Toward an evidence-based, operational definition of treatment-resistant depression: when enough is enough. JAMA Psychiatry. 2017;74:9–10.
Nierenberg AA. Methodological problems in treatment resistant depression research. Psychopharmacol Bull. 1990;26:461–4.
Xiong Y, Karlsson R, Song J, Kowalec K, Rück C, Sigström R, et al. Polygenic risk scores of lithium response and treatment resistance in major depressive disorder. Transl Psychiatry. 2023;13:301.
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.
Andersson E, Crowley JJ, Lindefors N, Ljótsson B, Hedman-Lagerlöf E, Boberg J, et al. Genetics of response to cognitive behavior therapy in adults with major depression: a preliminary report. Mol Psychiatry. 2019;24:484–90.
Boberg J, Kaldo V, Mataix-Cols D, Crowley JJ, Roelstraete B, Halvorsen M, et al. Swedish multimodal cohort of patients with anxiety or depression treated with internet-delivered psychotherapy (MULTI-PSYCH). BMJ Open. 2023;13:e069427.
Zagai U, Lichtenstein P, Pedersen NL, Magnusson PKE. The swedish twin registry: content and management as a research infrastructure. Twin Res Hum Genet. 2019;22:672–80.
Leitsalu L, Haller T, Esko T, Tammesoo M-L, Alavere H, Snieder H, et al. Cohort profile: estonian biobank of the Estonian genome center, university of Tartu. Int J Epidemiol. 2015;44:1137–47.
Ojalo T, Haan E, Kõiv K, Kariis HM, Krebs K, Uusberg H, et al. Cohort profile update: mental health online survey in the Estonian biobank (EstBB MHoS). Int J Epidemiol. 2024;53:dyae017.
Kurki MI, Karjalainen J, Palta P, Sipilä TP, Kristiansson K, Donner KM, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613:508–18.
Baghai TC, Möller H-J. Electroconvulsive therapy and its different indications. Dialogues Clin Neurosci. 2008;10:105–17.
Zhang Z, Cheng H, Hong X, Di Narzo AF, Franzen O, Peng S, et al. EnsembleCNV: an ensemble machine learning algorithm to identify and genotype copy number variation using SNP array data. Nucleic Acids Res. 2019;47:e39.
Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SFA, et al. PennCNV: an integrated hidden markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 2007;17:1665–74.
Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P, et al. QuantiSNP: an objective bayes hidden-markov model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res. 2007;35:2013–25.
Pinto D, Darvishi K, Shi X, Rajan D, Rigler D, Fitzgerald T, et al. Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol. 2011;29:512–20.
Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, et al. Common SNPs explain a large proportion of the heritability for human height. Nat Genet. 2010;42:565–9.
Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011;88:76–82.
Evans LM, Tahmasbi R, Vrieze SI, Abecasis GR, Das S, Gazal S, et al. Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits. Nat Genet. 2018;50:737–45.
Yap CX, Sidorenko J, Marioni RE, Yengo L, Wray NR, Visscher PM. Misestimation of heritability and prediction accuracy of male-pattern baldness. Nat Commun. 2018;9:2537.
Ormel J, Hartman CA, Snieder H. The genetics of depression: successful genome-wide association studies introduce new challenges. Transl Psychiatry. 2019;9:114.
Bulik-Sullivan BK, Loh P-R, Finucane HK, Ripke S, Yang J, Schizophrenia Working Group of the Psychiatric Genomics Consortium. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015;47:291–5.
Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.
Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604:502–8.
Mullins N, Forstner AJ, O’Connell KS, Coombes B, Coleman JRI, Qiao Z, et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet. 2021;53:817–29.
Watson HJ, Yilmaz Z, Thornton LM, Hübel C, Coleman JRI, Gaspar HA, et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet. 2019;51:1207–14.
Howard DM, Adams MJ, Clarke T-K, 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.
Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019;51:63–75.
Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51:431–44.
Nagel M, Jansen PR, Stringer S, Watanabe K, de Leeuw CA, Bryois J, et al. Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways. Nat Genet. 2018;50:920–7.
Lee JJ, Wedow R, Okbay A, Kong E, Maghzian O, Zacher M, et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat Genet. 2018;50:1112–21.
Savage JE, Jansen PR, Stringer S, Watanabe K, Bryois J, de Leeuw CA, et al. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat Genet. 2018;50:912–9.
Gupta P, Galimberti M, Liu Y, Beck S, Wingo A, Wingo T, et al. A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology. Nat. Hum. Behav. 2024;8:2235–49.
Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh P-R, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236–41.
Lloyd-Jones LR, Zeng J, Sidorenko J, Yengo L, Moser G, Kemper KE, et al. Improved polygenic prediction by bayesian multiple regression on summary statistics. Nat Commun. 2019;10:5086.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.
Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48.
Rees E, Walters JTR, Georgieva L, Isles AR, Chambert KD, Richards AL, et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry. 2014;204:108–14.
Rees E, Kendall K, Pardiñas AF, Legge SE, Pocklington A, Escott-Price V, et al. Analysis of intellectual disability copy number variants for association with schizophrenia. JAMA Psychiatry. 2016;73:963–9.
Kendall KM, Rees E, Bracher-Smith M, Legge S, Riglin L, Zammit S, et al. Association of rare copy number variants with risk of depression. JAMA Psychiatry. 2019;76:818–25.
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.
Dam AHDM, Koscinski I, Kremer JAM, Moutou C, Jaeger A-S, Oudakker AR, et al. Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am J Hum Genet. 2007;81:813–20.
Alliey-Rodriguez N, Grey TA, Shafee R, Asif H, Lutz O, Bolo NR, et al. NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis. Transl Psychiatry. 2019;9:230.
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.
Meng X, Navoly G, Giannakopoulou O, Levey DF, Koller D, Pathak GA, et al. Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference. Nat Genet. 2024;56:222–33.
Jansen PR, Watanabe K, Stringer S, Skene N, Bryois J, Hammerschlag AR, et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nat Genet. 2019;51:394–403.
Davies G, Armstrong N, Bis JC, Bressler J, Chouraki V, Giddaluru S, et al. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N = 53949). Mol Psychiatry. 2015;20:183–92.
Okbay A, Wu Y, Wang N, Jayashankar H, Bennett M, Nehzati SM, et al. Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals. Nat Genet. 2022;54:437–49.
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.
Pardiñas AF, Smart SE, Willcocks IR, Holmans PA, Dennison CA, Lynham AJ, et al. Interaction testing and polygenic risk scoring to estimate the association of common genetic variants with treatment resistance in schizophrenia. JAMA Psychiatry. 2022;79:260–9.
Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet. 2010;42:203–9.
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.