Medial Prefrontal Cortex Glutamate Is Reduced in Schizophrenia and Moderated by Measurement Quality: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

BACKGROUND: Magnetic resonance spectroscopy studies measuring brain glutamate separately from glutamine are helping elucidate schizophrenia pathophysiology. An expanded literature and improved methodologies motivate an updated meta-analysis examining effects of measurement quality and other moderating factors in characterizing abnormal glutamate levels in schizophrenia. METHODS: Searching previous meta-analyses and the MEDLINE database identified 83 proton magnetic resonance spectroscopy datasets published through March 25, 2020. Three quality metrics were extracted—Cramér–Rao lower bound (CRLB), line width, and coefficient of variation. Pooled effect sizes (Hedges’ g) were calculated with random-effects, inverse variance-weighted models. Moderator analyses were conducted using quality metrics, field strength, echo time, medication, age, and stage of illness. RESULTS: Across 36 datasets (2086 participants), medial prefrontal cortex glutamate was significantly reduced in patients (g = −0.19, confidence interval [CI] = −0.07 to −0.32). CRLB and coefficient of variation quality subgroups significantly moderated this effect. Glutamate was significantly more reduced in studies with lower CRLB or coefficient of variation (g = −0.44, CI = −0.29 to −0.60, and g = −0.43, CI = −0.29 to −0.57, respectively). Studies using echo time ≤20 ms also showed significantly greater reduction in glutamate (g = −0.41, CI = −0.26 to −0.55). Across 11 hippocampal datasets, group differences and moderator effects were nonsignificant. Group effects in thalamus and dorsolateral prefrontal cortex were also nonsignificant. CONCLUSIONS: High-quality measurements reveal consistently reduced medial prefrontal cortex glutamate in schizophrenia. Stricter CRLB criteria and reduced nuisance variance may increase the sensitivity of future studies examining additional regions and the pathophysiological significance of abnormal glutamate levels in schizophrenia.