Glymphatic Dysfunction in bipolar disorder: A scoping review and integrative pathophysiological framework.

The glymphatic system is a brain-wide perivascular clearance pathway increasingly implicated in neurodegenerative and neuropsychiatric disorders. This scoping review examines its potential role in bipolar disorder (BD), synthesizes evidence linking glymphatic function to BD, and outlines a testable integrative framework connecting glymphatic disruption with key clinical and biological features of the disorder. Preliminary neuroimaging work indicates that individuals with BD show alterations in glymphatic-related indices, including diffusion-based and volumetric measures, some of which correlate with illness duration and regional gray matter volumes. Complementary molecular and cellular findings suggest that activation of the hypothalamic-pituitary-adrenal (HPA) axis, neuroimmune signaling, and neuroinflammatory activity may perturb astrocytic aquaporin-4 (AQP4) and related markers in cerebrospinal fluid (CSF) and choroid plexus (CP), providing a mechanistically plausible link between chronic stress biology and impaired brain waste clearance. AQP4-bearing extracellular vesicles in CSF have emerged as a putative indicator of astrocyte stress in BD. Preclinical work further indicates that lithium can modulate circadian properties of the CP clock, blood-brain barrier (BBB) integrity, and AQP4-related indices, raising the possibility that aspects of its therapeutic profile are mediated through effects on glymphatic pathways. Although indirect and methodologically heterogeneous, current evidence supports glymphatic dysfunction as a candidate mechanism integrating sleep-wake cycle, stress-related and immune processes, astrocytic pathology, and progressive structural and cognitive changes in BD. The framework proposed here is intended to guide hypothesis generation and future longitudinal, multimodal, and mechanistic studies aimed at developing glymphatic-informed biomarkers and intervention targets.