title: N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia.
abstract: BACKGROUND
  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.
  
  
  METHODS
  First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity.
  
  
  RESULTS
  Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia.
  
  
  CONCLUSIONS
  Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; National Institute on Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut.
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Corlett
authors.affiliation: Center for Molecular & Behavioral Neuroscience, Rutgers University, Newark, New Jersey.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Cole
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut; University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb, Croatia.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Savic
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut.
authors.forename: Mark
authors.initials: M
authors.lastname: Gancsos
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Psychology, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Grega
authors.initials: G
authors.lastname: Repovs
authors.affiliation: Department of Neurobiology, Yale University, New Haven, Connecticut; Department of Physics, Yale University, New Haven, Connecticut.
authors.forename: John D
authors.initials: JD
authors.lastname: Murray
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Driesen
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Morgan
authors.affiliation: Department of Radiology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; Department of Radiology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, People's Republic of China. Electronic address: fei.wang@yale.edu.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut; National Institute on Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism, Connecticut Mental Health Center, New Haven, Connecticut; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut; Department of Psychiatry, Yale-New Haven Hospital, New Haven, Connecticut.
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
mesh_terms: D000328:Adult; D002908:Chronic Disease; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology*; D012559:Schizophrenia / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine
keywords: Chronic schizophrenia; Disinhibition; First episode; Glutamate; High-risk; Ketamine; NMDA receptor; Prefrontal connectivity