Potential preventive role of low-dose methotrexate against incident recorded psychosis: a retrospective cohort study based on electronic health records.

Background: Recent evidence suggests that low-dose methotrexate might have antipsychotic properties. However, it remains unknown whether low-dose methotrexate is associated with a reduced risk of incident recorded psychosis in real-world data, whether these associations extend to other putatively immune-related common psychiatric conditions, or whether similar associations are observed with other disease-modifying anti-rheumatic drugs (DMARDs). Methods: In this retrospective cohort study using electronic health records (TriNetX US Collaborative Network), we identified adults with rheumatoid arthritis (age ≤45 years at treatment initiation; data extracted from 1 January 2000 to 21 December 2025). The 5-year risk of an incident recorded psychosis (primary outcome) and bipolar, depression, or anxiety disorders (secondary outcomes) were compared between low-dose methotrexate and each of 14 comparator drugs used in rheumatoid arthritis - three primary comparators (non-steroidal anti-inflammatory drugs; NSAIDs, naproxen, diclofenac and celecoxib) and 11 secondary and exploratory DMARDs comparators. Cumulative incidences and ratios of restricted mean time lost (rRMTL) are reported. Results were Bonferroni-corrected for multiple comparison. Findings: Comparator cohort sizes ranged from 1161 to 21,445 (mean ages 33.7-37.4 years). For the primary outcome of psychosis, initiation of low-dose methotrexate was associated with lower 5-year incidence of newly recorded psychosis than initiation of naproxen (rRMTL 0.69, 95% CI 0.55-0.87) or diclofenac (rRMTL 0.71, 0.56-0.89); no significant difference was observed versus celecoxib or biologic DMARDs. For the secondary outcomes, low-dose methotrexate was similarly associated with lower 5-year incidence of newly recorded bipolar disorder, depression, and anxiety compared with non-selective NSAIDs naproxen and diclofenac, with the mood and anxiety associations extending to the selective cyclo-oxygenase-2 inhibitor celecoxib. Interpretation: In a real-world rheumatoid arthritis cohort, initiation of low-dose methotrexate was associated with lower 5-year incidence of newly recorded psychosis, bipolar disorder, depression, and anxiety than initiation of non-selective NSAIDs. Given that extensive trials of broad anti-inflammatories have yielded limited psychiatric benefit, the differential profile of low-dose methotrexate is consistent with a mechanism beyond simple inflammation suppression. We hypothesise potentiation of regulatory T cell-mediated control of systemic inflammation and neuro-glial regulation. The active-comparator observational design cannot establish causation; these findings are hypothesis-generating and confirmatory inference will require interventional studies. Funding: UK Research and Innovation (UKRI) Medical Research Council [grant number UKRI4403] Mental Health Platform. The National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research.