Meta-analysis of <sup>1</sup>H-MRS glutamate profiles in adult schizophrenia spectrum disorders and autism spectrum disorder: Study protocol.

Abstract

<h4>Background</h4>Schizophrenia spectrum disorders (SSDs) and autism spectrum disorder (ASD) share social-cognitive deficits, genetic architecture, and overlapping animal models, yet the neurochemical signatures that differentiate them remain unclear. This protocol describes a systematic review and meta-analysis of proton magnetic resonance spectroscopy (¹H-MRS) studies examining glutamate, glutamine, and their combined signals. The primary aim is to establish a human neurochemical benchmark to guide translational research.<h4>Methods</h4>Eligible studies will be those measuring ¹H-MRS glutamatergic metabolites at ≥3 T field strength in at least one of five brain regions: anterior cingulate cortex, dorsolateral prefrontal cortex, hippocampus, striatum, or thalamus. Adults (≥18 years) with SSD (stratified as ultra-high risk, first-episode psychosis, and treatment-resistant schizophrenia) and ASD diagnosed using standardized criteria will be compared to healthy controls. Systematic searches will be conducted in databases. Two independent reviewers will assess the risk of bias using the AXIS (Appraisal Tool for Cross-Sectional Studies) and MRS-Q (Magnetic Resonance Spectroscopy Quality Assessment Tool). Primary outcomes will be regional differences in metabolite concentrations. We will conduct random-effects meta-analyses integrating direct and indirect comparisons, with subgroup analyses by illness stage and medication status.<h4>Results</h4>We expect to identify both shared and distinct glutamatergic alterations across SSD subgroups and ASD, with potential stage-specific patterns in cortical and subcortical regions.<h4>Conclusions</h4>This comprehensive analysis aims to identify regional brain glutamatergic biomarkers differentiating SSD and ASD. These neurochemical signatures will provide an essential reference framework for validating and guiding reverse-translational research.<h4>Prospero registration number</h4>CRD420251003550.