Neurometabolites in schizophrenia and bipolar disorder — A systematic review and meta-analysis

Abstract

This meta-analysis evaluates alterations of neurometabolites in schizophrenia and bipolar disorder. PubMed was searched to find controlled studies evaluating N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr) assessed with 1H-MRS (proton magnetic resonance spectroscopy) in patients with schizophrenia and bipolar disorder up to September 2010. Random effects meta-analyses were conducted to estimate pooled standardized mean differences. I2 statistic was used to quantify inconsistencies. Subgroup analyses were conducted to explore potential explanations for inconsistencies. 146 studies with 5643 participants were included in the systematic review. NAA levels were affected in schizophrenia and bipolar disorder. Decreased levels in the basal ganglia and frontal lobe were the most consistent findings in schizophrenia, decreased levels in the basal ganglia were the most consistent findings in bipolar disorder. Cho and Cr levels were not altered in either disorder. Findings for Cr were most consistent in the thalamus, frontal lobe and dorsolateral prefrontal cortex in schizophrenia and the basal ganglia and frontal lobe in bipolar disorder. Findings for Cho were most consistent in the thalamus, frontal lobe and anterior cingulate cortex in schizophrenia and basal ganglia in bipolar disorder. Large, carefully designed studies are needed to better estimate the extent of alterations in neurometabolites.

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

“…The meta-analyses 4,5 are generally consistent in supporting NAAc reductions in the hippocampus, thalamus, frontal and temporal lobe, with no apparent differences between GM and WM nor differences related to stage of illness. However, these analyses did not consider criteria for quality of spectral fits nor partial-volume tissue correction, factors known to affect metabolite values.…”

“…4,5 When discussing this literature, 1 H-MRS methods (eg, spectral quality), brain region examined and state vs trait issues must be considered. The glutamate meta-analysis reported increased glutamine and reduced glutamate, in medial frontal single-voxel studies, 6 with progressive reductions with age.…”

“…42 In addition to the unaddressed methodological heterogeneity, only 8 of the 103 studies were powered to detect a 10% difference in NAAc (with SP, N ≥ 39). 4,5 Furthermore, there were only 8 1 H-MRSI studies, and only 2 with SP samples ≥39, 4 both of which focused only on one structure: the thalamus 43 and the hippocampus. 44 Hence the likelihood of detecting subtle cortical GM vs WM tissue differences in the current literature is slim.…”

“…We also examined total-choline, myo-inositol, and total-creatine (Bonferroni-corrected P = .05/3 = .018), other metabolites frequently reported in the schizophrenia literature. 4 Because tissue type and age are known variables to affect the metabolites of interest 3 and there are progressive tissue changes in schizophrenia, 8 the overall approach for each metabolite for all voxels (dependent variable), involved diagnosis as the grouping factor, tissue type (predominantly GM or WM voxels) as the within group factor, and age as a covariate (omnibus test; we also examined if the quadratic effect of age improved the model). If the groups differed in other relevant demographic, substance use or spectral quality measures, these where entered into the model as additional covariates.…”

“…3 Although many studies have measured these metabolites in schizophrenia, samples have been small and brain coverage restricted to a few regions resulting in limited ascertainment of age and tissue composition effects. [4][5][6] For example, GM Glx concentration is about twice as high as in WM. 7 In schizophrenia, a disease with subtle but broad GM and WM involvement and progressive structural changes, 8 1 H-MRS imaging ( 1 H-MRSI) is potentially a more powerful tool since it enables measurement in a much larger brain region.…”