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.

Figure1: Dopamine Receptor Blockers, Treatment Response, and Adverse Effects

Figure: Dopamine Receptor Blockers, Treatment Response, and Adverse Effects

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. Ageing, 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.


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Figure Reference: McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia – An Overview. JAMA Psychiatry. Published online 2020. doi:10.1001/jamapsychiatry.2019.3360

Inspector: Elif BÖCÜ 

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