686. Glutamate dysfunction in treatment-resistant depression: translational and clinical insights

Abstract Background Treatment-resistant depression (TRD) represents a major clinical challenge and is associated with substantial symptom burden, functional impairment, and poor prognosis. Beyond traditional monoaminergic models, converging evidence indicates that dysfunction of the glutamatergic system plays a central role in the pathophysiology of TRD, contributing to impaired neuroplasticity and altered stress-related neural circuitry. Aims & Objectives This lecture aims to provide an integrated overview of the clinical relevance of glutamatergic dysfunction in TRD, combining translational neurobiological evidence with findings from clinical trials and real-world studies. Particular attention is given to the implications of glutamate-based mechanisms for diagnostic refinement, symptom profiling, and personalized treatment strategies.

Method: A narrative synthesis of evidence from translational research, randomized controlled trials, and real-world observational studies is presented. Key neurobiological findings related to glutamate-mediated synaptic plasticity, excitation–inhibition balance, and NMDA- and AMPA-receptor–dependent mechanisms are discussed alongside clinical data from studies evaluating glutamatergic agents, with a focus on adjunctive intranasal esketamine in routine clinical practice.

Results: Translational evidence indicates that alterations in glutamatergic signaling contribute to disrupted cortico-limbic network functioning and impaired adaptive stress responses in TRD. Clinically, glutamatergic abnormalities are associated with specific symptom dimensions, including anhedonia, cognitive impairment, affective instability, and sleep–wake dysregulation. Real-world studies of intranasal esketamine demonstrate rapid reductions in depressive severity, improvements in functional outcomes, and an acceptable tolerability profile in heterogeneous and comorbid patient populations. Discussion & Conclusions Glutamatergic dysfunction represents a clinically meaningful dimension of TRD that extends beyond categorical diagnostic boundaries. Integrating mechanistic insights with real-world effectiveness data supports a dimensional and personalized approach to the assessment and management of treatment-resistant mood disorders. Identification of glutamate-related clinical phenotypes may improve prognostic stratification and inform treatment selection in clinical practice.