Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: A systematic review and meta-analysis

Abstract

Abstract N-acetyl aspartate (NAA) is a marker of neuronal integrity and metabolism. Deficiency in neuronal plasticity and hypometabolism are implicated in the pathophysiology of Major Depressive Disorder (MDD). To test if cerebral NAA concentrations decrease progressively over the MDD course, we conducted a meta-analysis of Proton Magnetic Resonance Spectroscopy ( 1 H-MRS) studies comparing NAA concentrations in chronic MDD (cMDD) and first episode of depression (FED) to healthy controls. We searched Scopus® and Web of Knowledge □ using search terms related to depression and NAA. Hedges’ g was used as effect size measure, together with heterogeneity analyses, test of moderators and publication bias and quality assessment. The protocol is registered in PROSPERO (CRD42020221050). Sixty-two studies were included and meta-analyzed using a random-effect model for each brain region. NAA concentrations were significantly reduced in cMDD compared to healthy controls within the frontal lobe (n=26, Hedges’ g= -0.330, 95% CI -0.598 to -0.062; p= 0.018), the occipital lobe (n = 4, Hedges’ g= -0.677, 95% CI -1.013 to -0.341; p = 0.007), the thalamus (n= 4, Hedges’ g= -0.673, 95% CI -1.108 to -0.238; p = 0.016) and the frontal (n = 6, Hedges’ g= -0.471, 95% CI -0.891 to -0.052; p= 0.034) and periventricular white matter (n= 3, Hedges’ g= -0.478, 95% CI -0.938 to -0.018; p= 0.047). We highlighted a gap of knowledge regarding NAA levels in FED. Sensitivity analyses indicated that antidepressant treatment may reverse NAA alterations in the frontal lobe. Our findings are in line with previous evidence showing alterations in the aforementioned brain areas in MDD. Future studies should assess NAA alterations in the early stages of the illness and their longitudinal progression, also considering our preliminary results on the modifying effect of antidepressant treatment.