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

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.

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

“…Methotrexate treatment provided a selective improvement on positive symptoms in early schizophrenia, without effect on negative symptoms or on cognitive performance. Although the study was not designed to evaluate efficacy, methotrexate proved well tolerated and, largely, exerted an overall improvement in total symptoms and general functioning (Chaudhry et al, 2020). This study, together with others, supports the premise for anti-inflammatory drugs to potentially alleviate psychiatric symptoms or prevent inflammation-related pathways associated with psychiatric disorders.…”

“…NMDA autoantibody encephalitis, which is characterized by brain swelling caused by autoantibody production against NMDA receptors, is a further disorder that provides us with insight into a potential role for immunity in psychosis. Although patients of sporadic schizophrenia do not typically have antibodies against NMDA receptors, NMDA autoantibody encephalitis can present as schizophrenia ( Dalmau, 2016 ), implicating the inflammatory components of either disorder as a potential cause of their psychotic symptoms ( Lennox et al, 2017 ; Chaudhry et al, 2020 ; Pollak et al, 2014 ). Other non-neuronal autoimmune disorders, such as psoriasis, have also been reported to be associated with psychosis, with a 45% increased risk for schizophrenia for patients of any autoimmune disease ( Eaton et al, 2006 ; Cullen et al, 2019 ).…”

“…In this regard, a recent clinical trial evaluated “low dose” methotrexate plus folic acid in schizophrenia ( Chaudhry et al, 2020 ), as a means to provide an immune-suppressant effect by acting on cell-mediated adaptive immunity with indirect anti-inflammatory actions on the innate immune system. This, in part, mirrors low dose methotrexate’s relatively routine use to treat and reset immune signaling dysfunctions of regulatory T cells in autoimmune disorders, epitomized by rheumatoid arthritis and psoriasis ( Friedman and Cronstein, 2019 ).…”

“…This, in part, mirrors low dose methotrexate’s relatively routine use to treat and reset immune signaling dysfunctions of regulatory T cells in autoimmune disorders, epitomized by rheumatoid arthritis and psoriasis ( Friedman and Cronstein, 2019 ). In the study of low dose methotrexate in schizophrenia ( Chaudhry et al, 2020 ), patients with early schizophrenia spectrum disorders within 5 years of onset were evaluated, as neuroinflammation was considered to still be active and such patients would have less exposure to antipsychotic drugs. Methotrexate treatment provided a selective improvement on positive symptoms in early schizophrenia, without effect on negative symptoms or on cognitive performance.…”

Monocyte Transcriptional Profiling Highlights a Shift in Immune Signatures Over the Course of Illness in Schizophrenia

“…For example, it has been demonstrated in rodents that following immune activation inflammatory monocytes are recruited to brain borders such as the choroid plexus, and that monocytes can drive both viral-induced learning and memory deficits and stressinduced behavioral alterations (10)(11)(12). Importantly, results from clinical trials indicate that adjunct treatment with immune modifying drugs may improve symptoms in schizophrenia and thus understanding the nature of alterations to immune activity in relation to illness progression may advance the development of new treatment targets (13)(14)(15)(16).…”