Methylphenidate for Depression in Advanced Cancer: Exploratory Meta-Analysis of Randomized Trials

Depression is prevalent and often undertreated in people living with advanced cancer. Methylphenidate (MPH) has been proposed as a faster-acting pharmacologic intervention in this setting, yet evidence remains limited.

To evaluate MPH's efficacy and safety for depression management in adults with advanced malignancies.

We conducted a pairwise systematic review and meta-analysis of double-blind, placebo-controlled randomized trials following Cochrane and PRISMA standards. PubMed, Embase, and CENTRAL were searched through April 04, 2025. The primary outcome was between-group change in depressive scores at 2 ± 1 weeks, expressed as standardized mean difference (SMD). Secondary outcomes included depression remission at 2 ± 1 weeks, expressed as risk ratio (RR) and risk difference (RD), and treatment-emergent adverse events (TEAEs). Random-effects models were applied.

Three studies were included (MPH, n = 90; control, n = 99). Compared with placebo, MPH (10-45 mg/day as monotherapy or 10-20 mg/day as augmentation to conventional antidepressants) reduced depressive symptom severity (SMD, -0.81; 95%CI, -1.22 to -0.39; P < 0.001; I² = 32%). While relative risk for depression remission narrowly missed significance (RR, 1.69; 95%CI, 0.97 to 2.96; P = 0.07; I² = 50%), MPH increased the absolute probability of remission (RD, 0.22; 95%CI, 0.09 to 0.34; P < 0.001; I² = 0%; number needed to treat ≈ 5). Incidence of all analyzed TEAEs was similar between groups.

MPH may provide rapid, potentially meaningful improvement in depressive symptoms for people living with advanced cancer, while maintaining a favorable safety profile. Considering the small sample sizes and short follow-up durations across studies included in this exploratory meta-analysis, future large-scale trials are needed to confirm efficacy and define optimal candidates.