Schizophrenia may be caused by disordered functioning of the immune system

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A study by clinical scientists at the University of Manchester has shown that schizophrenia may – in some part – be caused by disordered functioning of the immune system.

The first ever trial in schizophrenia of the powerful immune suppressant drug, Methotrexate, produced what the team described as ‘promising’ effects on what are known as positive symptoms, such as hearing voices.

Though the team stress the sample size was too small to show if Methotrexate could work as an add-on treatment for schizophrenia, they found a ‘puzzling’ therapeutic effect on symptoms of early schizophrenia.

And that, they argue, warrants further investigation.

The findings published in the Journal of Translational Psychiatry shed new light on the devastating and difficult to treat condition, which causes distress and disability worldwide.

Schizophrenia is categorized by so called ‘positive symptoms’ such as hearing voices (hallucinations) and ‘negative symptoms’ (disordered thinking, poor motivation, poor social function).

Negative symptoms, which contribute significantly to the disability associated with schizophrenia are hard to treat with currently available medication.

The study was funded by the Stanley Medical Research Institute in the United States in collaboration with the Pakistan Institute of Living and Learning.

The trial took place in Pakistan, led by Professor Imran Chaudhry from The University of Manchester who after years of service to the NHS relocated to Pakistan to continue to practice psychiatry.

The lack of available treatments for these symptoms encouraged Professor Chaudhry’s team to investigate new treatment options for schizophrenia.

Methotrexate is often used to treat inflammatory diseases such as rheumatoid arthritis and Crohn’s disease.

Inflammatory and autoimmune conditions are more common in patients with schizophrenia, possibly indicating that there is a shared underlying cause to these diseases.

“Methotrexate is thought to help treat autoimmune disorders by resetting the way T cells – an important part of the immune system – work,” said Professor Chaudhry.

“This action on the central nervous system may account for the improvement in symptoms we found in our study,” he added.

They used a low 10mg dose of the drug, which was given alongside the patients’ routine psychiatric medication.

No significant side-effects were reported by the patients taking Methotrexate, suggesting it was relatively well tolerated.

Nusrat Husain, Professor of Psychiatry and Director of Research in Global Mental Health at The University of Manchester added: “We used the lowest clinically effective dose in autoimmune disorders which often needs to be increased so higher doses could produce a more powerful effect in schizophrenia.

“However, the health risks of methotrexate are substantial and require careful monitoring which is why we would rule out large unfocussed trials.”

Psychiatrist Dr. Omair Husain, who is an honorary researcher at The University of Manchester and an Assistant Professor based at The University of Toronto said: “Immune systems could be involved in schizophrenia and that raises fascinating questions.

“Perhaps one day we might be able to identify subsets of people with schizophrenia who may respond to treatments that act on the immune system.

“The small, unexpected effect we found in our study warrants further investigation which we now believe is feasible.

“Future work needs to focus on identifying these subgroups possibly through studies that use advanced brain imaging techniques and state of the art immune profiling techniques.”


Historically, it has been nearly a hundred years since the first time in scientific literature that the temporal relationship between a viral infection and schizophrenia was discussed (Graves, 1928). In a retrospective study, the highest birth rate among schizophrenic patients, after the 1957 influenza epidemic, was about 5 months after the peak of the A2 influenza outbreak.

The study was conducted about 30 years after the epidemic and the time of birth assessment was in the range from two years before to two years after the epidemic peak (O’Callaghan et al., 1991). However, there has been some controversy regarding the causal relationship between these two issues .

The most important reason is the set of other factors that affect the disease (Selten et al., 2010).

The link between the effects of the time of birth and schizophrenia is based on the theory of the influence of environmental factors on the formation of psychiatric disorders and in particular schizophrenia. It has been thought for many years that both individual and environmental factors are effective in the development of schizophrenia (Allardyce and Boydell, 2006).

The question that arises is how respiratory viruses can be effective in the etiopathology of neuropsychiatric disorders. According to some studies, some respiratory viruses have neuroinvasive capacities (Desforges et al., 2020). In a study that examined human coronavirus anti-strains antibodies (229E, HKU1, NL63, and OC43) in patients with new psychotic symptoms compared to the control group, a higher level of antibodies was found in this group(especially anti-NL63 antibodies in patients with schizophrenia spectrum) (Severance et al., 2011).

Human respiratory coronaviruses have the ability to infect nerve cells and remain in the human brain. In some animal models, it has been shown that the virus can lead to direct neurological involvement. In addition, prominent spongiform-like degradation has been observed that can initiate underlying neuropathology (Jacomy and Talbot, 2003).

In some studies, schizophrenia has been described as a pathogenic autoimmune disease that is caused by the interaction of viruses, pathogens, and the immune system (Carter, 2011). Also there are some reports about the coexistence of a genetically modified immune system with the activity of microorganisms such as viruses that have deleterious consequences for the central nervous system (Severance and Yolken, 2019).

Accordingly, the increasing spread of COVID-19 has raised serious concerns that, in addition to the acute psychiatric problems associated with the present condition (Li et al., 2020), the psychiatric consequences of the disorder particularly in the context of the increasing prevalence of schizophrenia, may become apparent in subsequent years.

In this regard, health policy makers, while seeking more accurate epidemiological information and identifying different aspects of the activity of the virus, should pay attention to the different aspects of the psychiatric status of those affected.

References

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More information: I. B. Chaudhry et al. A randomized clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis, Translational Psychiatry (2020). DOI: 10.1038/s41398-020-01095-8

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