Schizophrenia is a serious psychiatric disorder bearing both genetic and environmental causes 1 2. Whilst it has an impact on 1% of the population, it causes important consequences on society and the economy 3. Each 1 in 300 people worldwide has a schizophrenia diagnosis according to World Health Organization 2022 data *[1]. Because the exact pathophysiological process is still unknown, novel schizophrenia treatments implicate several limitations 4 3. Variety of factors are considered and shown to be involved in schizophrenia such as structural alterations in the brain including frontotemporal thickness and area and cortical, ventricle, and hippocampal volumes, variability in subcortical structures, thalamus and amygdala 5. Not only anatomical but also clinical heterogeneity in terms of symptoms, response to treatment and long-term prognosis alter among patients diagnosed with schizophrenia 6 7 8. Regarding the remedy of schizophrenia, in half of the patients’ responses to the treatment positive symptoms such as hallucinations and thought disorders are ameliorated 9. However negative including flat affect and social withdrawal and cognitive symptoms like learning and attention disorders remain unaffected 9.
The dopaminergic hypothesis is proposed to explain the pathophysiology of schizophrenia. According to the dopaminergic hypothesis, a change in dopamine neurotransmission in the mesolimbic system is the source of positive symptoms, while the change happens in the mesocortical pathway, which leads to negative symptoms 10. The glutamatergic hypothesis which supports alterations in prefrontal neuronal connectivity including the glutamatergic neurotransmission at NMDA receptors is followed-up 10. First (dopamine D2 receptor antagonists), second (multi-target antagonists with greater antagonism at serotonin 5-HT2A receptor), and third-generation antipsychotics are utilized as therapeutic strategies for schizophrenia 3. As for the dopaminergic hypothesis, hyperactivated mesolimbic dopamine projections resulting in overactivation of striatal dopamine D2 receptor are associated with positive symptoms whereas decreased mesocortical dopamine projections causing hypostimulation of prefrontal cortex dopamine D1 receptor is linked to negative and cognitive symptoms of the disease 11 12.

A variety of approaches are present to explain what sort of factors can take part in psychotic disorders. For example, some studies indicated that exposure to viruses and other infectious agents including influenza, toxoplasmosis, etc. are considered to increase the risk of the disorders 13. Aging, especially older than 34, is considered the risk factor for schizophrenia as it especially results in a go up of male germ cells de novo mutations 14 15 16 17. Studies on childhood trauma revealed the existence of a correlation between childhood trauma and schizophrenic symptoms in particular positive symptoms, and affective symptoms which come off in adulthood 18 19 20 21. Substance abuse is another causal agent shown to increase the risk of schizophrenia 22 23 24.
Polygenic risk score (PRS) is the total of common genetic risk alleles contributed to schizophrenia 25. Studies refer to the linkage between PRS and negative symptoms of schizophrenia, and cognitive disability of the patients 26. Association of Polygenic burden with the thinner frontal cortex and prefrontal working memory-related activity revealed the role of the frontal cortex and hippocampus in the pathophysiological mechanism of schizophrenia 27 28 29. In contrast, the polygenic risk for schizophrenia possesses a weak linkage to subcortical structures in accordance with several studies 30. The phenotypic changeableness among patients diagnosed with schizophrenia is reasoned with the impact of risk alleles on environmental sensitivity 31.
References:
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- Van Rheenen TE, Lewandowski KE, Tan EJ, et al. Characterizing cognitive heterogeneity on the schizophrenia-bipolar disorder spectrum. Psychol Med. Published online 2017. doi:10.1017/S0033291717000307
- Malhotra AK. Dissecting the Heterogeneity of Treatment Response in First-Episode Schizophrenia. Schizophr Bull. Published online 2015. doi:10.1093/schbul/sbv117
- Huber G. The heterogeneous course of schizophrenia. In: Schizophrenia Research. ; 1997. doi:10.1016/S0920-9964(97)00113-8
- Carbon M, Correll CU. Thinking and acting beyond the positive: The role of the cognitive and negative symptoms in schizophrenia. CNS Spectr. Published online 2014. doi:10.1017/S1092852914000601
- Laruelle M. Schizophrenia: From dopaminergic to glutamatergic interventions. Curr Opin Pharmacol. Published online 2014. doi:10.1016/j.coph.2014.01.001
- Lau CI, Wang HC, Hsu JL, Liu ME. Does the dopamine hypothesis explain schizophrenia? Rev Neurosci. Published online 2013. doi:10.1515/revneuro-2013-0011
- Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: A review and reconceptualization. Am J Psychiatry. Published online 1991. doi:10.1176/ajp.148.11.1474
- Stilo SA, Murray RM. Non-Genetic Factors in Schizophrenia. Curr Psychiatry Rep. Published online 2019. doi:10.1007/s11920-019-1091-3
- schurhoff F, Hubert A, Szoke A, Meary A, Leboyer M. INFLUENCE OF PATERNAL AGE IN SCHIZOPHRENIA. Schizophr Res. Published online 2010. doi:10.1016/j.schres.2010.02.791
- Buizer-Voskamp JE, Laan W, Staal WG, et al. Paternal age and psychiatric disorders: Findings from a Dutch population registry. Schizophr Res. Published online 2011. doi:10.1016/j.schres.2011.03.021
- Brown AS, Schaefer CA, Wyatt RJ, et al. Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry. Published online 2002. doi:10.1176/appi.ajp.159.9.1528
- Sipos A, Rasmussen F, Harrison G, et al. Paternal age and schizophrenia: A population based cohort study. Br Med J. Published online 2004. doi:10.1136/bmj.38243.672396.55
- Janssen I, Krabbendam L, Bak M, et al. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. Published online 2004. doi:10.1046/j.0001-690X.2003.00217.x
- Read J, Van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: A literature review with theoretical and clinical implications. Acta Psychiatr Scand. Published online 2005. doi:10.1111/j.1600-0447.2005.00634.x
- Vallejos M, Cesoni OM, Farinola R, Bertone MS, Prokopez CR. Adverse Childhood Experiences among Men with Schizophrenia. Psychiatr Q. Published online 2017. doi:10.1007/s11126-016-9487-2
- Matheson SL, Shepherd AM, Pinchbeck RM, Laurens KR, Carr VJ. Childhood adversity in schizophrenia: A systematic meta-analysis. Psychol Med. Published online 2013. doi:10.1017/S0033291712000785
- Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: Historical cohort study. Br Med J. Published online 2002. doi:10.1136/bmj.325.7374.1199
- Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: Longitudinal prospective study. Br Med J. Published online 2002. doi:10.1136/bmj.325.7374.1212
- Van Os J, Bak M, Hanssen M, Bijl R V., De Graaf R, Verdoux H. Cannabis use and psychosis: A longitudinal population-based study. Am J Epidemiol. Published online 2002. doi:10.1093/aje/kwf043
- Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. Published online 2009. doi:10.1038/nature08185
- Jones HJ, Stergiakouli E, Tansey KE, et al. Phenotypic manifestation of genetic risk for schizophrenia during adolescence in the general population. JAMA Psychiatry. Published online 2016. doi:10.1001/jamapsychiatry.2015.3058
- Walton E, Geisler D, Lee PH, et al. Prefrontal inefficiency is associated with polygenic risk for schizophrenia. Schizophr Bull. Published online 2014. doi:10.1093/schbul/sbt174
- Chen Q, Ursini G, Romer AL, et al. Schizophrenia polygenic risk score predicts mnemonic hippocampal activity. Brain. Published online 2018. doi:10.1093/brain/awy004
- Lieberman JA, Girgis RR, Brucato G, et al. Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention. Mol Psychiatry. Published online 2018. doi:10.1038/mp.2017.249
- J.T. R, J.L. D, T. L, D. L, J.T. W, J. H. Genomic and imaging biomarkers in schizophrenia. Curr Top Behav Neurosci. Published online 2018.
- Fraser HB, Schadt EE. The quantitative genetics of phenotypic robustness. PLoS One. Published online 2010. doi:10.1371/journal.pone.0008635
Visual References:
- McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia – An Overview. JAMA Psychiatry. Published online 2020. doi:10.1001/jamapsychiatry.2019.3360
*[1] https://www.who.int/news-room/fact-sheets/detail/schizophrenia#:~:text=Schizophrenia%20affects%20approximately%2024%20million,as%20many%20other%20mental%20disorders.
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