N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia

Biol Psychiatry. 2015 Mar 15;77(6):569-80. doi: 10.1016/j.biopsych.2014.07.022. Epub 2014 Jul 31.

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.

Keywords: Chronic schizophrenia; Disinhibition; First episode; Glutamate; High-risk; Ketamine; NMDA receptor; Prefrontal connectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Chronic Disease
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Humans
  • Ketamine / pharmacology*
  • Male
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiopathology*
  • Schizophrenia / physiopathology*
  • Young Adult

Substances

  • Excitatory Amino Acid Antagonists
  • Ketamine