Schizophrenia is a complex syndrome where people interpret reality abnormally resulting in hallucinations, delusions, and disordered thinking (‘Schizophrenia’, 2020). The specific mechanism of how this disorder presents is unknown. Could inflammation be the underlying cause of this disorder? By Oriella Stellakis
Two case studies informed this theory. The first patient is a 67-year-old male diagnosed with chronic lymphocytic leukaemia. This patient had no psychiatric history. For treatment, the patient received a stem cell transplant from his brother who had schizophrenia since early adulthood. A few weeks later, the patient developed acute psychotic symptoms (Sommer et al., 2015). Another similar case investigated a 24-year-old male with a diagnosis of treatment-resistant schizophrenia. He received a bone marrow transplant for his acute leukaemia diagnosis from a donor with no history of psychosis. which significantly improved his social functioning and psychosis (Miyaoka et al., 2017). Although this research is not robust enough to warrant significant findings, the results are unquestionably fascinating and have opened many mental health researcher’s eyes into the field of immunology (see key concepts in Figure 1).
Figure 1. Neuroinflammation involves the activation of immune cells within the central nervous system (CNS). These immune cells, such as microglia, maintain brain homeostasis and respond to injury and infection. With inflammation, cytokines can dysregulate and lead to imbalances in immune responses leading to further inflammation. Image created in BioRender.
Unlike the case studies, Genome-Wide Association Studies (GWAS) provide this field with stronger evidence. GWAS is a type of research used to detect genomic variants statistically associated with risk of a specific trait, such as susceptibility to disease or a particular disorder (‘Talking glossary of...’). This method has involved surveying the genomes of hundreds of thousands of people, in 40 countries over 150 institutions. UCL has been closely involved with contributors including Nicholas Bass, Elvira Bramon, David Curtis, and Andrew McQuillin (Trubetskoy, 2022).
A 2022 GWAS sampled 69,300 people with schizophrenia and 236,600 controls to identify genetic causes of schizophrenia. The study identified more than 270 genetic associations to Schizophrenia with the most significant finding being a locus on chromosome 6, the major histocompatibility complex, which is fundamental for immunity (see Figure 2) (‘Talking glossary of...’). These results suggest a correlation between the immune system and schizophrenia and provided evidence for further investigation.
Figure 2. A Manhattan plot from Trubetskoy et al. illustrates the significance levels of different alleles on each chromosome when controls and schizophrenic patients are compared. Significantly different alleles lie above the red line on the y-axis, with the x-axis indicating where on each chromosome the gene locus is found.
Rodent studies have found that maternal infection causes changes in behaviour and neurotransmitter function, such as schizophrenia. Case-control studies identified a correlation between elevated cytokines in pregnant mothers to increased risk of schizophrenia in offspring later in life (Brown et al., 2004). Another study finds a similar correlation, as children admitted to hospital have an increased risk of developing schizophrenia (Nielsen et al. 2014). Hence, prenatal and premorbid immune risks could contribute to the strength of the association.
A 2021 meta-analysis found cytokine levels in the blood of schizophrenic patients to be significantly higher compared to those without schizophrenia (Zhou et al., 2021). These levels seemed to improve after pharmacological treatment – suggesting a link between inflammation and the symptoms of schizophrenia (Zhou et al., 2021).
Few brain imaging studies have been successful. However, one MRI study found elevated cytokine levels to be closely associated with schizophrenia when compared to controls (Wu et al., 2019). Furthermore, schizophrenic participants had reduced cortical thickness (Wu et al., 2019).
Pharmacological studies are also helpful in investigating immunological origins of schizophrenia. Clozapine is an antipsychotic medication prescribed to treatment-resistant schizophrenia patients. A study looking at clozapine-prescribed patients found immunoglobulin levels to significantly decrease in these groups compared to controls (Ponsford et al., 2018). A similar study suggested that aspirin, an anti-inflammatory medication, could reduce symptoms of schizophrenia (Laan et al., 2010). Both these studies provide good evidence that some antipsychotics could target the inflammatory pathway which leads to schizophrenia and supports this mechanism of pathogenesis.
The evidence supporting immunological origins of schizophrenia is limited by the way it is studied. Similar evidence was produced for several mental disorders including depression and anxiety. Without a theorised role of inflammation in schizophrenia, no targeted medications can be produced yet. Furthermore, cytokines levels are measured through the blood and may not represent inflammation in the CNS due to the blood brain barrier. Future studies should investigate the underlying mechanisms with schizophrenia, as well as more brain imaging studies which look at inflammation within the CNS.
References
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Miyaoka T, Wake R, Hashioka S, Hayashida M, Oh-Nishi A, Azis IA, Izuhara M, Tsuchie K, Araki T, Arauchi R, Abdullah RA, Horiguchi J. Remission of Psychosis in Treatment-Resistant Schizophrenia following Bone Marrow Transplantation: A Case Report. Front Psychiatry. 2017 Sep 21;8:174. doi: 10.3389/fpsyt.2017.00174. PMID: 28983259; PMCID: PMC5613125.
‘Talking glossary of genomic and genetic terms’ [Internet]. [cited 2024 Apr 5]. Available from: https://www.genome.gov/genetics-glossary
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