Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine

Introduction

Earlier preclinical and clinical work has implicated abnormalities in excitatory and inhibitory neurotransmission—principally involving glutamate (Glu) and gamma-aminobutyric acid (GABA)—in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). Animal models using pharmacologic and stress-induction paradigms have shown cortical Glu alterations that are reversible with conventional antidepressant interventions, motivating a glutamatergic hypothesis that extends beyond monoaminergic explanations. Human neurochemical studies using proton magnetic resonance spectroscopy (1H-MRS), positron emission tomography (PET), and functional imaging (EEG, MEG, fMRI) have reported region-specific changes in Glu, Gln, Glx (combined Glu and Gln), and GABA, and concurrent evidence has linked these neurochemical alterations with aberrant large-scale network functional connectivity in depressed patients. Lener and colleagues present a narrative review that synthesises neurochemical and functional imaging literature to explore links between Glu/GABA disturbances, network-level dysfunction, and the rapid antidepressant effects of subanesthetic-dose ketamine. The review highlights ketamine as a molecular probe for glutamatergic modulation in humans because of its reproducible rapid antidepressant effects and relatively lower side-effect burden compared with other glutamatergic agents. The authors argue for combined multimodal imaging approaches to better characterise biologically homogeneous subgroups and to identify biomarkers predictive of treatment response to glutamatergic interventions such as ketamine.