1H-MRS at 4 Tesla in minimally treated early schizophrenia

Department of Psychiatry, University of New Mexico, Albuquerque, NM 87131-0001, USA.
Molecular Psychiatry (Impact Factor: 15.15). 11/2009; 15(6):629-36. DOI: 10.1038/mp.2009.121
Source: PubMed

ABSTRACT We investigated glutamate-related neuronal dysfunction in the anterior cingulate (AC) early in schizophrenia before and after antipsychotic treatment. A total of 14 minimally treated schizophrenia patients and 10 healthy subjects were studied with single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) of the AC, frontal white matter and thalamus at 4 T. Concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln) and Gln/Glu ratios were determined and corrected for the partial tissue volume. Patients were treated with antipsychotic medication following a specific algorithm and (1)H-MRS was repeated after 1, 6 and 12 months. There were group x region interactions for baseline NAA (P=0.074) and Gln/Glu (P=0.028): schizophrenia subjects had lower NAA (P=0.045) and higher Gln/Glu (P=0.006) in the AC before treatment. In addition, AC Gln/Glu was inversely related to AC NAA in the schizophrenia (P=0.0009) but not in the control group (P=0.92). Following antipsychotic treatment, there were no further changes in NAA, Gln/Glu or any of the other metabolites in any of the regions studied. We conclude that early in the illness, schizophrenia patients already show abnormalities in glutamatergic metabolism and reductions in NAA consistent with glutamate-related excitotoxicity.

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Available from: Rex Eugene Jung, Aug 18, 2015
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    • "However , this could not be specifically attributed to declining ACC glutamate levels in the UHR compared with Control group , as the time by group interaction was above the threshold for statistical significance , and there was no evidence in UHR individuals that change in ACC glutamate levels were related to change in mental state . Nonetheless , lower levels of ACC glutamate in UHR subjects would consistent with the lower levels of frontal glutamate in schizophrenia reported by meta - analysis ( Marsman et al , 2011 ) , and in unaffected twins of patients with schizophrenia ( Lutkenhoff et al , 2010 ) , and partially consistent with studies in early psychosis that have reported elevated ACC glutamine ( Theberge et al , 2002 ; Theberge et al , 2007 ) , or elevated glutamine / glutamate ratio ( Bustillo et al , 2010 "
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    ABSTRACT: Alterations in brain glutamate levels may be associated with psychosis risk, but the relationship to clinical outcome in at risk individuals is unknown. Glutamate concentration was measured in the left thalamus and anterior cingulate cortex (ACC) using 3 Tesla proton magnetic resonance spectroscopy in 75 participants at Ultra High Risk (UHR) of psychosis and 56 healthy controls. The severity of attenuated positive symptoms and overall functioning was assessed. Measures were repeated in 51 UHR and 33 Control subjects after a mean of 18 months. UHR subjects were allocated to either remission (no longer meeting UHR criteria) or non-remission (meeting UHR or psychosis criteria) status on follow-up assessment. Thalamic glutamate levels at presentation were lower in the UHR non-remission (N=29) compared to the remission group (N=22) (t(49)=3.03; P=0.004), and were associated with an increase in the severity of total positive symptoms over time (r=-0.33; df=47; P=0.02), most notably abnormal thought content (r=-0.442; df=47; P=0.003). In the UHR group, ACC glutamate levels were lower at follow-up compared to baseline (F(80)=4.28; P=0.04). These findings suggest that measures of brain glutamate function may be useful as predictors of clinical outcome in individuals at high risk of psychosis.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.143.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.143 · 8.68 Impact Factor
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    • "To our knowledge, this is the first evidence that anterior cingulate glutamate levels differ between patients with schizophrenia in remission following antipsychotic treatment and patients who are still symptomatic. Higher levels of glutamate and Glx in the anterior cingulate cortex in symptomatic compared with remitted patients are consistent with reports of elevated anterior cingulate glutamate turnover in non-medicated or minimally treated patients, who generally have high levels of psychotic symptoms (Bustillo et al, 2010; Theberge et al, 2002). It is also in line with evidence that frontal glutamate is reduced in chronic patients with a long history of antipsychotic treatment and who are generally less symptomatic (Marsman et al, 2011; Tayoshi et al, 2009; Theberge et al, 2003). "
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    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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2012; 37(11):2515-21. DOI:10.1038/npp.2012.113 · 7.83 Impact Factor
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    • "Of the five studies we found reporting measurements in the basal ganglia (Bertolino et al. 2001; Bustillo et al. 2001; Bustillo et al. 2008; Fannon et al. 2003; Heimberg et al. 1998) only Heimberg et al. reported any change, a decrease in Cho/ Cr. In the thalamus, three of five papers found no effects of medication (Bertolino et al. 2001; Bustillo et al. 2009; Heimberg et al. 1998). However, Szulc et al. (2007) reported decreased NAA/Cr in patients treated with typical antipsychotics compared with normal controls, but no differences in NAA/Cr between patients treated with typical or atypical antipsychotics. "
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    ABSTRACT: Proton magnetic resonance spectroscopy (MRS) studies of schizophrenic patients generally reveal reduced levels of N-acetyl aspartate (NAA) when compared with healthy controls. Whether this reduction is due to the disease or to the drugs used for treatment remains an open question. Numerous human and animal studies have attempted to determine the effects of antipsychotics on NAA levels with mixed results. The majority of the animal studies were ex vivo, which may not accurately reflect the in vivo situation, and limitations of the human studies include previous or concomitant medications or other confounds. To overcome these limitations, we dosed 10 rats/group for six months via drinking water with 0.2 or 2 mg/kg/day haloperidol or 10 or 30 mg/kg/day clozapine. Control rats received unadulterated water. Proton MRS data were collected longitudinally over the six month period from a 64 μL voxel containing primarily the right striatum prior to and monthly during drug administration and used to estimate the concentrations of NAA, creatine, and choline. Ratios of NAA, choline, inositol and glutamate+glutamine to creatine were also calculated. Only the Cho/Cr ratio showed a significant time-by-treatment effect (p=0.0285). These results are in agreement with previous studies of the striatum. However, regional and disease-specific effects remain unresolved.
    Schizophrenia Research 03/2011; 128(1-3):83-90. DOI:10.1016/j.schres.2011.02.019 · 4.43 Impact Factor
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