Background:Dysregulations of the major inhibitory and excitatory amino neurotransmitter systems of γ-aminobutyric acid and glutamate, respectively, have been described in patients with schizophrenia. However, it is unclear whether these abnormalities are present in subjects at ultra-high risk for psychosis.Methods:Twenty-three antipsychotic naïve subjects at ultra-high risk and 24 healthy control subjects, matched for age, sex, handedness, cigarette smoking, and parental education, underwent proton magnetic resonance spectroscopy scans in the dorsal caudate bilaterally and the medial prefrontal cortex at 3T. Levels of γ-aminobutyric acid and of the combined resonance of glutamate and glutamine (Glx) were obtained using the standard J-editing technique and expressed as peak area ratios relative to the synchronously acquired unsuppressed voxel water signal.Results:Higher levels of γ-aminobutyric acid (P<.001) and Glx (P=.007) were found in the dorsal caudate of the subjects at ultra-high risk than in the healthy controls. In the medial prefrontal cortex, likewise, both γ-aminobutyric acid (P=.03) and Glx (P=.006) levels were higher in the ultra-high risk group than in the healthy controls. No group differences were found for any of the other metabolites (N-acetylaspartate, total choline, or total creatine) in the 2 regions of interest.Conclusions:This study presents the first evidence of abnormal elevations, in subjects at ultra-high risk, of γ-aminobutyric acid and Glx in 2 brain regions that have been implicated in the pathophysiology of psychosis, warranting longitudinal studies to assess whether these neurotransmitter abnormalities can serve as noninvasive biomarkers of conversion risk to psychosis as well as of illness progression and treatment response.

The results of the present study documented elevations of GABA levels both in the mPFC and, for the first time, in the dorsal caudate of antipsychotic-naïve patients with FEP, which normalized in both regions following 4 weeks of antipsychotic treatment.

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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.

Neuroimaging studies investigating patients with schizophrenia often report appreciable volumetric reductions and cortical thinning, yet the cause of these deficits is unknown. The association between subcortical and cortical structural alterations, and glutamatergic neurometabolites is of particular interest due to glutamate's capacity for neurotoxicity; elevated levels may be related to neuroanatomical compromise through an excitotoxic process. To this end, we explored the relationships between glutamatergic neurometabolites and structural measures in antipsychotic-naive patients experiencing their first non-affective episode of psychosis (FEP). Sixty antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls underwent a magnetic resonance imaging session, which included a T1-weighted volumetric image and proton magnetic resonance spectroscopy in the precommissural dorsal caudate. Group differences in precommissural caudate volume (PCV) and cortical thickness (CT), and the relationships between glutamatergic neurometabolites (ie, glutamate+glutamine (Glx) and glutamate) and these structural measures, were examined. PCV was decreased in the FEP group (p<0.001), yet did not differ when controlling for total brain volume. Cortical thinning existed in the FEP group within frontal, parietal, temporal, occipital, and limbic regions at a 5% false discovery rate. Glx levels were negatively associated with PCV only in the FEP group (p=0.018). The observed relationship between Glx and PCV in the FEP group is supportive of a focal excitotoxic mechanism whereby increased levels of glutamatergic markers are related to local structural losses. This process may be related to the prominent structural deficits that exist in patients with schizophrenia.