Glymphatic-Related Alterations in Major Depressive Disorder and Treatment-Resistant Depression: Imaging Proxies, Mechanistic Links, and Therapeutic Opportunities.

Abstract

Major depressive disorder is increasingly conceptualized as a condition involving brain network dysfunction, neuroimmune imbalance, sleep-circadian disruption, hypothalamic-pituitary-adrenal (HPA)-axis dysregulation, monoaminergic arousal instability, and impaired synaptic plasticity. In parallel, the glymphatic system has emerged as a plausible integrative mechanism linking these domains, because it is a glia-dependent pathway supporting cerebrospinal fluid-interstitial fluid exchange and metabolic-waste clearance, with activity strongly modulated by deep non-rapid eye movement (NREM) sleep. This narrative review synthesizes evidence that glymphatic-related magnetic resonance imaging (MRI) proxies, particularly diffusion tensor imaging along the perivascular space (DTI-ALPS), are altered in depression, while emphasizing that DTI-ALPS is an indirect marker of perivascular diffusion rather than a direct measure of glymphatic flow. We define four key research gaps: scarcity of treatment-resistant depression (TRD)-specific cohorts, regional and technical heterogeneity across MRI studies, and uncertainty about causal direction relative to sleep disturbance and inflammation. Altered indices appear to relate to fatigue, psychomotor retardation, cognitive impairment, rumination, suicidality, systemic inflammation, oxidative stress, and HPA-axis dysregulation. We integrate opposite-direction findings, including elevated ALPS in drug-naive somatic depression, into a state- and subtype-dependent working model rather than a unidirectional dysfunction framework. Therapeutic implications are organized by target specificity, including sleep-dependent clearance, perivascular exchange, aquaporin-4 (AQP4) polarization, vascular pulsatility, and neuroimmune modulation. We propose falsifiable predictions and negative-control analyses to distinguish a glymphatic-related model from additive effects of insomnia, inflammation, and vascular risk. Overall, the current evidence supports a cautious translational framework for biomarker-informed trials in TRD-relevant phenotypes rather than a validated diagnostic biomarker.