Editing Major depressive disorder (section)

==Pathophysiology==
{{further|Biology of depression|Epigenetics of depression}}
The pathophysiology of depression is not completely understood, but current theories center around [[monoamine]]rgic systems, the [[circadian rhythm]], immunological dysfunction, [[HPA axis|HPA-axis]] dysfunction, and structural or functional abnormalities of emotional circuits.

Derived from the effectiveness of monoaminergic drugs in treating depression, the monoamine theory posits that insufficient activity of [[monoamine neurotransmitter]]s is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. First, acute depletion of [[tryptophan]]—a necessary precursor of [[serotonin]] and a monoamine—can cause depression in those in remission or relatives of people who are depressed, suggesting that decreased serotonergic neurotransmission is important in depression.<ref name="g648">{{cite book | last=Silva | first=Hernán | title=Etiopathogenic Theories and Models in Depression | chapter=Neurobiology of Depression | series=Depression and Personality | publisher=Springer International Publishing | publication-place=Cham | date=2021 | isbn=978-3-030-77328-1 | doi=10.1007/978-3-030-77329-8_8 | pages=155–166}}</ref> Second, the correlation between depression risk and polymorphisms in the [[5-HTTLPR]] gene, which codes for serotonin receptors, suggests a link.<ref name="t044">{{cite book | last1=Manchia | first1=Mirko | last2=Schatzberg | first2=Alan | title=Tasman's Psychiatry | chapter=Neurobiology of Mood Disorders | publisher=Springer International Publishing | publication-place=Cham | date=2024 | isbn=978-3-030-51365-8 | doi=10.1007/978-3-030-51366-5_83 | pages=651–682}}</ref> Third, decreased size of the [[locus coeruleus]], reduced activity of [[tyrosine hydroxylase]], increased density of [[alpha-2 adrenergic receptor]], and evidence from rat models suggest decreased [[Adrenergic nervous system|adrenergic]] neurotransmission in depression.<ref>{{cite journal |vauthors=Delgado PL, Moreno FA |title=Role of norepinephrine in depression |journal=The Journal of Clinical Psychiatry |volume=61 |issue=Suppl 1 |pages=5–12 |year=2000 |pmid=10703757 }}</ref> Furthermore, decreased levels of [[homovanillic acid]], altered response to [[dextroamphetamine]], responses of depressive symptoms to [[dopamine receptor]] agonists, decreased [[dopamine receptor D1|dopamine receptor D<sub>1</sub>]] binding in the [[striatum]],<ref>{{cite journal |vauthors=Savitz JB, Drevets WC |title=Neuroreceptor imaging in depression |journal=Neurobiology of Disease |volume=52 |pages=49–65 |date=April 2013 |pmid=22691454 |doi=10.1016/j.nbd.2012.06.001 |doi-access=free }}</ref> and [[Polymorphism (biology)|polymorphism]] of [[dopamine receptor]] genes implicate [[dopamine]], another monoamine, in depression.<ref>{{cite journal |vauthors=Hasler G |title=Pathophysiology of depression: do we have any solid evidence of interest to clinicians? |journal=World Psychiatry |volume=9 |issue=3 |pages=155–61 |date=October 2010 |pmid=20975857 |pmc=2950973 |doi=10.1002/j.2051-5545.2010.tb00298.x}}</ref><ref>{{cite journal |vauthors=Dunlop BW, Nemeroff CB |title=The role of dopamine in the pathophysiology of depression |journal=Archives of General Psychiatry |volume=64 |issue=3 |pages=327–37 |date=March 2007 |pmid=17339521 |doi=10.1001/archpsyc.64.3.327 |s2cid=26550661 |url=https://www.researchgate.net/publication/6466257}}</ref> Lastly, increased activity of [[monoamine oxidase]], which degrades monoamines, has been associated with depression.<ref>{{cite journal |vauthors=Meyer JH, Ginovart N, Boovariwala A, et al |title=Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression |journal=Archives of General Psychiatry |volume=63 |issue=11 |pages=1209–16 |date=November 2006 |pmid=17088501 |doi=10.1001/archpsyc.63.11.1209|doi-access=free }}</ref> However, the monoamine theory is inconsistent with observations that serotonin depletion does not cause depression in healthy persons, that antidepressants instantly increase levels of monoamines but take weeks to work, and the existence of atypical antidepressants which can be effective despite not targeting this pathway.<ref>{{cite book | veditors = Davis KL, Charney D, Coyle JT, Nemeroff C |title= Neuropsychopharmacology: the fifth generation of progress: an official publication of the American College of Neuropsychopharmacology|date=2002|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-2837-9|pages=1139–63|edition=5th}}</ref>

One proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is a desensitization of self-inhibition in [[raphe nuclei]] by the increased serotonin mediated by antidepressants.<ref>{{cite journal |vauthors=Adell A |title=Revisiting the role of raphe and serotonin in neuropsychiatric disorders |journal=The Journal of General Physiology |volume=145 |issue=4 |pages=257–59 |date=April 2015 |pmid=25825168 |doi=10.1085/jgp.201511389 |pmc=4380212}}</ref> However, disinhibition of the dorsal raphe has been proposed to occur as a result of decreased serotonergic activity in tryptophan depletion, resulting in a depressed state mediated by increased serotonin. Further countering the monoamine hypothesis is the fact that rats with lesions of the dorsal raphe are not more depressive than controls; the finding of increased jugular [[5-Hydroxyindoleacetic acid|5-HIAA]] in people who are depressed that normalized with [[selective serotonin reuptake inhibitor]] (SSRI) treatment, and the preference for [[carbohydrate]]s in people who are depressed.<ref>{{cite journal |vauthors=Andrews PW, Bharwani A, Lee KR, Fox M, Thomson JA |title=Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response |journal=Neuroscience and Biobehavioral Reviews |volume=51 |pages=164–88 |date=April 2015 |pmid=25625874 |doi=10.1016/j.neubiorev.2015.01.018 |s2cid=23980182 }}</ref> Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.<ref>{{cite journal |vauthors=Lacasse JR, Leo J |title=Serotonin and depression: a disconnect between the advertisements and the scientific literature |journal=PLOS Medicine |volume=2 |issue=12 |page=e392 |date=December 2005 |pmid=16268734 |pmc=1277931 |doi=10.1371/journal.pmed.0020392 |doi-access=free }}</ref> A 2022 review found no consistent evidence supporting the serotonin hypothesis linking serotonin levels and depression.<ref>{{cite journal |journal= Mol Psychiatry |date= July 2022 |title= The serotonin theory of depression: a systematic umbrella review of the evidence |vauthors= Moncrieff J, Cooper RE, Stockman T, et al |volume= 28 |issue= 8 |pages= 3243–3256 |pmid=35854107 |doi=10.1038/s41380-022-01661-0|pmc= 10618090 |s2cid= 250646781 |doi-access= free }} Lay source [https://medicalxpress.com/news/2022-07-evidence-depression-serotonin-comprehensive.html Medicalxpress]</ref>

[[HPA axis|HPA-axis]] abnormalities have been suggested in depression given the association of [[CRHR1]] with depression and the increased frequency of [[Dexamethasone suppression test|dexamethasone test]] non-suppression in people who are depressed. However, this abnormality is not adequate as a diagnosis tool because its sensitivity is only 44%.<ref>{{cite journal |vauthors=Arana GW, Baldessarini RJ, Ornsteen M |title=The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Commentary and review |journal=Archives of General Psychiatry |volume=42 |issue=12 |pages=1193–204 |date=December 1985 |pmid=3000317 |doi=10.1001/archpsyc.1985.01790350067012}}</ref> These stress-related abnormalities are thought to be the cause of hippocampal volume reductions seen in people who are depressed.<ref>{{cite journal |vauthors=Varghese FP, Brown ES |title=The Hypothalamic-Pituitary-Adrenal Axis in Major Depressive Disorder: A Brief Primer for Primary Care Physicians |journal=Primary Care Companion to the Journal of Clinical Psychiatry |volume=3 |issue=4 |pages=151–55 |date=August 2001 |pmid=15014598 |pmc=181180 |doi=10.4088/pcc.v03n0401 }}</ref> Furthermore, a [[meta-analysis]] yielded decreased dexamethasone suppression, and increased response to psychological stressors.<ref>{{cite journal |vauthors=Lopez-Duran NL, Kovacs M, George CJ |title=Hypothalamic-pituitary-adrenal axis dysregulation in depressed children and adolescents: a meta-analysis |journal=Psychoneuroendocrinology |volume=34 |issue=9 |pages=1272–1283 |year=2009 |pmid=19406581 |pmc=2796553 |doi=10.1016/j.psyneuen.2009.03.016}}</ref> Further abnormal results have been obscured with the [[cortisol awakening response]], with increased response being associated with depression.<ref>{{cite journal |vauthors=Dedovic K, Ngiam J |title=The cortisol awakening response and major depression: examining the evidence |journal=Neuropsychiatric Disease and Treatment |volume=11 |pages=1181–1189 |year=2015 |pmid=25999722 |pmc=4437603 |doi=10.2147/NDT.S62289 |doi-access=free }}</ref>

There is also a connection between the gut microbiome and the central nervous system, otherwise known as the [[Gut–brain axis|Gut-Brain axis]], which is a two-way communication system between the brain and the gut. Experiments have shown that [[microbiota]] in the gut can play an important role in depression, as people with MDD often have gut-brain dysfunction. One analysis showed that those with MDD have different bacteria in their guts. Bacteria ''[[Bacteroidota|Bacteroidetes]]'' and ''Firmicutes'' were most affected in people with MDD, and they are also impacted in people with [[irritable bowel syndrome]].<ref name="GB">{{cite journal | vauthors = Zhu F, Tu H, Chen T | title = The Microbiota-Gut-Brain Axis in Depression: The Potential Pathophysiological Mechanisms and Microbiota Combined Antidepression Effect | journal = Nutrients | volume = 14 | issue = 10 | pages = 2081 | date = May 2022 | pmid = 35631224 | pmc = 9144102 | doi = 10.3390/nu14102081 | doi-access = free }}</ref> Another study showed that people with IBS have a higher chance of developing depression, which shows the two are connected.<ref>{{cite journal | vauthors = Fond G, Loundou A, Hamdani N, Boukouaci W, Dargel A, Oliveira J, Roger M, Tamouza R, Leboyer M, Boyer L | title = Anxiety and depression comorbidities in irritable bowel syndrome (IBS): a systematic review and meta-analysis | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 264 | issue = 8 | pages = 651–660 | date = December 2014 | pmid = 24705634 | doi = 10.1007/s00406-014-0502-z}}</ref> There is even evidence suggesting that altering the microbes in the gut can have regulatory effects on developing depression.<ref name="GB" />

Theories unifying [[neuroimaging]] findings have been proposed. The first model proposed is the limbic-cortical model, which involves hyperactivity of the ventral paralimbic regions and hypoactivity of frontal regulatory regions in emotional processing.<ref>{{cite journal |vauthors=Mayberg HS |title=Limbic-cortical dysregulation: a proposed model of depression |journal=The Journal of Neuropsychiatry and Clinical Neurosciences |volume=9 |issue=3 |pages=471–81 |year=1997 |pmid=9276848 |doi=10.1176/jnp.9.3.471}}</ref> Another model, the cortico-striatal model, suggests that abnormalities of the [[prefrontal cortex]] in regulating striatal and subcortical structures result in depression.<ref>{{cite journal |vauthors=Graham J, Salimi-Khorshidi G, Hagan C, Walsh N, Goodyer I, Lennox B, Suckling J |title=Meta-analytic evidence for neuroimaging models of depression: state or trait? |journal=Journal of Affective Disorders |volume=151 |issue=2 |pages=423–431 |year=2013 |pmid=23890584 |doi=10.1016/j.jad.2013.07.002 |doi-access=free }}</ref> Another model proposes hyperactivity of [[Salience network|salience structures]] in identifying negative stimuli and hypoactivity of cortical regulatory structures resulting in a negative [[emotional bias]] and depression, consistent with emotional bias studies.<ref>{{cite journal |vauthors=Hamilton JP, Etkin A, Furman DJ, Lemus MG, Johnson RF, Gotlib IH |title=Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line activation and neural response data |journal=The American Journal of Psychiatry |volume=169 |issue=7 |pages=693–703 |date=July 2012 |pmid=22535198 |doi=10.1176/appi.ajp.2012.11071105 |pmc=11889638 }}</ref>

=== Immune pathogenesis theories on depression ===
The newer field of [[psychoneuroimmunology]], the study between the immune system and the nervous system and emotional state, suggests that cytokines may impact depression.

[[Depression and immune function|Immune system abnormalities]] have been observed, including increased levels of [[cytokines]] -cells produced by immune cells that affect inflammation- involved in generating [[sickness behavior]], creating a pro-inflammatory profile in MDD.<ref>{{cite journal | vauthors = Krishnadas R, Cavanagh J | title = Depression: an inflammatory illness? | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 83 | issue = 5 | pages = 495–502 | date = May 2012 | pmid = 22423117 | doi = 10.1136/jnnp-2011-301779 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Patel A | title = Review: the role of inflammation in depression | journal = Psychiatria Danubina | volume = 25 | issue = Suppl 2 | pages = S216–S223 | date = September 2013 | pmid = 23995180 }}</ref><ref>{{cite journal | vauthors = Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL | title = A meta-analysis of cytokines in major depression | journal = Biological Psychiatry | volume = 67 | issue = 5 | pages = 446–457 | date = March 2010 | pmid = 20015486 | doi = 10.1016/j.biopsych.2009.09.033 | s2cid = 230209 }}</ref> Some people with depression have increased levels of pro-inflammatory cytokines and some have decreased levels of anti-inflammatory cytokines.<ref>{{cite journal | vauthors = Osimo EF, Pillinger T, Rodriguez IM, Khandaker GM, Pariante CM, Howes OD | title = Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls | journal = Brain, Behavior, and Immunity | volume = 87 | pages = 901–909 | date = July 2020 | pmid = 32113908 | doi = 10.1016/j.bbi.2020.02.010 | pmc = 7327519 }}</ref> Research suggests that treatments can reduce pro-inflammatory cell production, like the experimental treatment of ketamine with treatment-resistant depression.<ref>{{cite journal | vauthors = Sukhram SD, Yilmaz G, Gu J | title = Antidepressant Effect of Ketamine on Inflammation-Mediated Cytokine Dysregulation in Adults with Treatment-Resistant Depression: Rapid Systematic Review | journal = Oxidative Medicine and Cellular Longevity | volume = 2022 | pages = 1061274 | date = 16 September 2022 | pmid = 36160713 | pmc = 9507757 | doi = 10.1155/2022/1061274 | doi-access = free | editor-first = Ajinkya | editor-last = Sase }}</ref> With this, in MDD, people will more likely have a Th-1 dominant immune profile, which is a pro-inflammatory profile. This suggests that there are components of the immune system affecting the pathology of MDD.<ref>{{cite journal | vauthors = Rachayon M, Jirakran K, Sodsai P, Sughondhabirom A, Maes M | title = T cell activation and deficits in T regulatory cells are associated with major depressive disorder and severity of depression | journal = Scientific Reports | volume = 14 | issue = 1 | pages = 11177 | date = May 2024 | pmid = 38750122 | doi = 10.1038/s41598-024-61865-y | pmc = 11096341 | bibcode = 2024NatSR..1411177R }}</ref>

Another way [[cytokine]]s can affect depression is in the [[kynurenine pathway]], and when this is overactivated, it can cause depression. This can be due to too much [[microglia]]l activation and too little [[Astrocyte|astrocytic]] activity. When microglia get activated, they release pro-inflammatory cytokines that cause an increase in the production of [[Cytochrome c oxidase subunit 2|COX<sub>2</sub>]]. This, in turn, causes the production of [[Prostaglandin E2|PGE<sub>2</sub>]], which is a [[prostaglandin]], and this catalyzes the production of [[Indolamines|indolamine]], IDO. IDO causes [[tryptophan]] to get converted into [[kynurenine]], and kynurenine becomes [[quinolinic acid]].<ref>{{cite journal | vauthors = McNally L, Bhagwagar Z, Hannestad J | title = Inflammation, glutamate, and glia in depression: a literature review | journal = CNS Spectrums | volume = 13 | issue = 6 | pages = 501–510 | date = June 2008 | pmid = 18567974 | doi = 10.1017/S1092852900016734 }}</ref> Quinolinic acid is an agonist for [[NMDA receptor]]s, so it activates the pathway. Studies have shown that the post-mortem brains of patients with MDD have higher levels of quinolinic acid than people who did not have MDD. With this, researchers have also seen that the concentration of quinolinic acid correlates to the severity of depressive symptoms.<ref>{{cite journal | vauthors = Hestad K, Alexander J, Rootwelt H, Aaseth JO | title = The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases | journal = Biomolecules | volume = 12 | issue = 7 | pages = 998 | date = July 2022 | pmid = 35883554 | pmc = 9313172 | doi = 10.3390/biom12070998 | doi-access = free }}</ref><!--

[[MRI]] scans of people with depression have revealed a number of differences in brain structure compared to those who are not depressed. Meta-analyses of neuroimaging studies in major depression report that, compared to [[Scientific control|controls]], people who are depressed have increased volume of the [[lateral ventricles]] and [[adrenal gland]] and smaller volumes of the [[basal ganglia]], [[thalamus]], [[hippocampus]], and [[frontal lobe]] (including the [[orbitofrontal cortex]] and [[gyrus rectus]]).<ref>{{cite journal |vauthors=Kempton MJ, Salvador Z, Munafò MR, Geddes JR, Simmons A, Frangou S, Williams SC |title=Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder |journal=Archives of General Psychiatry |volume=68 |issue=7 |pages=675–690 |year=2011 |pmid=21727252 |doi=10.1001/archgenpsychiatry.2011.60|doi-access=free }}</ref><ref>{{cite journal |vauthors=Arnone D, McIntosh AM, Ebmeier KP, Munafò MR, Anderson IM |title=Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses |journal=European Neuropsychopharmacology |volume=22 |issue=1 |pages=1–16 |year=2012 |pmid=21723712 |doi=10.1016/j.euroneuro.2011.05.003 |s2cid=42105719 }}</ref> [[Hyperintensities]] have been associated with people with a late age of onset, and have led to the development of the theory of [[Subcortical ischemic depression|vascular depression]].<ref>{{cite journal |vauthors=Herrmann LL, Le Masurier M, Ebmeier KP |title=White matter hyperintensities in late life depression: a systematic review |journal=Journal of Neurology, Neurosurgery, and Psychiatry |volume=79 |issue=6 |pages=619–624 |year=2008 |pmid=17717021 |doi=10.1136/jnnp.2007.124651 |s2cid=23759460 }}</ref> -->