BACKGROUND: Methylphenidate is sometimes used to address residual symptoms of major depressive disorder (MDD), but concerns about psychiatric destabilization and limited long-term evidence have constrained its use. We examined the psychiatric safety of methylphenidate in adults with MDD in a large, real-world cohort. METHODS: Using the TriNetX Global Collaborative Network, we identified adults with MDD who initiated methylphenidate and matched them 1:1 with controls who did not receive methylphenidate. Patients with attention-deficit/hyperactivity disorder, bipolar disorder, mania, or recent psychiatric destabilization were excluded. The primary outcome was a composite of all-cause hospitalization or emergency room visits; secondary outcomes included hospitalization, emergency visits, suicidal behavior, manic episodes, and recurrence of MDD. Hazard ratios (HRs) were estimated with Cox proportional hazards models after propensity score matching. RESULTS: Of 425,190 eligible patients, 3,211 matched pairs were included (mean age, 55.8 years; 58% female). Over 1 year, the composite outcome occurred less frequently in the methylphenidate group than in controls (574 vs. 694; HR, 0.85; 95% CI, 0.76-0.95). No significant differences were observed for hospitalization, emergency visits, suicidal behavior, manic episodes, or MDD recurrence. Results were consistent across subgroups defined by sex, age, and antidepressant class. CONCLUSIONS: In adults with MDD, methylphenidate use was associated with a lower risk of hospitalization or emergency visits and was not linked to increased risk of suicidality, mania, or recurrence. These findings support the psychiatric safety of methylphenidate as an adjunctive treatment for selected patients, though longer follow-up is needed.
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