Abstract

Major depressive disorder (MDD) remains a leading cause of disability; however, monoaminergic models do not fully explain delayed treatment onset, incomplete remission, or rapid responses to glutamatergic interventions. In this study, we proposed a system-level ionic homeostasis framework for MDD. In this model, genetic susceptibility, chronic stress, metabolic burden, and neuroinflammation converge in neuronal and glial ion-channel systems, disrupting calcium, potassium, chloride, and purinergic homeostasis. These disturbances alter intrinsic excitability, synaptic integration, inhibitory tone, glial buffering, and neuron–glia signaling, thereby promoting excitation–inhibition imbalance, impaired plasticity, and corticolimbic network instability. We reviewed the evidence implicating the CACNA1C/Cav1.2, TREK-1, KCNQ, NKCC1/KCC2, HCN, transient receptor potential/acid-sensing ion channels, and glial mediators, including P2X7R, Kir4.1, and AQP4. We also discuss how ketamine-related mechanisms, chloride-restoring strategies, anti-inflammatory ion channel targeting, neuromodulation, EEG biomarkers, and AI/multiomics approaches support mechanism-informed precision therapeutics. MDD could be conceptualized as a distributed failure of ionic homeostasis that links neuroinflammation, E/I imbalance, network instability, and impaired adaptive plasticity.

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