Neurometabolics of the anterior cingulate cortex (ACC) in major depressive disorder (MDD): A systematic review and meta-analysis

• Biomarker identification is crucial for understanding the pathology of depression. • Depression may be associated with deficits in NAA and GABA in the ACC. • Observed glutamine elevations highlight deviations in glutamatergic functioning. • Myo-inositol and choline increases observed in unmedicated subjects only. • Medications, MRI magnet strength, and ACC subregion may drive heterogeneity. Major Depressive Disorder (MDD) diagnoses have drastically increased in the United States from 6.5% to 21–30% since 2019, burdening individuals and society alike. Despite considerable efforts to understand the pathogenesis of MDD, the heterogeneity of the disorder has made it difficult to delineate its underpinnings, highlighting the need for biomarker identification. This study assessed the concentrations of key neurometabolites in the anterior cingulate cortex (ACC) in people with MDD (average n = 496) compared to healthy controls (average n = 404). We conducted a systematic review that ultimately led to the inclusion of n = 43 proton magnetic resonance spectroscopy ( 1 H-MRS) studies for meta -analysis. Average concentrations of eight neurometabolites were compared using a random effects model. We found that subjects with MDD had significantly decreased N-acetylaspartate (NAA; Hedges’ g = -0.16, 95% CI −0.299 to −0.030, p = 0.017), and gamma-aminobutyric acid (GABA; Hedges’ g = -0.26, 95% CI −0.434 to −0.082, p = 0.004), and increased levels of glutamine (Gln; Hedges’ g = 0.21, 95% CI 0.105 to 0.311, p < 0.001) in the ACC. Subgroup analyses suggested significantly increased NAA detected by magnets stronger than 1.5 Tesla only, glutamate (Glu) in the dorsal ACC only and significantly increased myo-inositol (mI) and choline (Cho) in exclusively unmedicated subjects. This study provides a summative picture of the neurometabolic profile of the ACC in people with MDD and provides a foundation for the development of biomarker-based diagnostic criteria and novel pharmacological treatments.