Editing Psychosis (section)

=== Neurobiology ===
{{Further|Dopamine hypothesis of schizophrenia}}
{{Technical|section|date=November 2019}}<!-- Probably need further explanations on: NMDA mediated top down predictions and bottom up AMPA mediated predictions errors. -->
Psychosis has been traditionally linked to the overactivity of the [[neurotransmitter]] [[dopamine]]. In particular to its effect in the [[mesolimbic pathway]]. The two major sources of evidence given to support this theory are that [[dopamine receptor D2]] blocking drugs (i.e., [[antipsychotic]]s) tend to reduce the intensity of psychotic symptoms, and that drugs that accentuate dopamine release, or inhibit its reuptake (such as [[amphetamine]]s and [[cocaine]]) can trigger psychosis in some people (see [[stimulant psychosis]]).<ref name="Kapur">{{cite journal | vauthors = Kapur S, Mizrahi R, Li M | title = From dopamine to salience to psychosis—linking biology, pharmacology and phenomenology of psychosis | journal = Schizophrenia Research | volume = 79 | issue = 1 | pages = 59–68 | date = November 2005 | pmid = 16005191 | doi = 10.1016/j.schres.2005.01.003 | s2cid = 2654713 }}</ref> However, there is substantial evidence that dopaminergic overactivity does not fully explain psychosis, and that neurodegerative pathophysiology plays a significant role. This is evidenced by the fact that psychosis commonly occurs in neurodegenerative diseases of the dopaminergic nervous system, such as Parkinson's disease, which involved reduced, rather than increased, dopaminergic activity.<ref>{{Cite journal |last1=Fénelon |first1=Gilles |last2=Alves |first2=Guido |date=2010-02-15 |title=Epidemiology of psychosis in Parkinson's disease |url=https://www.sciencedirect.com/science/article/abs/pii/S0022510X09007679 |journal=Journal of the Neurological Sciences |series=Mental Dysfunction in Parkinson's Disease |volume=289 |issue=1 |pages=12–17 |doi=10.1016/j.jns.2009.08.014 |pmid=19740486 |issn=0022-510X}}</ref>

The [[endocannabinoid system]] is also implicated in psychosis. This is evidenced by the propensity of [[Cannabinoid receptor 1|CB<sub>1</sub> receptor]] agonists such as [[THC]] to induce psychotic symptoms,<ref>{{Citation |last=D'Souza |first=Deepak Cyril |title=Cannabinoids and Psychosis |date=2007-01-01 |journal=International Review of Neurobiology |volume=78 |pages=289–326 |url=https://www.sciencedirect.com/science/article/abs/pii/S0074774206780102 |access-date=2024-11-06 |series=Integrating the Neurobiology of Schizophrenia |publisher=Academic Press|doi=10.1016/S0074-7742(06)78010-2 |pmid=17349865 |isbn=978-0-12-373737-3 }}</ref> and the efficacy of [[Cannabinoid receptor 1|CB<sub>1</sub> receptor]] antagonists such as [[Cannabidiol|CBD]] in ameliorating psychosis.<ref>{{Cite journal |last1=Chesney |first1=Edward |last2=Oliver |first2=Dominic |last3=McGuire |first3=Philip |date=2022-05-01 |title=Cannabidiol (CBD) as a novel treatment in the early phases of psychosis |journal=Psychopharmacology |language=en |volume=239 |issue=5 |pages=1179–1190 |doi=10.1007/s00213-021-05905-9 |issn=1432-2072 |pmc=9110455 |pmid=34255100}}</ref>

NMDA receptor dysfunction has been proposed as a mechanism in psychosis.<ref>{{cite journal | vauthors = Egerton A, Fusar-Poli P, Stone JM | title = Glutamate and psychosis risk | journal = Current Pharmaceutical Design | volume = 18 | issue = 4 | pages = 466–478 | date = 2012 | pmid = 22239577 | doi = 10.2174/138161212799316244 }}</ref>  This theory is reinforced by the fact that [[dissociative]] [[NMDA receptor antagonist]]s such as [[ketamine]], [[Phencyclidine|PCP]] and [[dextromethorphan]] (at large overdoses) induce a psychotic state. The symptoms of dissociative [[Substance intoxication|intoxication]] are also considered to mirror the symptoms of schizophrenia, including [[Schizophrenia#Negative symptoms|negative symptoms]].<ref>{{cite journal | vauthors = Bergeron R, Coyle JT | title = NAAG, NMDA receptor and psychosis | journal = Current Medicinal Chemistry | volume = 19 | issue = 9 | pages = 1360–1364 | date = 2012 | pmid = 22304714 | pmc = 3424071 | doi = 10.2174/092986712799462685 }}</ref>  NMDA receptor antagonism, in addition to producing symptoms reminiscent of psychosis, mimics the neurophysiological aspects, such as reduction in the amplitude of [[P50 (neuroscience)|P50]], [[P300 (neuroscience)|P300]], and [[Mismatch negativity|MMN]] [[evoked potential]]s.<ref>{{cite journal | vauthors = Adams RA, Stephan KE, Brown HR, Frith CD, Friston KJ | title = The computational anatomy of psychosis | journal = Frontiers in Psychiatry | volume = 4 | pages = 47 | date = 2013 | pmid = 23750138 | pmc = 3667557 | doi = 10.3389/fpsyt.2013.00047 | doi-access = free }}</ref> Hierarchical Bayesian neurocomputational models of sensory feedback, in agreement with neuroimaging literature, link NMDA receptor hypofunction to delusional or hallucinatory symptoms via proposing a failure of NMDA mediated top down predictions to adequately cancel out enhanced bottom up AMPA mediated predictions errors.<ref>{{cite journal | vauthors = Corlett PR, Frith CD, Fletcher PC | title = From drugs to deprivation: a Bayesian framework for understanding models of psychosis | journal = Psychopharmacology | volume = 206 | issue = 4 | pages = 515–530 | date = November 2009 | pmid = 19475401 | pmc = 2755113 | doi = 10.1007/s00213-009-1561-0 }}</ref> Excessive prediction errors in response to stimuli that would normally not produce such a response is thought to root from conferring excessive salience to otherwise mundane events.<ref>{{cite journal | vauthors = Corlett PR, Honey GD, Krystal JH, Fletcher PC | title = Glutamatergic model psychoses: prediction error, learning, and inference | journal = Neuropsychopharmacology | volume = 36 | issue = 1 | pages = 294–315 | date = January 2011 | pmid = 20861831 | pmc = 3055519 | doi = 10.1038/npp.2010.163 }}</ref> Dysfunction higher up in the hierarchy, where representation is more abstract, could result in delusions.<ref>{{cite journal | vauthors = Corlett PR, Taylor JR, Wang XJ, Fletcher PC, Krystal JH | title = Toward a neurobiology of delusions | journal = Progress in Neurobiology | volume = 92 | issue = 3 | pages = 345–369 | date = November 2010 | pmid = 20558235 | pmc = 3676875 | doi = 10.1016/j.pneurobio.2010.06.007 }}</ref> The common finding of reduced [[GAD67]] expression in psychotic disorders may explain enhanced AMPA mediated signaling, caused by reduced GABAergic inhibition.<ref>{{cite journal | vauthors = Kalkman HO, Loetscher E | title = GAD(67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis | journal = Journal of Neural Transmission | volume = 110 | issue = 7 | pages = 803–812 | date = July 2003 | pmid = 12811640 | doi = 10.1007/s00702-003-0826-8 | s2cid = 31685339 }}</ref><ref>{{cite journal | vauthors = Akbarian S, Huang HS | title = Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders | journal = Brain Research Reviews | volume = 52 | issue = 2 | pages = 293–304 | date = September 2006 | pmid = 16759710 | doi = 10.1016/j.brainresrev.2006.04.001 | s2cid = 25771139 }}</ref>

The connection between dopamine and psychosis is generally believed to be complex. While dopamine receptor D2 suppresses [[adenylate cyclase]] activity, the [[Dopamine receptor D1|D1]] receptor increases it. If D2-blocking drugs are administered, the blocked dopamine spills over to the D1 receptors. The increased adenylate cyclase activity affects [[genetic expression]] in the nerve cell, which takes time. Hence antipsychotic drugs take a week or two to reduce the symptoms of psychosis. Moreover, newer and equally effective antipsychotic drugs actually block slightly less dopamine in the brain than older drugs whilst also blocking 5-HT2A receptors, suggesting the 'dopamine hypothesis' may be oversimplified.<ref>{{cite journal | vauthors = Jones HM, Pilowsky LS | title = Dopamine and antipsychotic drug action revisited | journal = The British Journal of Psychiatry | volume = 181 | issue = 4 | pages = 271–275 | date = October 2002 | pmid = 12356650 | doi = 10.1192/bjp.181.4.271 | doi-access = free }}</ref> Soyka and colleagues found no evidence of dopaminergic dysfunction in people with alcohol-induced psychosis<ref>{{cite journal | vauthors = Soyka M, Zetzsche T, Dresel S, Tatsch K | title = FDG-PET and IBZM-SPECT suggest reduced thalamic activity but no dopaminergic dysfunction in chronic alcohol hallucinosis | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 12 | issue = 2 | pages = 287–288 | date = May 2000 | pmid = 11001615 | doi = 10.1176/appi.neuropsych.12.2.287 }}</ref> and Zoldan et al. reported moderately successful use of [[ondansetron]], a 5-HT<sub>3</sub> receptor antagonist, in the treatment of [[levodopa]] psychosis in [[Parkinson's disease]] patients.<ref name="Zoldan_et_al_1995">{{cite journal | vauthors = Zoldan J, Friedberg G, Livneh M, Melamed E | title = Psychosis in advanced Parkinson's disease: treatment with ondansetron, a 5-HT3 receptor antagonist | journal = Neurology | volume = 45 | issue = 7 | pages = 1305–1308 | date = July 1995 | pmid = 7617188 | doi = 10.1212/WNL.45.7.1305 | s2cid = 45540572 }}</ref>

A review found an association between a first-episode of psychosis and prediabetes.<ref>{{cite journal | vauthors = Perry BI, McIntosh G, Weich S, Singh S, Rees K | title = The association between first-episode psychosis and abnormal glycaemic control: systematic review and meta-analysis | journal = The Lancet. Psychiatry | volume = 3 | issue = 11 | pages = 1049–1058 | date = November 2016 | pmid = 27720402 | doi = 10.1016/S2215-0366(16)30262-0 | url = http://wrap.warwick.ac.uk/84089/1/WRAP-association-episode-abnormal-review-Perry-2016.pdf | access-date = 2019-07-03 | url-status = live | archive-url = https://web.archive.org/web/20201001200220/http://wrap.warwick.ac.uk/84089/1/WRAP-association-episode-abnormal-review-Perry-2016.pdf | archive-date = 2020-10-01 }}</ref>

Prolonged or high dose use of [[psychostimulants]] can alter normal functioning, making it similar to the manic phase of bipolar disorder.<ref>{{cite journal | vauthors = Curran C, Byrappa N, McBride A | title = Stimulant psychosis: systematic review | journal = The British Journal of Psychiatry | volume = 185 | issue = 3 | pages = 196–204 | date = September 2004 | pmid = 15339823 | doi = 10.1192/bjp.185.3.196 | doi-access = free }}</ref> NMDA antagonists replicate some of the so-called "negative" symptoms like [[thought disorder]] in subanesthetic doses (doses insufficient to induce [[anesthesia]]), and [[catatonia]] in high doses. Psychostimulants, especially in one already prone to psychotic thinking, can cause some "positive" symptoms, such as delusional beliefs, particularly those persecutory in nature.