Treatment of apathy in stroke patients. A systematic review

Maria Luisa Ruiz Franco¹Laura Amaya-Pascasio^1*Mercedes Gil-Rodriguez²Antonio Arjona-Padillo³José García-Pinteño²Antonio Jose Rodriguez Sanchez²Ana Sánchez-Kuhn⁴Pilar Flores⁴Patricia Martínez-Sánchez^1,5*

• ¹Complejo Hospitalario Torrecardenas Servicio de Neurologia, Almería, Spain
• ²Fundacion Publica Andaluza para la investigacion Biosanitaria Andalucia Oriental, Granada, Spain
• ³Hospital Universitario Torrecardenas, Almería, Spain
• ⁴Faculty of Psychology, Department of Psychology, CTS-280 Clinical and Experimental Neuroscience research group and Research Center CiBiS, University of Almeria, Almería, Spain
• ⁵4Department of Nursing, Physiotherapy and Medicine, Faculty of Health Science, Health Research Center (CEINSA), University of Almería., Almería, Spain

Abstract Introduction: Post-stroke apathy is a prevalent yet frequently underdiagnosed neuropsychiatric syndrome, reported in up to one-third of stroke survivors, and is consistently associated with poorer functional recovery and cognitive decline. We aimed to review the current evidence on available pharmacological and non-pharmacological treatments for post-stroke apathy, and to evaluate their efficacy and safety. Methods: A systematic review was conducted following PRISMA guidelines and registered in the PROSPERO database (CRD42022332559). We searched PubMed, Web of Science, and Scopus for randomized and non-randomized clinical trials published until November 2024. Eligible studies included adults with ischemic or hemorrhagic stroke and a defined diagnosis of apathy. Interventions included pharmacological treatments and non-pharmacological strategies, such as neuromodulation techniques. Data extraction and risk of bias assessment were independently performed by two reviewers using the RoB-2 tool. Results: Ten clinical trials involving 2,359 patients were included. Pharmacological interventions with escitalopram and donepezil (alone or combined with intensive language action therapy) showed potential benefits. Nefiracetam yielded mixed results depending on dose and coexisting depression. Non-pharmacological approaches such as problem-solving therapy, motor relearning programs, strategy training, and complex rehabilitation programs demonstrated significant improvement in apathy scores. High-frequency repetitive transcranial magnetic stimulation also showed efficacy. However, heterogeneity in study design and apathy assessment scales limited direct comparisons. Conclusion: Several interventions, including escitalopram, donepezil, motor relearning programs, strategy training, and rTMS, have demonstrated potential effectiveness in treating post-stroke apathy. Nevertheless, evidence remains scarce and heterogeneous, underscoring the need for larger, high-quality randomized controlled trials to establish definitive treatment guidelines.