Editing Major depressive disorder (section)

==Cause==
{{further|Biology of depression|Epigenetics of depression}}
[[File:Diathesis_stress_model_cup_analogy.svg|thumb|A cup analogy demonstrating the [[diathesis–stress model]] that under the same amount of stressors, person 2 is more vulnerable than person 1, because of their predisposition<ref>{{cite book | vauthors = Hankin BL, Abela JR |title=Development of Psychopathology: A Vulnerability-Stress Perspective |date=2005 |publisher=SAGE Publications |isbn=978-1-4129-0490-2 |pages=32–34 |url=https://books.google.com/books?id=1Fd0LneB724C&pg=PR7 |language=en}}</ref>]]
The [[etiology]] of depression is not yet fully understood.<ref>{{cite journal | vauthors = Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF | title = Major depressive disorder | journal = Nature Reviews. Disease Primers | volume = 2 | issue = 1 | page = 16065 | date = September 2016 | pmid = 27629598 | doi = 10.1038/nrdp.2016.65 | publisher = [[Springer Nature]] | quote = Despite advances in our understanding of the neuro-biology of MDD, no established mechanism can explain all aspects of the disease. | s2cid = 4047310 | url = https://kclpure.kcl.ac.uk/ws/files/57263080/Major_Deppressive_Disorder_.pdf | publication-date = 15 September 2016 }}</ref><ref>{{Cite book | vauthors = Boland RJ, Verduin ML |title=Kaplan & Sadock's concise textbook of clinical psychiatry  |date=14 March 2022 |publisher=[[Wolters Kluwer]] |isbn=978-1-9751-6748-6 |edition=5th |location=Philadelphia |language=en |oclc=1264172789 |quote=Although there is no single unifying theory, several theories have emerged over the last century that attempt to account for the various clinical, psychological, and biologic findings in depression.}}</ref><ref>{{Cite book | vauthors = Sontheimer H |title=Diseases of the nervous system |date=20 May 2021 |publisher=[[Elsevier]] |isbn=978-0-12-821396-4 |edition=2nd |page=286 |language=en |oclc=1260160457 |quote=A number of risk factors for depression are known or suspected, but only in rare cases is the link to disease strong.}}</ref> The [[biopsychosocial model]] proposes that biological, psychological, and social factors all play a role in causing depression.{{sfn|American Psychiatric Association|2013|p=166}}<ref>{{cite web |author=Department of Health and Human Services |year=1999 |url=http://www.surgeongeneral.gov/library/mentalhealth/pdfs/c2.pdf |title=The fundamentals of mental health and mental illness |website=Mental Health: A Report of the Surgeon General |access-date=11 November 2008 |url-status=live |archive-url=https://web.archive.org/web/20081217031913/http://www.surgeongeneral.gov/library/mentalhealth/pdfs/c2.pdf |archive-date=17 December 2008 }}</ref> The [[diathesis–stress model]] specifies that depression results when a preexisting vulnerability, or [[Diathesis (medicine)|diathesis]], is activated by stressful life events. The preexisting vulnerability can be either [[gene]]tic,<ref>{{cite journal | vauthors = Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R | title = Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene | journal = Science | volume = 301 | issue = 5631 | pages = 386–389 | date = July 2003 | pmid = 12869766 | doi = 10.1126/science.1083968 | s2cid = 146500484 | bibcode = 2003Sci...301..386C }}</ref><ref>{{cite journal | vauthors = Haeffel GJ, Getchell M, Koposov RA, Yrigollen CM, Deyoung CG, Klinteberg BA, Oreland L, Ruchkin VV, Grigorenko EL | title = Association between polymorphisms in the dopamine transporter gene and depression: evidence for a gene-environment interaction in a sample of juvenile detainees | journal = Psychological Science | volume = 19 | issue = 1 | pages = 62–69 | date = January 2008 | pmid = 18181793 | doi = 10.1111/j.1467-9280.2008.02047.x | url = http://www.nd.edu/~ghaeffel/Resources/Haeffel%20et%20al.,%202008.pdf | url-status = live | s2cid = 15520723 | archive-url = https://web.archive.org/web/20081217031910/http://www.nd.edu/~ghaeffel/Resources/Haeffel%20et%20al.%2C%202008.pdf | archive-date = 17 December 2008 }}</ref> implying an interaction between [[nature and nurture]], or [[Schema (psychology)|schematic]], resulting from views of the world learned in childhood.<ref>{{cite web | vauthors = Slavich GM |year=2004 |url=http://www.psychologicalscience.org/observer/getArticle.cfm?id=1640 |title=Deconstructing depression: A diathesis-stress perspective (Opinion) |website=APS Observer |access-date=11 November 2008 |url-status=live |archive-url=https://web.archive.org/web/20110511233644/http://www.psychologicalscience.org/observer/getArticle.cfm?id=1640 |archive-date=11 May 2011 }}</ref> American psychiatrist [[Aaron Beck]] suggested that a [[Beck's cognitive triad|triad]] of automatic and spontaneous negative thoughts about the [[Self-image|self]], the [[Social environment|world or environment]], and the future may lead to other depressive signs and symptoms.<ref name=Beck>{{cite book |vauthors=Beck AT, Rush AJ, Shaw BF, Emery G |title=Cognitive therapy of depression |year=1979|publication-place=New York|publisher=The Guilford Press|isbn=0-89862-000-7|pages=11–12 |url=https://books.google.com/books?id=L09cRS0xWj0C |access-date=26 February 2022}}</ref><ref>{{cite journal | vauthors = Nieto I, Robles E, Vazquez C | title = Self-reported cognitive biases in depression: A meta-analysis | journal = Clinical Psychology Review | volume = 82 | page = 101934 | date = December 2020 | pmid = 33137610 | doi = 10.1016/j.cpr.2020.101934 | s2cid = 226243519 }}</ref>

===Genetics===
Genes play a major role in the development of depression.<ref>{{Cite book | vauthors = Do MC, Weersing VR |title=The SAGE encyclopedia of abnormal and clinical psychology  |date=3 April 2017 |publisher=[[SAGE Publishing]] |isbn=978-1-4833-6582-4 | veditors = Wenzel A |location=Thousand Oaks, California |page=1014 |doi=10.4135/9781483365817 |oclc=982958263 |quote=Depression is highly heritable, as youths with a parent with a history of depression are approximately 4 times as likely to develop the disorder as youths who do not have a parent with depression.}}</ref> [[Behavioural genetics|Family and twin studies]] suggest that genetic factors account for nearly 40% of the variation in risk for major depressive disorder. Like most psychiatric disorders, major depression is likely shaped by a combination of many individual genetic influences.<ref name="h988">{{cite journal | last1=Cui | first1=Lulu | last2=Li | first2=Shu | last3=Wang | first3=Siman | last4=Wu | first4=Xiafang | last5=Liu | first5=Yingyu | last6=Yu | first6=Weiyang | last7=Wang | first7=Yijun | last8=Tang | first8=Yong | last9=Xia | first9=Maosheng | last10=Li | first10=Baoman | title=Major depressive disorder: hypothesis, mechanism, prevention and treatment | journal=Signal Transduction and Targeted Therapy | publisher=Springer Science and Business Media LLC | volume=9 | issue=1 | date=9 February 2024 | issn=2059-3635 | doi=10.1038/s41392-024-01738-y | doi-access=free | url=https://www.nature.com/articles/s41392-024-01738-y.pdf | access-date=17 March 2025 | page=30| pmid=38331979 | pmc=10853571 }}</ref> In 2018, a [[genome-wide association study]] discovered 44 genetic variants linked to risk for major depression;<ref>{{cite journal | vauthors = Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, etal | title = Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression | journal = Nature Genetics | volume = 50 | issue = 5 | pages = 668–681 | date = May 2018 | pmid = 29700475 | pmc = 5934326 | doi = 10.1038/s41588-018-0090-3 | hdl = 11370/3a0e2468-99e7-40c3-80f4-9d25adfae485 }}</ref> a 2019 study found 102 variants in the genome linked to depression.<ref>{{cite journal | vauthors = Howard DM, Adams MJ, Clarke TK, Hafferty JD, Gibson J, Shirali M, Coleman JR, Hagenaars SP, Ward J, Wigmore EM, Alloza C, Shen X, Barbu MC, Xu EY, Whalley HC, Marioni RE, Porteous DJ, Davies G, Deary IJ, Hemani G, Berger K, Teismann H, Rawal R, Arolt V, Baune BT, Dannlowski U, Domschke K, Tian C, Hinds DA, Trzaskowski M, Byrne EM, Ripke S, Smith DJ, Sullivan PF, Wray NR, Breen G, Lewis CM, McIntosh AM | title = Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions | journal = Nature Neuroscience | volume = 22 | issue = 3 | pages = 343–352 | date = March 2019 | pmid = 30718901 | pmc = 6522363 | doi = 10.1038/s41593-018-0326-7 }}</ref> However, it appears that major depression is less heritable compared to bipolar disorder and schizophrenia.<ref>{{cite book | last1=Oraki Kohshour | first1=Mojtaba | last2=Strom | first2=Nora I. | last3=Meier | first3=Sandra Melanie | last4=McMahon | first4=Francis J. | last5=Merikangas | first5=Kathleen R. | last6=Schulze | first6=Thomas G. | last7=Mattheisen | first7=Manuel | title=Tasman's Psychiatry | chapter=Genetics of Psychiatric Disorders: Advances in Genetic Epidemiology and Genomic Approaches | publisher=Springer International Publishing | publication-place=Cham | date=2024 | isbn=978-3-030-51365-8 | doi=10.1007/978-3-030-51366-5_51 | pages=485–510}}</ref><ref>{{Cite book | vauthors = Jorde LB, Carey JC, Bamshad MJ |title=Medical genetics |date=27 September 2019 |publisher=[[Elsevier]] |isbn=978-0-323-59653-4 |edition=6th |location=Philadelphia |page=247 |language=en |oclc=1138027525 |quote=Thus it appears that bipolar disorder is more strongly influenced by genetic factors than is major depressive disorder.}}</ref> Research focusing on specific candidate genes has been criticized for its tendency to generate false positive findings.<ref name="r473">{{cite journal | last1=McIntosh | first1=Andrew M. | last2=Sullivan | first2=Patrick F. | last3=Lewis | first3=Cathryn M. | title=Uncovering the Genetic Architecture of Major Depression | journal=Neuron | volume=102 | issue=1 | date=2019 | pmid=30946830 | pmc=6482287 | doi=10.1016/j.neuron.2019.03.022 | doi-access=free | pages=91–103 | url=http://www.cell.com/article/S0896627319302855/pdf | access-date=17 March 2025}}</ref> There are also other efforts to examine interactions between life stress and polygenic risk for depression.<ref>{{cite journal | vauthors = Peyrot WJ, Van der Auwera S, Milaneschi Y, Dolan CV, Madden PA, Sullivan PF, Strohmaier J, Ripke S, Rietschel M, Nivard MG, Mullins N, Montgomery GW, Henders AK, Heat AC, Fisher HL, Dunn EC, Byrne EM, Air TA, Baune BT, Breen G, Levinson DF, Lewis CM, Martin NG, Nelson EN, Boomsma DI, Grabe HJ, Wray NR, Penninx BW | title = Does Childhood Trauma Moderate Polygenic Risk for Depression? A Meta-analysis of 5765 Subjects From the Psychiatric Genomics Consortium | journal = Biological Psychiatry | volume = 84 | issue = 2 | pages = 138–147 | date = July 2018 | pmid = 29129318 | pmc = 5862738 | doi = 10.1016/j.biopsych.2017.09.009}}</ref>

===Other health problems===
Depression can also arise after a chronic or terminal medical condition, such as [[HIV/AIDS]] or [[asthma]], and may be labeled "secondary depression".<ref>{{cite journal |vauthors=Simon GE |title=Treating depression in patients with chronic disease: recognition and treatment are crucial; depression worsens the course of a chronic illness |journal=The Western Journal of Medicine |volume=175 |issue=5 |pages=292–93 |date=November 2001 |pmid=11694462 |pmc=1071593 |doi=10.1136/ewjm.175.5.292}}</ref><ref>{{cite journal|author1-link=Paula Clayton |vauthors=Clayton PJ, Lewis CE |title=The significance of secondary depression |journal=Journal of Affective Disorders |volume=3 |issue=1 |pages=25–35 |date=March 1981 |pmid=6455456 |doi=10.1016/0165-0327(81)90016-1 }}</ref> It is unknown whether the underlying diseases induce depression through effect on quality of life, or through shared etiologies (such as degeneration of the [[basal ganglia]] in [[Parkinson's disease]] or immune dysregulation in asthma).<ref>{{cite journal |vauthors=Kewalramani A, Bollinger ME, Postolache TT |title=Asthma and Mood Disorders |journal=International Journal of Child Health and Human Development |volume=1 |issue=2 |pages=115–23 |date=1 January 2008 |pmid=19180246 |pmc=2631932 }}</ref> Depression may also be [[iatrogenic]] (the result of healthcare), such as drug-induced depression. Therapies associated with depression include [[interferon]]s, [[beta blocker]]s,<ref name="e058">{{cite journal | last1=Qato | first1=Dima Mazen | last2=Ozenberger | first2=Katharine | last3=Olfson | first3=Mark | title=Prevalence of Prescription Medications With Depression as a Potential Adverse Effect Among Adults in the United States | journal=JAMA | volume=319 | issue=22 | date=12 June 2018 | pages=2289–2298 | issn=0098-7484 | pmid=29896627 | pmc=6583503 | doi=10.1001/jama.2018.6741 | doi-access=free | url=https://jamanetwork.com/journals/jama/articlepdf/2684607/jama_qato_2018_oi_180056.pdf | access-date=21 March 2025}}</ref> [[isotretinoin]],<ref name="w764">{{cite journal | last=Bremner | first=J. Douglas | title=Isotretinoin and neuropsychiatric side effects: Continued vigilance is needed | journal=Journal of Affective Disorders Reports | volume=6 | date=2021 | pmid=37168254 | pmc=10168661 | doi=10.1016/j.jadr.2021.100230 | doi-access=free | page=100230}}</ref> [[contraceptives]],<ref name="e058"/> cardiac agents,<ref name="r630">{{cite journal | last1=Zhang | first1=Lijun | last2=Bao | first2=Yanping | last3=Tao | first3=Shuhui | last4=Zhao | first4=Yimiao | last5=Liu | first5=Meiyan | title=The association between cardiovascular drugs and depression/anxiety in patients with cardiovascular disease: A meta-analysis | journal=Pharmacological Research | volume=175 | date=2022 | doi=10.1016/j.phrs.2021.106024 | doi-access=free | page=106024| pmid=34890773 }}</ref> [[anticonvulsant]]s,<ref name="j396">{{cite book | last=de Araujo Filho | first=Gerardo Maria | title=Psychiatric and Behavioral Aspects of Epilepsy | chapter=Can We Anticipate and Prevent the Occurrence of Iatrogenic Psychiatric Events Caused by Anti-seizure Medications and Epilepsy Surgery? | series=Current Topics in Behavioral Neurosciences | publisher=Springer International Publishing | publication-place=Cham | volume=55 | date=2021 | isbn=978-3-031-03222-6 | doi=10.1007/7854_2021_228 | pages=281–305| pmid=33860467 }}</ref> and [[Hormone therapy|hormonal agents]].<ref name="m323">{{cite journal | last1=Wium-Andersen | first1=Marie K. | last2=Jørgensen | first2=Terese S. H. | last3=Halvorsen | first3=Anniken H. | last4=Hartsteen | first4=Birgitte H. | last5=Jørgensen | first5=Martin B. | last6=Osler | first6=Merete | title=Association of Hormone Therapy With Depression During Menopause in a Cohort of Danish Women | journal=JAMA Network Open | volume=5 | issue=11 | date=1 November 2022 | issn=2574-3805 | pmid=36318208 | pmc=9627415 | doi=10.1001/jamanetworkopen.2022.39491 | doi-access=free | page=e2239491 | url=https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2798003/wiumandersen_2022_oi_221117_1666637052.78827.pdf | access-date=21 March 2025}}</ref> [[Celiac disease]] is another possible contributing factor.<ref name="a192">{{cite journal | last1=Mikulska | first1=Joanna | last2=Pietrzak | first2=Diana | last3=Rękawek | first3=Paweł | last4=Siudaj | first4=Krystian | last5=Walczak-Nowicka | first5=Łucja Justyna | last6=Herbet | first6=Mariola | title=Celiac disease and depressive disorders as nutritional implications related to common factors – A comprehensive review | journal=Behavioural Brain Research | volume=462 | date=2024 | doi=10.1016/j.bbr.2024.114886 | page=114886| pmid=38309373 }}</ref>

Substance use in early age is associated with increased risk of developing depression later in life.<ref>{{cite journal | vauthors = Brook DW, Brook JS, Zhang C, Cohen P, Whiteman M | title = Drug use and the risk of major depressive disorder, alcohol dependence, and substance use disorders | journal = Archives of General Psychiatry | volume = 59 | issue = 11 | pages = 1039–44 | date = November 2002 | pmid = 12418937 | doi = 10.1001/archpsyc.59.11.1039 | doi-access = free }}</ref> Depression occurring after giving birth is called [[postpartum depression]] and is thought to be the result of hormonal changes associated with [[pregnancy]].<ref>{{cite journal |vauthors=Meltzer-Brody S |title=New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum |journal=Dialogues in Clinical Neuroscience |volume=13 |issue=1 |pages=89–100 |date=9 January 2017 |doi=10.31887/DCNS.2011.13.1/smbrody |pmid=21485749 |pmc=3181972 }}</ref> [[Seasonal affective disorder]], a type of depression associated with seasonal changes in sunlight, is thought to be triggered by decreased sunlight.<ref name="x376">{{cite book | last1=Roecklein | first1=Kathryn A. | last2=Wong | first2=Patricia M. | title=Encyclopedia of Behavioral Medicine | chapter=Seasonal Affective Disorder | publisher=Springer International Publishing | publication-place=Cham | date=2020 | isbn=978-3-030-39901-6 | doi=10.1007/978-3-030-39903-0_836 | pages=1964–1966}}</ref>
Vitamin B<sub>2</sub>, B<sub>6</sub> and B<sub>12</sub> deficiency may cause depression in females.<ref>{{cite journal |vauthors= Wu Y, Zhang L, Li S, Zhang D | title=Associations of dietary vitamin B1, vitamin B2, vitamin B6, and vitamin B12 with the risk of depression: a systematic review and meta-analysis | journal=Nutrition Reviews | publisher=Oxford University Press (OUP) | date=29 April 2021 | volume=80 | issue=3 | pages=351–366 | issn=0029-6643 | doi=10.1093/nutrit/nuab014 | pmid=33912967 }}</ref>

A 2025 study found that, among more than 172,500 adults in the [[United Kingdom|UK]] aged 39 and older, those with a history of depression experienced the onset of [[chronic illnesses]] approximately 30% earlier than those without depression.<ref>{{Cite journal |last1=Fleetwood |first1=Kelly J. |last2=Guthrie |first2=Bruce |last3=Jackson |first3=Caroline A. |last4=Kelly |first4=Paul A. T. |last5=Mercer |first5=Stewart W. |last6=Morales |first6=Daniel R. |last7=Norrie |first7=John D. |last8=Smith |first8=Daniel J. |last9=Sudlow |first9=Cathie |last10=Prigge |first10=Regina |date=13 February 2025 |title=Depression and physical multimorbidity: A cohort study of physical health condition accrual in UK Biobank |journal=PLOS Medicine |language=en |volume=22 |issue=2 |pages=e1004532 |doi=10.1371/journal.pmed.1004532 |doi-access=free |issn=1549-1676 |pmc=11825000 |pmid=39946376}}</ref>

===Environmental===
[[Adverse childhood experiences]] (incorporating [[Child abuse|childhood abuse]], neglect and [[Dysfunctional family|family dysfunction]]) markedly increase the risk of major depression, especially if more than one type.<ref name="e625">{{cite book | last1=Luyten | first1=Patrick | last2=Fonagy | first2=Peter | title=Etiopathogenic Theories and Models in Depression | chapter=An Integrative Developmental Psychopathology Approach to Depression | publisher=Springer International Publishing | publication-place=Cham | date=2021 | isbn=978-3-030-77328-1 | doi=10.1007/978-3-030-77329-8_13 | pages=245–263}}</ref> Childhood trauma also correlates with severity of depression, poor responsiveness to treatment and length of illness.<ref name="r126">{{cite journal | last1=Lippard | first1=Elizabeth T.C. | last2=Nemeroff | first2=Charles B. | title=The Devastating Clinical Consequences of Child Abuse and Neglect: Increased Disease Vulnerability and Poor Treatment Response in Mood Disorders | journal=American Journal of Psychiatry | volume=177 | issue=1 | date=1 January 2020 | issn=0002-953X | pmid=31537091 | pmc=6939135 | doi=10.1176/appi.ajp.2019.19010020 | doi-access=free | pages=20–36 }}</ref> Some are more susceptible than others to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility.<ref name="n391">{{cite journal | last1=Li | first1=Muzi | last2=Liu | first2=Sibei | last3=D'Arcy | first3=Carl | last4=Gao | first4=Tingting | last5=Meng | first5=Xiangfei | title=Interactions of childhood maltreatment and genetic variations in adult depression: A systematic review | journal=Journal of Affective Disorders | volume=276 | date=2020 | doi=10.1016/j.jad.2020.06.055 | doi-access=free | pages=119–136 | pmid=32697690 | url=http://escholarship.mcgill.ca/downloads/dr26z282p | access-date=21 March 2025}}</ref>  Couples in unhappy marriages have a higher risk of developing clinical depression.<ref>{{cite journal |vauthors= Goldfarb MR, Trudel G |date= 6 May 2019|title= Marital quality and depression: a review |journal= Marriage & Family Review |publisher= Routledge: Taylor & Francis Group|volume= 55 |issue= 8 |pages= 737–763 |doi= 10.1080/01494929.2019.1610136 |s2cid= 165116052}} Citing among others: {{cite journal |vauthors=Weissman MM |title=Advances in psychiatric epidemiology: rates and risks for major depression |journal=Am J Public Health |volume=77 |issue=4 |pages=445–51 |date=April 1987 |pmid=3826462 |pmc=1646931 |doi=10.2105/ajph.77.4.445 }}</ref>

There appears to be a link between [[air pollution]] and depression and suicide. There may be an association between long-term [[PM2.5]] exposure and depression, and a possible association between short-term [[PM10]] exposure and suicide.<ref name="pmid31850801">{{cite journal | vauthors = Braithwaite I, Zhang S, Kirkbride JB, Osborn DP, Hayes JF | title = Air Pollution (Particulate Matter) Exposure and Associations with Depression, Anxiety, Bipolar, Psychosis and Suicide Risk: A Systematic Review and Meta-Analysis | journal = Environmental Health Perspectives | volume = 127 | issue = 12 | page = 126002 | date = December 2019 | pmid = 31850801 | pmc = 6957283 | doi = 10.1289/EHP4595 | bibcode = 2019EnvHP.127l6002B }}</ref>

Living alone has been found to increase the risk of depression by 42%.<ref name="PMH">{{cite journal |doi= 10.3389/fpsyt.2022.954857 |doi-access= free |pmid= 36111305 |pmc= 9468273 |title= Assessment of the relationship between living alone and the risk of depression based on longitudinal studies: A systematic review and meta-analysis |date= 2022 |last1= Wu |first1= Daolin |last2= Liu |first2= Fuwei |last3= Huang |first3= Shan |journal= Frontiers in Psychiatry |volume= 13 }}</ref>