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.

Synaptic Proteins in the Postmortem Anterior Cingulate Cortex in Schizophrenia: Relationship to Treatment and Treatment Response

“…The only association of treatment resistance with vGLUT1 levels was that a greater proportion of the TR population lacked vGLUT1 than did responders, whereas average protein levels between groups were similar. MRS spectroscopy in the ACC showed increased glutamate in SZ patients who were still symptomatic after treatment, compared with that in SZ patients who were responsive after treatment (Egerton et al, 2012), suggesting that reducing glutamate transmission is related to successful treatment. One mechanism to decrease glutamate transmission would be to reduce vGLUT1 levels.…”

“…The reason for treatment resistance is poorly understood but appears to have a biological basis (Sheitman and Lieberman, 1998;Altamura et al, 2005) as a relationship between pathophysiology and the degree of treatment response has been shown in several neuroimaging studies (Rodríguez et al, 1997;Staal et al, 2001). In particular, the anterior cingulate cortex (ACC) has abnormalities linked to and predictive of treatment response (Lahti et al, 2009;Egerton et al, 2012). SPECT shows differential values for cerebral perfusion, an index of neuronal activity (Gemmell et al, 1990), in treatment-responsive vs -resistant SZ subjects (Rodríguez et al, 1997).…”

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

“…[26][27][28][29][30] However, the quality of the spectral fits is not always clear in these reports (except for [27][28][29] ) and the samples were small (9 to 30 for the schizophrenia groups 6 ). More recent studies reported increases, [31][32][33][34][35] reductions 25,[36][37][38] and no differences 39 in Glx or glutamate. Two 33,34 of the 5 recent studies documenting elevations involved more ventral regions.…”

The quest for biomarkers in Schizophrenia: from neuroimaging to machine learning

“…This suggests that brain glutamatergic activity is increased in the early stages of the disorder, when patients are usually experiencing acute psychotic symptoms [30].…”