Efficacy of methylphenidate for the treatment of apathy in patients with Alzheimer’s disease: a systematic review and meta-analysis of randomized controlled studies

Rationale: Despite the reported efficacy of methylphenidate (MET) against Alzheimer’s disease (AD)–associated apathy, a recent larger clinical trial was not included in pooled analysis. Objectives: This study aimed at investigating the efficacy of MET for attenuating apathy in patients diagnosed with AD. Methods: The PubMed, Cochrane Library, and EMBASE databases were searched from inception until March, 2022 to identify randomized controlled trials (RCTs). The primary outcome was apathy improvement assessed with the Neuropsychiatric Inventory (NPI) apathy subscale, Apathy Evaluation Scale (AES), or Clinical Global Impressions of Change scale (CGI-C apathy). Results: Meta-analysis of four RCTs revealed an improvement in apathy among patients receiving MET compared to placebo (MD = − 5.12, p = 0.04, three trials, 144 participants) at follow-ups of 1–3 months assessed with AES score. Despite the absence of improvement on NPI-apathy subscale at follow-ups of 1–2 months (MD = − 0.74, p = 0.37, three trials, 265 participants), significant improvement was noted at follow-ups of 6 months (MD = − 1.4, p = 0.02, one trial, 180 participants). Assessment with CGI-C apathy revealed no significant association between improvement in apathy with MET use (RR = 1.38, p = 0.05, three trials, 265 participants). No significant differences in global cognitive function (using the Mini Mental State Exam) or adverse events were noted between the two groups. Conclusion: While AES score suggested an early attenuation effect of MET on apathy in different domains, the NPI-apathy subscale did not show early improvement in apathy until the 6-month follow-up. Further studies with longer follow-ups are needed to elucidate the efficacy of MET for relieving caregiver burden and improving global functional performance.