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Capitalizing on Extrasynaptic Glutamate Neurotransmission to Treat Antipsychotic-Resistant Symptoms in Schizophrenia

  • John H. Krystal
    Correspondence
    Address reprint requests to John H. Krystal, M.D., Schizophrenia Biological Research Center, VA Connecticut Healthcare System (151-D), 950 Campbell Avenue, West Haven, CT 06516
    Affiliations
    Department of Psychiatry, Yale University School of Medicine, New Haven; Schizophrenia Biological Research Center, VA Connecticut Healthcare System, West Haven; and Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut.
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      The pursuit of treatments for schizophrenia aimed at correcting disturbances in glutamatergic neurotransmission associated with this disorder is directing medication development in a number of exciting new directions (
      • Krystal J.H.
      • D'Souza D.C.
      • Mathalon D.
      • Perry E.
      • Belger A.
      • Hoffman R.E.
      NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: Toward a paradigm shift in medication development.
      ). Over the past 15 years, psychopharmacologic studies, postmortem studies, and molecular genetic studies have provided evidence that glutamate synaptic abnormalities, particularly those that reduce N-methyl-D-aspartate (NMDA) glutamate receptor function, contribute to the neurobiology of schizophrenia (
      • McCullumsmith R.E.
      • Clinton S.M.
      • Meador-Woodruff J.H.
      Schizophrenia as a disorder of neuroplasticity.
      ,
      • Lewis D.A.
      • Gonzalez-Burgos G.
      Neuroplasticity of neocortical circuits in schizophrenia.
      ,
      • MacDonald 3rd, A.W.
      • Chafee M.V.
      Translational and developmental perspective on N-methyl-D-aspartate synaptic deficits in schizophrenia.
      ). Preliminary signs of efficacy in pharmacotherapy studies of substances that directly or indirectly enhance NMDA glutamate receptor function, including glycine, D-serine, and sarcosine, further support the hypothesis that NMDA receptor functional deficits contribute to schizophrenia (
      • Javitt D.C.
      Glutamate as a therapeutic target in psychiatric disorders.
      ). However, the largest trial of adjunctive glycine for schizophrenia yielded negative results, raising the question of whether glycine was a poor choice or whether aspects of the underlying hypothesis were flawed (
      • Buchanan R.W.
      • Javitt D.C.
      • Marder S.R.
      • Schooler N.R.
      • Gold J.M.
      • McMahon R.P.
      • et al.
      The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): The efficacy of glutamatergic agents for negative symptoms and cognitive impairments.
      ). After more than 10 years of anticipation (
      • Krystal J.H.
      • D'Souza D.C.
      D-serine and the therapeutic challenge posed by the N-methyl-D-aspartate antagonist model of schizophrenia.
      ), this line of research still awaits a definitive clinical trial of a glycine transporter antagonist with a favorable pharmacodynamic and pharmacokinetic profile.
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