Previous research has established that glutamatergic dysfunction plays a role in the pathogenesis of schizophrenia; however, it is uncertain if the extent of glutamatergic dysfunction is comparable among individuals with schizophrenia or if there are significant variances among this patient population when compared with the general population.

In a recent publication in Molecular Psychiatry, researchers conducted meta-analyses to evaluate the following: 1) variability of glutamate (Glx) measures in patients compared with controls (log coefficient of variation ratio: CVR); 2) standardized mean differences (SMD) employing Hedges g of glutamatergic metabolites; and 3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test).

The authors wrote, “In the current meta-analysis, we hypothesized that patients with schizophrenia would exhibit greater variability of brain glutamate, glutamine, and Glx levels than controls. We complemented this with analysis of the distribution of individual-level data, as a bimodal distribution of glutamatergic metabolites in patients would support the existence of discrete glutamate subgroups.”

A total of 123 studies involving 8,256 patients and 7,532 controls were included. The results revealed that “Patients demonstrated more significant variability in glutamatergic metabolites in the medial frontal cortex (MFC; glutamate: CVR = 0.15, P <.001; glutamine: CVR = 0.15, P = .003; Glx: CVR = 0.11, P = .002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, P = .05; Glx: CVR = 0.25, P <.001) and thalamus (glutamate: CVR = 0.16, P = .008; Glx: CVR = 0.19, P = .008).”

Relative to the control group, the percentage of males was negatively correlated with MFC glutamate and frontal white matter Glx in patients. On the other hand, Patient Positive and Negative Syndrome Scale total score was positively associated with glutamate SMD in basal ganglia (BG) and the temporal lobe.

The results also revealed that studies in younger, more symptomatic patients were correlated with more significant variability in the basal ganglia and temporal lobe, while studies with older, more symptomatic patients were correlated with more significant variability in MFC, and the majority of studies revealed a unimodal distribution of glutamatergic metabolites for individual patient data. The meta-analysis of average variations observed lower MFC glutamate, greater thalamic glutamine, and higher BG Glx in patients compared to controls.

The authors noted that the primary findings of this meta-analysis are that schizophrenia is linked with augmented variability in the concentrations of glutamatergic metabolites in the brain, in conjunction with regional variances in average glutamatergic metabolite concentrations. They also indicated that the heightened variability in glutamatergic metabolites was most evident in studies analyzing more symptomatic patients.

“In summary, this meta-analysis demonstrates increased regional variability in glutamatergic metabolites in schizophrenia in addition to mean differences compared to controls. Increased inter-individual differences in glutamatergic metabolites in schizophrenia are likely to have a complex mechanistic basis. Further work is also required to determine the clinical consequences along the spectrum of glutamate dysregulation,” the authors concluded.

Lastly, the authors noted that their findings are significant to the current research efforts to develop innovative pharmacotherapies that target glutamate dysfunction in schizophrenia since glutamatergic heterogeneity may signify the significance of targeting more specific patient subgroups.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.