The Monoamine-Glutamate Continuum of Depression: A Neurobiological Framework for Precision Psychiatry.

Background/Objectives: Major depressive disorder (MDD) remains a leading cause of disability worldwide and exhibits substantial biological heterogeneity that is not adequately captured by current symptom-based diagnostic systems. While the classical monoamine hypothesis has historically guided antidepressant development, it does not fully account for variability in treatment response, delayed therapeutic onset, or the persistence of cognitive and anhedonic symptoms. Converging evidence from molecular, neuroimaging, and translational studies increasingly implicates glutamatergic dysregulation and impaired neuroplasticity as key mechanisms in depressive pathology. This narrative review aims to integrate monoaminergic and glutamatergic perspectives within a dimensional framework that may help explain clinical heterogeneity and inform mechanism-based treatment strategies.

Methods: A narrative synthesis of the literature was conducted using major biomedical databases including PubMed, Scopus, and Web of Science. Preclinical studies, neuroimaging investigations, biomarker research, randomized clinical trials, and meta-analyses examining monoaminergic dysfunction, glutamatergic signaling, neuroplasticity pathways, and rapid-acting antidepressants were reviewed and thematically integrated.

Results: Evidence indicates that depressive syndromes may reflect varying contributions of monoaminergic dysregulation and glutamatergic-neuroplastic impairment. Monoaminergic disturbances interact with inflammatory and neuroendocrine processes, including cytokine-driven activation of the kynurenine pathway. In parallel, alterations in glutamatergic signaling, glial function, and BDNF-TrkB-mTOR pathways contribute to synaptic atrophy and network dysfunction. Rapid-acting antidepressants such as ketamine, esketamine, and dextromethorphan-bupropion provide clinical proof-of-concept that direct engagement of synaptic plasticity mechanisms can accelerate symptom improvement, particularly in treatment-resistant depression.

Conclusions: Integrating monoaminergic and glutamatergic mechanisms within a "monoamine-glutamate continuum" offers a conceptual framework for understanding depressive heterogeneity and treatment response. Multimodal approaches combining clinical phenotyping with inflammatory, neuroimaging, and molecular markers may ultimately support mechanism-informed precision psychiatry strategies in major depressive disorder.