Increased Glutamate Plus Glutamine in the Right Middle Cingulate in Early Schizophrenia but Not in Bipolar Psychosis: A Whole Brain (1)H-MRS Study

Proton magnetic resonance spectroscopy ((1)H-MRS) studies have examined glutamatergic abnormalities in schizophrenia and bipolar-I disorders, mostly in single voxels. Though the critical nodes remain unknown, schizophrenia and bipolar-I involve brain networks with broad abnormalities. To provide insight on the biochemical differences that may underlie these networks, the combined glutamine and glutamate signal (Glx) and other metabolites were examined in patients in early psychosis with whole brain (1)H-MRS imaging ((1)H-MRSI). Data were acquired in young schizophrenia subjects (N = 48), bipolar-I subjects (N = 21) and healthy controls (N = 51). Group contrasts for Glx, as well as for N-acetyl aspartate, choline, myo-inositol and creatine, from all voxels that met spectral quality criteria were analyzed in standardized brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05) analysis. Schizophrenia subjects had higher Glx in the right middle cingulate gyrus (19 voxels, CCLAV = 0.05) than bipolar-I subjects. Healthy controls had intermediate Glx values, though not significant. Schizophrenia subjects also had higher N-acetyl aspartate (three clusters, left occipital, left frontal, right frontal), choline (two clusters, left and right frontal) and myo-inositol (one cluster, left frontal) than bipolar-I, with healthy controls having intermediate values. These increases were likely accounted for by antipsychotic medication effects in the schizophrenia subgroup for N-acetyl aspartate and choline. Likewise, creatine was increased in two clusters in treated vs. antipsychotic-naïve schizophrenia, supporting a medication effect. Conversely, the increments in Glx in right cingulate were not driven by antipsychotic medication exposure. We conclude that increments in Glx in the cingulate may be critical to the pathophysiology of schizophrenia and are consistent with the NMDA hypo-function model. This model however may be more specific to schizophrenia than to psychosis in general. Postmortem and neuromodulation schizophrenia studies focusing on right cingulate, may provide critical mechanistic and therapeutic advancements, respectively.