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: 14.5). 11/2009; 15(6):629-36. DOI: 10.1038/mp.2009.121
Source: PubMed


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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    • "Postmortem studies in patients with schizophrenia showed significant alterations of glutamate metabolism, with abnormalities of phosphate-activated glutaminase and glutamic acid decarboxylase activities and NMDA receptor binding (Kornhuber et al., 1989; Gluck et al., 2002). More recently, a number of functional neuroimaging studies showed changes of glutamine levels or the glutamine/glutamate ratio in the anterior cingulate cortex and the thalamus in patients with schizophrenia in vivo as measured with magnetic resonance spectroscopy (MRS) (Theberge et al., 2002; Bustillo et al., 2010; Kegeles et al., 2012), indicating higher turnover rates of glutamate. It was also shown that clinical response to antipsychotic treatment is associated with the degree of glutamatergic dysfunction as assessed with MRS (Szulc et al., 2013; Egerton et al., 2012). "
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    ABSTRACT: Schizophrenia has been associated with disturbances of thalamic functioning. In the light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether the modulation of the glutamatergic system via blockage of the NMDA-receptor might lead to changes of thalamic functional connectivity. Based on the "ketamine-model" of psychosis we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55 minutes resting-state scan. 30 healthy volunteers were measured with pharmacological functional magnetic resonance imaging (fMRI) using a double-blind, randomized, placebo-controlled, crossover design. Functional connectivity analysis revealed significant ketamine-specific changes within the "thalamus hub network", more precisely an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex. Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behaviour during the application of NMDA-receptor antagonists. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 04/2015; DOI:10.1093/ijnp/pyv040 · 4.01 Impact Factor
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    • "It has been suggested that glutamatergic anomalies may be more pronounced to DA-rich regions such as the striatum (de la Fuente-Sandoval et al., 2011). In the DLPFC and putamen , we found no correlations between Glx levels and antipsychotic dose (CPZEs) in line with other studies, suggesting that antipsychotics do not have a dose-dependent effect on glutamatergic metabolites (Szulc et al., 2005; Theberge et al., 2007; de la Fuente-Sandoval et al., 2009; Bustillo et al., 2010; Aoyama et al., 2011 "
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    ABSTRACT: Background: According to the current schizophrenia treatment guidelines three levels of responsiveness to antipsychotic medication exist; those who respond to first-line antipsychotics, those with treatment resistant schizophrenia (TRS) who respond to clozapine and those with clozapine-resistant or ultra-treatment resistant schizophrenia (UTRS). Proton magnetic resonance spectroscopy ((1)H-MRS) studies indicate that antipsychotic medication decreases glutamate or total glutamate + glutamine (Glx) in the brains of patients with schizophrenia and may represent a biomarker of treatment response; however, the three levels of treatment responsiveness have not been evaluated. Methods: (1)H-MRS spectra were acquired at 3 Tesla from patients taking a second generation non-clozapine antipsychotic (first-line responders), patients with TRS taking clozapine, patients with UTRS taking a combination of antipsychotics and healthy comparison subjects. Results: Group differences in CSF-corrected Glx levels scaled to creatine (Glx/Cr) were detected in the DLPFC [df(3,48); F = 3.07, p = 0.04, partial η(2) = 0.16] and the putamen [df(3,32); F = 2.93, p = 0.05, partial η(2) = 0.22]. The first-line responder group had higher DLPFC Glx/Cr than those with UTRS [mean difference (MD) = 0.25, standard error (SE) = 0.09, p = 0.04, family-wise error (FWE)-corrected]. Those with TRS had higher Glx/Cr in the putamen than the first-line responders (MD = 0.31, SE = 0.12, p = 0.05, FWE-corrected) and those with UTRS (MD = 0.39, SE = 0.12, p = 0.02, FWE-corrected). Conclusions: Glx in the putamen may represent a marker of response to clozapine. Future studies should investigate glutamatergic anomalies prior to clozapine initiation and following successful treatment. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(6). DOI:10.1093/ijnp/pyu117 · 4.01 Impact Factor
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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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