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Combining Data Across Methodologies and Continents to Test a Mechanistic Hypothesis: Setting Up the Future

  • Raquel E. Gur
    Correspondence
    Address correspondence to Raquel E. Gur, M.D., Ph.D., Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 10th floor Gates Pavilion, Philadelphia, PA 19104.
    Affiliations
    Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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      The role of glutamatergic neurotransmission in the pathophysiology of schizophrenia has been intensively examined and supported by converging lines of basic and clinical research, spanning from animal models to neuroimaging and postmortem investigations (
      • Javitt D.C.
      • Zukin S.R.
      • Heresco-Levy U.
      • Umbricht D.
      Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.
      ,
      • Ripke S.
      • Neale B.M.
      • Corvin A.
      • Walters J.T.R.
      • Farh K.H.
      • Holman P.A.,
      and Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Biological insights from 108 schizophrenia-associated genetic loci.
      ,
      • Hu W.
      • MacDonald M.L.
      • Elswick D.E.
      • Sweet R.A.
      The glutamate hypothesis of schizophrenia: Evidence from human brain tissue studies [published online ahead of print Oct 14].
      ,
      • Marsman A.
      • van den Heuvel M.P.
      • Klomp D.W.
      • Kahn R.S.
      • Luijten P.R.
      • Hulshoff Pol H.E.
      Glutamate in schizophrenia: A focused review and meta-analysis of 1H-MRS studies.
      ). However, the mechanistic path from genetic vulnerability to clinical manifestation is still uncharted. Such a path can be established by identifying reliable endophenotypes that can serve as biomarkers. These continuous quantitative parameters can provide stepping-stones, in which, for example, N-methyl-D-aspartate perturbations known to produce psychotic symptoms (
      • Javitt D.C.
      • Zukin S.R.
      • Heresco-Levy U.
      • Umbricht D.
      Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.
      ) are demonstrated to exist in populations at risk or patients in early stages of the disorder. Advances in complementary neuropharmacology and neuroimaging methodologies offer novel tools for establishing such biomarkers and using them to test increasingly refined hypotheses regarding the presence of glutamatergic dysfunction and its effects on regional brain parameters measured in systems that regulate neurocognitive domains implicated in schizophrenia (
      • Driesen N.R.
      • McCarthy G.
      • Bhagwagar Z.
      • Bloch M.H.
      • Calhoun V.D.
      • DʼSouza D.C.
      • et al.
      The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity.
      ).
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      Linked Article

      • N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia
        Biological PsychiatryVol. 77Issue 6
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          Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity.
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