Psychosis in multiple sclerosis—a narrative review of an underestimated, but clinically significant problem

Abstract Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system characterized by immune-mediated demyelination and subsequent axonal injury and neurodegeneration. Traditionally, the pathogenesis of MS has been attributed primarily to autoreactive immune responses targeting myelin sheaths antigens. However, growing evidence highlights the role of neurotransmitter dysregulation, particularly involving glutamate, acetylcholine, and dopamine pathways, in the development and progression of MS. These alterations in neurotransmitter systems may be especially relevant to the emergence of neuropsychiatric manifestations, including psychosis, which appears to occur more frequently in individuals with MS than in the general population. Also, some of the medications used in MS treatment might cause psychosis itself. Despite increasing recognition of MS-associated psychosis (P-MS), its underlying mechanisms remain poorly understood. This narrative review aims to provide a comprehensive overview of this often underestimated and potentially underdiagnosed clinical phenomenon. The current literature was reviewed with regard to the prevalence and risk factors of P-MS, as well as proposed pathophysiological mechanisms, including inflammatory, neurochemical, and structural contributors. Clinical presentations and differential diagnostic considerations are also discussed. Furthermore, evidence-based strategies for the management of P-MS are examined, with emphasis on the importance of interdisciplinary collaboration between neurologists and psychiatrists. By synthesizing current knowledge, this review seeks to raise awareness of P-MS as a clinically significant comorbidity that warrants further research and improved diagnostic and therapeutic approaches.