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

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.