Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders

Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune encephalitis (AE), represent a growing global health burden due to their multifaceted pathophysiology and limited treatment options. These disorders are characterized by neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier (BBB) disruption, which contribute to neuronal damage and progressive functional decline. Emerging evidence underscores the pivotal role of B cells in driving disease progression through antibody production, antigen presentation, and cytokine release. Rituximab, a chimeric monoclonal antibody targeting CD20 on B cells, has shown promise as a potential immunomodulatory therapy for these conditions. Rituximab mediates its therapeutic effects via mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. In MS, rituximab reduces pro-inflammatory cytokines, demyelination, and immune cell activity, thereby delaying disease progression. Preclinical studies suggest its neuroprotective potential in AD and PD by mitigating B-cell-mediated neuroinflammation and oxidative stress. Furthermore, rituximab demonstrates efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse rates. Despite its proven efficacy, rituximab poses risks such as hypogammaglobulinemia, infection, and infusion-related reactions, necessitating careful patient selection, continued monitoring, and optimization of dosing regimens. This review highlights rituximab's immunomodulatory mechanisms and its expanding role in neurodegenerative and neuropsychiatric disorders. While ongoing clinical trials explore its efficacy in ALS, depression, and schizophrenia, future research should focus on identifying biomarkers of treatment response, improving CNS penetration, and combining rituximab with other therapies to enhance safety and therapeutic outcomes. Rituximab's ability to target B-cell-driven pathology positions it as a promising agent in the evolving landscape of neuroimmunology.