Editing Psychosis (section)

== Pathophysiology ==
=== Neuroimaging ===
The first brain image of an individual with psychosis was completed as far back as 1935 using a technique called [[pneumoencephalography]]<ref>{{cite journal | vauthors = Moore MT, Nathan D, Elliott AR, Laubach C |title=Encephalographic studies in mental disease |journal=American Journal of Psychiatry|volume=92|issue=1|pages=43–67|doi= 10.1176/ajp.92.1.43|year=1935 }}</ref> (a painful and now obsolete procedure where [[cerebrospinal fluid]] is drained from around the brain and replaced with air to allow the structure of the brain to show up more clearly on an [[X-ray]] picture).

Both [[Antipsychotic#First episode psychosis|first episode psychosis]], and high risk status is associated with reductions in grey matter volume (GMV). First episode psychotic and high risk populations are associated with similar but distinct abnormalities in GMV. Reductions in the right [[middle temporal gyrus]], right [[superior temporal gyrus]] (STG), right [[parahippocampus]], right [[hippocampus]], right [[middle frontal gyrus]], and left [[anterior cingulate cortex]] (ACC) are observed in high risk populations. Reductions in first episode psychosis span a region from the right STG to the right insula, left insula, and cerebellum, and are more severe in the right ACC, right STG, insula and cerebellum.<ref>{{cite journal | vauthors = Fusar-Poli P, Radua J, McGuire P, Borgwardt S | title = Neuroanatomical maps of psychosis onset: voxel-wise meta-analysis of antipsychotic-naive VBM studies | journal = Schizophrenia Bulletin | volume = 38 | issue = 6 | pages = 1297–1307 | date = November 2012 | pmid = 22080494 | pmc = 3494061 | doi = 10.1093/schbul/sbr134 }}</ref><ref>{{cite journal | vauthors = Palaniyappan L, Balain V, Liddle PF | title = The neuroanatomy of psychotic diathesis: a meta-analytic review | journal = Journal of Psychiatric Research | volume = 46 | issue = 10 | pages = 1249–1256 | date = October 2012 | pmid = 22790253 | doi = 10.1016/j.jpsychires.2012.06.007 }}</ref>

Another meta analysis reported bilateral reductions in insula, operculum, STG, medial frontal cortex, and ACC, but also reported increased GMV in the right [[lingual gyrus]] and left [[precentral gyrus]].<ref name="Radua">{{cite journal | vauthors = Radua J, Borgwardt S, Crescini A, Mataix-Cols D, Meyer-Lindenberg A, McGuire PK, Fusar-Poli P | title = Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication | journal = Neuroscience and Biobehavioral Reviews | volume = 36 | issue = 10 | pages = 2325–2333 | date = November 2012 | pmid = 22910680 | doi = 10.1016/j.neubiorev.2012.07.012 | quote = Patients with an FEP showed large and robust bilateral decreases of GMV in a peri-Sylvian cluster that included the insula, operculum and the superior temporal gyrus, and in the medial frontal and anterior cingulate cortices (MeF/ACC) (Fig. 2A and Supplementary Table S2). Patients had relatively greater GMV than controls in the right lingual gyrus and left precentral gyrus. | doi-access = free }}</ref>  The [[Kraepelinian dichotomy]] is made questionable{{Clarify | date = November 2019 | reason = Non sequitur.  Also, even the provided link doesn't clarify why GMV abnormalities would make the Kraepelinian dichotomy, which also separates schizophrenia from bipolar disorder, questionable. }} by grey matter abnormalities in bipolar and schizophrenia; schizophrenia is distinguishable from bipolar in that regions of grey matter reduction are generally larger in magnitude, although adjusting for gender differences reduces the difference to the left [[dorsomedial prefrontal cortex]], and right [[dorsolateral prefrontal cortex]].<ref>{{cite journal | vauthors = Bora E, Fornito A, Yücel M, Pantelis C | title = The effects of gender on grey matter abnormalities in major psychoses: a comparative voxelwise meta-analysis of schizophrenia and bipolar disorder | journal = Psychological Medicine | volume = 42 | issue = 2 | pages = 295–307 | date = February 2012 | pmid = 21835091 | doi = 10.1017/S0033291711001450 | s2cid = 206252132 }}</ref>

During attentional tasks, first episode psychosis is associated with hypoactivation in the right middle frontal gyrus, a region generally described as encompassing the dorsolateral prefrontal cortex (dlPFC).Altered Behavioral Inhibition System functioning could possibly cause reduced sustained attention in psychosis and overall contribute to more negative reactions.<ref>{{Cite journal |last1=Osborne |first1=K. Juston |last2=Zhang |first2=Wendy |last3=Gupta |first3=Tina |last4=Farrens |first4=Jaclyn |last5=Geiger |first5=McKena |last6=Kraus |first6=Brian |last7=Krugel |first7=Chloe |last8=Nusslock |first8=Robin |last9=Kappenman |first9=Emily S. |last10=Mittal |first10=Vijay A. |date=November 2023 |title=Clinical high risk for psychosis syndrome is associated with reduced neural responding to unpleasant images. |journal=Journal of Psychopathology and Clinical Science |language=en |volume=132 |issue=8 |pages=1060–1071 |doi=10.1037/abn0000862 |pmid=37796541 |issn=2769-755X|doi-access=free |pmc=11812458 }}</ref> In congruence with studies on grey matter volume, hypoactivity in the right insula, and right inferior parietal lobe is also reported.<ref>{{cite journal | vauthors = Del Casale A, Kotzalidis GD, Rapinesi C, Sorice S, Girardi N, Ferracuti S, Girardi P | title = Functional Magnetic Resonance Imaging Correlates of First-Episode Psychoses during Attentional and Memory Task Performance | journal = Neuropsychobiology | volume = 74 | issue = 1 | pages = 22–31 | date = 2016 | pmid = 27698323 | doi = 10.1159/000448620 | s2cid = 5806628 }}</ref> During cognitive tasks, hypoactivities in the right insula, dACC, and the left precuneus, as well as reduced deactivations in the right [[basal ganglia]], right [[thalamus]], right [[Inferior frontal gyrus|inferior frontal]] and left precentral gyri are observed. These results are highly consistent and replicable possibly except the abnormalities of the right inferior frontal gyrus.<ref>{{harvnb|Radua|Borgwardt|Crescini|Mataix-Cols|2012|loc=3.3. Changes in regional brain response to cognitive tasks.}} "In the anterior part of the right insula and in the dorsal ACC there was hypoactivation relative to controls, whereas in the right basal ganglia/thalamus extending to the posterior part of the insula and in the medial frontal cortex, there was a relative reduction in deactivation... Patients also showed reductions in deactivation in the right inferior frontal and left precentral gyri, as well as hypoactivation in left precuneus. ... The analyses of robustness showed that all these results were highly replicable, with the possible exception of the abnormalities in right inferior frontal gyrus..."</ref> Decreased grey matter volume in conjunction with bilateral hypoactivity is observed in anterior insula, dorsal medial frontal cortex, and dorsal ACC. Decreased grey matter volume and bilateral hyperactivity is reported in posterior insula, ventral medial frontal cortex, and ventral ACC.<ref>{{Harvnb|Radua|Borgwardt|Crescini|Mataix-Cols|2012|loc=3.4. Multimodal analysis of grey matter volume and brain response.}} "Specifically, the anterior parts of the insulae and the dorsal part of the MeF/ACC showed hypoactivation, whereas the posterior parts of the insulae and the ventral part of the MeF/ACC showed reductions in deactivation (Fig. 3 and Table 1)."</ref>

=== Hallucinations ===
Studies during acute experiences of hallucinations demonstrate increased activity in primary or secondary sensory cortices. As auditory hallucinations are most common in psychosis, most robust evidence exists for increased activity in the left [[middle temporal gyrus]], left [[superior temporal gyrus]], and left [[inferior frontal gyrus]] (i.e. [[Broca's area]]). Activity in the [[ventral striatum]], [[hippocampus]],<ref>{{cite journal |last1=Pines |first1=Andrew R. |last2=Frandsen |first2=Summer B. |last3=Drew |first3=William |last4=Meyer |first4=Garance M. |last5=Howard |first5=Calvin |last6=Palm |first6=Stephan T. |last7=Schaper |first7=Frederic L. W. V. J. |last8=Lin |first8=Christopher |last9=Butenko |first9=Konstantin |last10=Ferguson |first10=Michael A. |last11=Friedrich |first11=Maximilian U. |last12=Grafman |first12=Jordan H. |last13=Kappel |first13=Ari D. |last14=Neudorfer |first14=Clemens |last15=Rost |first15=Natalia S. |last16=Sanderson |first16=Lauren L. |last17=Taylor |first17=Joseph J. |last18=Wu |first18=Ona |last19=Kletenik |first19=Isaiah |last20=Vogel |first20=Jacob W. |last21=Cohen |first21=Alexander L. |last22=Horn |first22=Andreas |last23=Fox |first23=Michael D. |last24=Silbersweig |first24=David |last25=Siddiqi |first25=Shan H. |title=Mapping Lesions That Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target |url=https://pubmed.ncbi.nlm.nih.gov/39937525/ |journal=JAMA Psychiatry |doi=10.1001/jamapsychiatry.2024.4534 |date=12 February 2025|volume=82 |issue=4 |pages=368–378 |pmid=39937525 |pmc=11822627 |pmc-embargo-date=February 12, 2026 }}</ref> and ACC are related to the lucidity of hallucinations, and indicate that activation or involvement of emotional circuitry are key to the impact of abnormal activity in sensory cortices. Together, these findings indicate abnormal processing of internally generated sensory experiences, coupled with abnormal emotional processing, results in hallucinations. One proposed model involves a failure of feedforward networks from sensory cortices to the inferior frontal cortex, which normally cancel out sensory cortex activity during internally generated speech. The resulting disruption in expected and perceived speech is thought to produce lucid hallucinatory experiences.<ref>{{cite book| vauthors = Brown G, Thompson W | veditors = Swerdlow N |title=Behavioral Neurobiology of Schizophrenia and its Treatment|publisher=Springer|pages=185–189|chapter=Functional Brain Imaging in Schizophrenia: Selected Results and Methods}}</ref>

=== Delusions ===
The two-factor model of delusions posits that dysfunction in both belief formation systems and belief evaluation systems are necessary for delusions. Dysfunction in evaluations systems localized to the right lateral prefrontal cortex, regardless of delusion content, is supported by neuroimaging studies and is congruent with its role in conflict monitoring in healthy persons. Abnormal activation and reduced volume is seen in people with delusions, as well as in disorders associated with delusions such as [[frontotemporal dementia]], psychosis and [[Lewy body dementia]]. Furthermore, lesions to this region are associated with "jumping to conclusions", damage to this region is associated with post-stroke delusions, and hypometabolism this region associated with caudate strokes presenting with delusions.

The [[Aberrant salience|aberrant salience model]] suggests that delusions are a result of people assigning excessive importance to irrelevant stimuli. In support of this hypothesis, regions normally associated with the [[salience network]] demonstrate reduced grey matter in people with delusions, and the neurotransmitter [[dopamine]], which is widely implicated in salience processing, is also widely implicated in psychotic disorders.

Specific regions have been associated with specific types of delusions. The volume of the hippocampus and parahippocampus is related to paranoid delusions in [[Alzheimer's disease]], and has been reported to be abnormal post mortem in one person with delusions. [[Capgras delusion]]s have been associated with occipito-temporal damage, and may be related to failure to elicit normal emotions or memories in response to faces.<ref>{{cite book | vauthors = Naasan G | chapter=The Anatomy of Delusions | veditors = Lehner T, Miller B, State M | title=Genomics, Circuits, and Pathways in Clinical Neuropsychiatry|publisher=Elsevier Science|pages=366–369}}</ref>

=== Negative symptoms ===
{{Technical|section|date=November 2019}}<!-- Probably need further explanations on: 1) implicit/explicit contingencies 2) reward prediction + positive/negative reward prediction errors. -->
Psychosis is associated with [[Ventral striatum|ventral striatum]] (VS), which is the part of the brain that is involved with the desire to naturally satisfy the body's needs.<ref name=":02">{{cite journal | vauthors = Jensen J, McIntosh AR, Crawley AP, Mikulis DJ, Remington G, Kapur S | title = Direct activation of the ventral striatum in anticipation of aversive stimuli | journal = Neuron | volume = 40 | issue = 6 | pages = 1251–1257 | date = December 2003 | pmid = 14687557 | doi = 10.1016/S0896-6273(03)00724-4 | s2cid = 14691522 | doi-access = free }}</ref> When high reports of [[Symptom#Negative symptoms|negative symptoms]] were recorded, there were significant irregularities in the left VS. Anhedonia, the inability to feel pleasure, is a commonly reported symptom in psychosis; experiences are present in most people with schizophrenia.<ref name=":12">{{Cite journal| vauthors = Germans MK, Kring AM |date=April 2000|title=Hedonic deficit in anhedonia: support for the role of approach motivation|url=https://linkinghub.elsevier.com/retrieve/pii/S0191886999001294|journal=Personality and Individual Differences|language=en|volume=28|issue=4|pages=659–672|doi=10.1016/S0191-8869(99)00129-4|access-date=2021-10-16|archive-date=2018-07-01|archive-url=https://web.archive.org/web/20180701042319/https://linkinghub.elsevier.com/retrieve/pii/S0191886999001294|url-status=live}}</ref> Anhedonia arises as a result of the inability to feel motivation and drive towards both the desire to engage in as well as to complete tasks and goals. Previous research has indicated that a deficiency in the [[neural representation]] in regards to goals and the motivation to achieve them, has demonstrated that when a reward is not present, a strong reaction is noted in the ventral striatum; reinforcement learning is intact when contingencies about stimulus-reward are implicit, but not when they require explicit neural processing; reward prediction errors are what the actual reward is versus what the reward was predicted to be.<ref name=":22">{{cite journal | vauthors = Schultz W | title = Reward prediction error | journal = Current Biology | volume = 27 | issue = 10 | pages = R369–R371 | date = May 2017 | pmid = 28535383 | doi = 10.1016/j.cub.2017.02.064 | s2cid = 29170534 | doi-access = free | bibcode = 2017CBio...27.R369S }}</ref> In most cases positive prediction errors are considered an abnormal occurrence. A positive prediction error response occurs when there is an increased activation in a brain region, typically the [[striatum]], in response to unexpected rewards. A negative prediction error response occurs when there is a decreased activation in a region when predicted rewards do not occur. [[Anterior Cingulate Cortex (ACC)]] response, taken as an indicator of effort allocation, does not increase with reward or reward probability increase, and is associated with negative symptoms; deficits in [[Dorsolateral prefrontal cortex|Dorsolateral Prefrontal Cortex (dlPFC)]] activity and failure to improve performance on cognitive tasks when offered monetary incentives are present; and dopamine mediated functions are abnormal.

=== 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.

=== Culture ===
Cross-cultural studies into schizophrenia have found that individual experiences of psychosis and 'hearing voices' vary across cultures.<ref name=":5">{{cite journal | vauthors = Luhrmann TM, Padmavati R, Tharoor H, Osei A | title = Hearing Voices in Different Cultures: A Social Kindling Hypothesis | journal = Topics in Cognitive Science | volume = 7 | issue = 4 | pages = 646–663 | date = October 2015 | pmid = 26349837 | doi = 10.1111/tops.12158 | doi-access = free }}</ref><ref>{{Cite book|url=http://dx.doi.org/10.1525/california/9780520291089.001.0001|title=Our Most Troubling Madness|date=2016-09-27|publisher=University of California Press|doi=10.1525/california/9780520291089.001.0001|isbn=978-0-520-29108-9| veditors = Luhrmann TM, Marrow J |access-date=2021-08-26|archive-date=2021-10-18|archive-url=https://web.archive.org/web/20211018155816/https://california.universitypressscholarship.com/view/10.1525/california/9780520291089.001.0001/upso-9780520291089|url-status=live}}</ref> In countries such as the [[United States]] where there exists a predominantly biomedical understanding of the body, the mind and in turn, mental health, subjects were found to report their hallucinations as having 'violent content' and self-describing as 'crazy'.<ref name=":5" /> This lived experience is at odds with the lived experience of subjects in [[Accra, Ghana]], who describe the voices they hear as having 'spiritual meaning' and are often reported as positive in nature; or subjects in [[Chennai, India]], who describe their hallucinations as kin, family members or close friends, and offering guidance.<ref name=":5" />

These differences are attributed to 'social kindling' or how one's social context shapes how an individual interprets and experiences sensations such as hallucinations. This concept aligns with pre-existing cognitive theory such as reality modelling and is supported by recent research that demonstrates that individuals with psychosis can be taught to attend to their hallucinations differently, which in turn alters the hallucinations themselves.<ref>{{cite journal | vauthors = Jenner JA, van de Willige G, Wiersma D | title = Effectiveness of cognitive therapy with coping training for persistent auditory hallucinations: a retrospective study of attenders of a psychiatric out-patient department | journal = Acta Psychiatrica Scandinavica | volume = 98 | issue = 5 | pages = 384–389 | date = November 1998 | pmid = 9845177 | doi = 10.1111/j.1600-0447.1998.tb10103.x | url = https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0447.1998.tb10103.x | access-date = 2021-08-26 | url-status = live | s2cid = 39279836 | archive-url = https://web.archive.org/web/20210826024511/https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0447.1998.tb10103.x | archive-date = 2021-08-26 }}</ref> Such research creates pathways for social or community-based treatment, such as reality monitoring, for individuals with schizophrenia and other psychotic disorders, providing alternatives to, or supplementing traditional pharmacologic management.

Cross-cultural studies explore the way in which psychosis varies in different cultures, countries and religions. The cultural differences are based on the individual or shared illness narratives surrounding cultural meanings of illness experience.<ref name="Jenkins J 2018">Jenkins J (2018) 'Anthropology and Psychiatry: A contemporary convergence for global mental health', in Bhugra D and Bhui K (eds) Textbook of Cultural Psychiatry, 2nd edn, Cambridge University Press, London.</ref> In countries such as [[India]], [[Cambodia]] and [[Muslim]] majority countries, they each share alternative epistemologies. These are known as knowledge systems that focus on the connections between mind, body, culture, nature, and society.<ref>Scheper-Hughes N and Lock M (1987) 'The mindful body: a prolegomenon to future work in medical anthropology', Medical Anthropology Quarterly, 1(1):6–41</ref> Cultural perceptions of mental disorders such as psychosis or schizophrenia are believed to be caused by [[jinn]] (spirits) in Muslim majority countries.<ref name="doi.org">{{Cite journal |last1=Valaitė |first1=Dovilė |last2=Berniūnas |first2=Renatas |date=2024 |title=Majnūn or Mental Disorders: Between Cultural Traditions and Western Psychology in Jordan |url=https://link.springer.com/article/10.1007/s11013-022-09787-0 |journal=Culture, Medicine, and Psychiatry |language=en |volume=48 |issue=1 |pages=136–157 |doi=10.1007/s11013-022-09787-0|pmid=35948861 }}</ref> Furthermore, those in [[Arab]]-Muslim societies perceive those who act differently than the social norm as "crazy" or as abnormal behaviour.<ref name="doi.org" /> This differs from the lived experience of individuals in India and how they attain their perspectives on mental health issues through a variety of spiritual and healing traditions.<ref>{{Cite journal |last1=Raghavan |first1=Raghu |last2=Brown |first2=Brian |last3=Horne |first3=Francesca |last4=Kamal |first4=Sreedevi Ram |last5=Parameswaran |first5=Uma |last6=Raghu |first6=Ardra |last7=Wilson |first7=Amanda |last8=Venkateswaran |first8=Chitra |last9=Svirydzenka |first9=Nadia |last10=Lakhanpaul |first10=Monica |last11=Dasan |first11=Chandra |date=2023 |title=Multiple Mental Health Literacies in a Traditional Temple Site in Kerala: The Intersection Between Beliefs, Spiritual and Healing Regimes |url=https://link.springer.com/article/10.1007/s11013-022-09800-6 |journal=Culture, Medicine, and Psychiatry |language=en |volume=47 |issue=3 |pages=743–765 |doi=10.1007/s11013-022-09800-6|pmid=35771306 |hdl=2086/21950 |hdl-access=free }}</ref> In Cambodia, hallucinations are linked with spirit visitation, a term they call "cultural kindling".<ref>{{Cite journal |last1=Hinton |first1=Devon E. |last2=Reis |first2=Ria |last3=de Jong |first3=Joop |date=2020 |title=Ghost Encounters Among Traumatized Cambodian Refugees: Severity, Relationship to PTSD, and Phenomenology |url=https://link.springer.com/article/10.1007/s11013-019-09661-6 |journal=Culture, Medicine, and Psychiatry |language=en |volume=44 |issue=3 |pages=333–359 |doi=10.1007/s11013-019-09661-6|pmid=31701326 }}</ref> These examples of differences are attributed to culture and the way it shapes conceptions of mental disorders.<ref name="doi.org" /> These cultural differences can be useful in bridging the gap of cultural understanding and psychiatric signs and symptoms.<ref name="Jenkins J 2018" />