In Vivo Glutamatergic and GABAergic Biomarkers of Auditory Verbal Hallucinations in Schizophrenia: A Systematic Review and Synthesis of Meta-Analytic Evidence from Proton Magnetic Resonance Spectroscopy and PET Studies

Auditory verbal hallucinations (AVH) are among the most distressing and treatment-refractory symptoms of schizophrenia. N-methyl-D-aspartate receptor hypofunction and parvalbumin interneuron deficits predict a regional excitation–inhibition imbalance in speech-processing cortex, but whether in vivo neurochemical imaging captures this imbalance in people who hallucinate is unclear. Following PRISMA 2020, we searched MEDLINE, Embase, PsycINFO, and Web of Science for proton magnetic resonance spectroscopy (1H-MRS) and positron emission tomography or single-photon emission computed tomography studies of glutamatergic or GABAergic markers in schizophrenia-spectrum disorders. Regional case–control estimates from published meta-analyses and mega-analyses were synthesized; AVH-stratified studies were synthesized narratively because voxel placement, metabolite composites, and hallucination metrics precluded valid pooling. Glutamatergic abnormalities were regionally patterned: thalamic glutamine (Hedges g = 0.53) and basal ganglia glutamate plus glutamine (Glx; g = 0.28–0.39) were elevated, medial frontal glutamate was reduced, and patient variability exceeded control variability. Pooled γ-aminobutyric acid (GABA) effects were nonsignificant (g = −0.004 to −0.30), and GABA-A receptor imaging showed no replicable differences. Across 5 AVH-stratified 1H-MRS cohorts, left superior temporal Glx or glutamate rose with hallucination severity, whereas medial prefrontal and anterior cingulate Glx fell (r = −0.30); GABA effects were null. In vivo evidence therefore favors a regionally dissociated temporo-cingulate glutamatergic gradient, rather than a global GABA deficit, as the neurochemical signature of AVH. Harmonized, medication-controlled, AVH-stratified multimodal studies are required before these measures can serve as clinical biomarkers.