Schizophrenia May Be Similar to Immune Disorders

Summary: Schizophrenia may, in part, be caused by immune system dysfunction, a new study reports. Treatment with Methotrexate, a drug commonly prescribed for autoimmune disorders like R.A, produced positive effects against some prominent schizophrenia symptoms.

Source: University of Manchester

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 Translational Psychiatry shed new light on the devastating and difficult to treat condition, which causes distress and disability worldwide.

Schizophrenia is categorised 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.

This shows a brain
Schizophrenia is categorised by so called ‘positive symptoms’ such as hearing voices (hallucinations) and ‘negative symptoms’ (disordered thinking, poor motivation, poor social function). Image is in the public domain

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”.

About this schizophrenia research news

Source: University of Manchester
Contact: Press Office – University of Manchester
Image: The image is in the public domain

Original Research: Open access.
A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis” by I. B. Chaudhry, M. O. Husain, A. B. Khoso, M. I. Husain, M. H. Buch, T. Kiran, B. Fu, P. Bassett, I. Qurashi, R. ur Rahman, S. Baig, A. Kazmi, F. Corsi-Zuelli, P. M. Haddad, B. Deakin & N. Husain. Translational Psychiatry


A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (β = −2.5; [95% CI −4.7 to −0.4]), whereas negative symptoms were unaffected by treatment (β = −0.39; [95% CI −2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

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