Anterior Cingulate Glutamate Levels Related to Clinical Status Following Treatment in First-Episode Schizophrenia

Department of Psychosis Studies, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 07/2012; 37(11):2515-21. DOI: 10.1038/npp.2012.113
Source: PubMed


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.

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Available from: Alice Egerton, Jan 05, 2015
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    • "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.
    Full-text · Article · Apr 2015 · The International Journal of Neuropsychopharmacology
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    • "Thus, while altered glutamate activity in PFC may increase vulnerability to adverse cognitive effects of antipsychotics, mGluR3 alterations at presynaptic terminals that could result from GRM3 SNPs may be reversed by antipsychotic effects in the striatum with the associated beneficial effect of negative symptom reduction . It may be helpful to further investigate these molecular hypotheses in human spectroscopy imaging studies as prior research has identified relationships between glutamate and related amino acid metabolites in the striatum and anterior cingulate and early treatment response and also treatmentresistant illness (Demjaha et al. 2014; Egerton et al. 2012). Some limitations and other considerations of our study must be recognized. "
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    ABSTRACT: Rationale Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. Objectives The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. Methods Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients’ level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. Results Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. Conclusions These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects.
    Full-text · Article · Aug 2014 · Psychopharmacology
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    • "In a more recent study, Demjaha et al. (2012) found that patients who were responsive to antipsychotics had increased dopamine synthesis compared to both healthy controls and patients with treatment resistant schizophrenia. Using MR spectroscopy , Egerton et al. (2012) found that a poor response to antipsychotic medication in first episode patients was associated with elevated glutamate levels in the anterior cingulate cortex. Demjaha and Egerton had initially reported on separate samples but in a new publication (Demjaha et al., 2014) they assessed the same patient sample with both PET and MRS and reported that elevated glutamate levels within the anterior cingulate and normal presynaptic dopamine synthesis were both features of poor response to antipsychotic medication. "
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    ABSTRACT: Early diagnosis and treatment of patients with psychosis is associated with improved outcome in terms of future functioning, symptoms and treatment response. Identifying neuroimaging biomarkers for illness onset and treatment response would lead to immediate clinical benefits. In this review we discuss if neuroimaging may be utilised to diagnose patients with psychosis, predict those who will develop the illness in those at high risk, and stratify patients. State-of-the-art developments in the field are critically examined including multicentre studies, longitudinal designs, multimodal imaging and machine learning as well as some of the challenges in utilizing future neuroimaging biomarkers in clinical trials. As many of these developments are already being applied in neuroimaging studies of Alzheimer's disease: we discuss what lessons have been learned from this field and how they may be applied to research in psychosis.
    Full-text · Article · Jul 2014 · European Neuropsychopharmacology
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