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

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

Journal: Translational psychiatry 2021;10(1):415

PMID: 33257661

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Abstract

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.

Address: Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.; Dow University of Health Sciences, Karachi, Pakistan.; Ziauddin University Hospital, Karachi, Pakistan.; Centre for Addiction and Mental Health, Toronto, ON, Canada. [email protected].; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. [email protected].; Pakistan Institute of Living and Learning, Karachi, Pakistan. [email protected].; Pakistan Institute of Living and Learning, Karachi, Pakistan.; Centre for Addiction and Mental Health, Toronto, ON, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; National Institute of Health Research Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.; Institute of Cellular Medicine, Newcastle University and National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation, Newcastle upon Tyne, UK.; School of Data Science, Fundan University, Shanghai, China.; Stats Consultancy, Amersham, UK.; Faculty of Biology, Medicine and Health, Division of Psychology and Mental Health, School of Biological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.; Baqai University, Karachi, Pakistan.; Karwan e Hayat, Karachi, Pakistan.; Division of Psychiatry, Department of Neuroscience and Behaviour, Ribeirão Preto Medical School, University of São Paulo (FMRP-USP), São Paulo, São Paulo, 14048-900, Brazil.; Hamad Medical Corporation, Doha, Qatar.

DOI: 10.1038/s41398-020-01095-8

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MeSH Terms: Humans, Immunosuppressive Agents, Methotrexate, Psychotic Disorders, Schizophrenia