Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia

Abstract

Many patients with schizophrenia show a limited symptomatic response to treatment with dopaminergic antipsychotics. This may reflect the additional involvement of non-dopaminergic neurochemical dysfunction in the pathophysiology of the disorder. We tested the hypothesis that brain glutamate levels would differ between patients with first-episode psychosis who were symptomatic compared with those with minimal symptoms following antipsychotic treatment. Proton magnetic resonance spectroscopy (1H-MRS) spectra were acquired at 3 Tesla in the anterior cingulate cortex and left thalamus in 15 patients with first-episode psychosis in symptomatic remission, and 17 patients with first-episode psychosis who were still symptomatic following at least one course of antipsychotic treatment. Metabolite levels were estimated in ratio to creatine (Cr) using LCModel. Levels of glutamate/Cr in the anterior cingulate cortex were significantly higher in patients who were still symptomatic than in those in remission (T(30)=3.02; P=0.005). Across the entire sample, higher levels of glutamate/Cr in the anterior cingulate cortex were associated with a greater severity of negative symptoms (r=0.42; P=0.017) and a lower level of global functioning (r=-0.47; P=0.007). These findings suggest that clinical status following antipsychotic treatment in schizophrenia is linked to glutamate dysfunction. Treatment with compounds acting on the glutamatergic system might therefore be beneficial in patients who respond poorly to dopaminergic antipsychotics.

Figures

Figure 1

Level of glutamate (scaled to creatine) in the anterior cingulate cortex. Glutamate levels were significantly higher in non-remitted (n=17) than remitted (n=15) schizophrenia patients (T(30)=3.02; P=0.005). This difference remained significant T(28)= 2.79; P=0.009) after removal of the two outlying values as identified by Cook's D and indicated by the filled symbols.

Figure 2

Level of Glx (glutamate plus glutamine, scaled to creatine) in the anterior cingulate cortex. There was no significant group difference in Glx including all cases (T(30)=1.24; P=0.223), but levels of Glx/Cr were significantly higher in non-remitted than remitted patients (T(27)=2.20; P=0.036) after removal of three outlying values as identified with Cook's D and indicated by the filled symbols.

Figure 3

Higher levels of glutamate (scaled to creatine) in the anterior cingulate cortex were associated with (a) greater severity of negative symptoms (left; r=0.42; P=0.017), and with (b) lower levels of global functioning (right; r=−0.47; P=0.007).