Elevated Myo-Inositol, Choline, and Glutamate Levels in the Associative Striatum of Antipsychotic-Naive Patients With First-Episode Psychosis: A Proton Magnetic Resonance Spectroscopy Study With Implications for Glial Dysfunction

Abstract

Glial disturbances are highly implicated in the pathophysiology of schizophrenia and may be linked with glutamatergic dysregulation. Myo-inositol (mI), a putative marker of glial cells, and choline (Cho), representative of membrane turnover, are both present in larger concentrations within glial cells than in neurons, and their elevation is often interpreted to reflect glial activation. Proton magnetic resonance spectroscopy ((1)H-MRS) allows for the evaluation of mI, Cho, glutamate, glutamate + glutamine (Glx), and N-acetylaspartate (NAA). A collective investigation of these measures in antipsychotic-naive patients experiencing their first nonaffective episode of psychosis (FEP) can improve the understanding of glial dysfunction and its implications in the early stages of schizophrenia. 3-Tesla (1)H-MRS (echo time = 35 ms) was performed in 60 antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls. mI, Cho, glutamate, Glx, and NAA were estimated using LCModel and corrected for cerebrospinal fluid composition within the voxel. mI, Cho, and glutamate were elevated in the FEP group. After correction for multiple comparisons, mI positively correlated with grandiosity. The relationships between mI and glutamate, and Cho and glutamate, were more positive in the FEP group. These findings are suggestive of glial activation in the absence of neuronal loss and may thereby provide support for the presence of a neuroinflammatory process within the early stages of schizophrenia. Dysregulation of glial function might result in the disruption of glutamatergic neurotransmission, which may influence positive symptomatology in patients with FEP.

Glutathione and glutamate in schizophrenia: a 7T MRS study

“…Our hypothesis is further supported by the finding that for the sub-group of patients defined a priori as having residual schizophrenia, the effect size was larger, and indeed was largely responsible for the difference in scores between patients and controls. This finding is consistent with prior evidence indicating increased glutamatergic transmission early in the illness but diminished glutamate in older or more functionally impaired cases [29][30][31][32][33][34][35][36][37]. All three metabolites measured in the ACC were significantly lower in the group with residual schizophrenia than in the control group.…”

“…These studies provide some evidence of elevated glutamine levels in ACC/mPFC, especially in the early phase of illness. Overall, these studies indicate that glutamate may be unchanged or reduced, especially in more chronic cases, depending on the persistence of symptoms or other factors associated with long-term illness [29][30][31][32][33][34][35][36][37].…”

“…However, glutamate and glutamine each participate in several other distinct cell processes and hence may not be closely coupled [28]. MRS studies of glutamate and glutamine concentrations in schizophrenia have been inconsistent, with some studies reporting an increase, others reporting a decrease or no abnormality ( [29][30][31][32][33][34][35], for reviews see [36,37]). One metaanalysis found that glutamate is reduced and glutamine is increased in the ACC in patients with schizophrenia, and both decrease more markedly with age in patients [38].…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Myo-inositol is believed to be an astroglial marker, suggesting an involvement of astrocytes in these findings (Brand et al, 1993;Haroon et al, 2009;Kim et al, 2005;Plitman et al, 2016). Taken together, these data indicate an association between inflammation and glutamate dysregulation in mood disorders including depression.…”

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part II: Cognition, neuroimaging and genetics

“…(This figure can be found in full colour in the online version of the article.) recent MRS study showed an increase of glutamate in the associative striatum of antipsychotic-na€ ıve patients with first-episode psychosis and found positive correlations between glutamate and myo-inositol (or choline) in the antipsychotic-na€ ıve patients with first-episode psychosis (Plitman et al 2015). Given the role of myoinositol and choline in the glial cells, dysregulation of glial function is likely to result in the disruption of glutamatergic neurotransmission, which may play a role in the psychosis in the first-episode patients.…”