A growing body of evidence suggests that deficits in glutamatergic function may underlie the pathophysiology of schizophrenia. Phencyclidine (PCP) is a noncompetitive antagonist for the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor. Ketamine is an FDA-approved anesthetic agent. It has an initial half-life of 15 minutes and a terminal half-life of 2 hours. General anesthetic doses of ketamine range from 1 mg/kg to 3 mg/kg IV bolus, with subsequent administration used as needed to maintain anesthesia. Ketamine is a noncompetitive NMDA receptor antagonist and has been used in sub-anesthetic doses to probe glutamatergic function in healthy subjects, schizophrenic patients, and chronic pain patients. In the present study, we propose to examine the effects of ketamine on behavioral, neuroendocrine, and neuropsychological parameters in neuroleptic-free schizophrenic patients and matched controls using a double blind, counter-balanced, placebo-controlled design. To explore the effects of antipsychotic treatment on glutamatergic function, ketamine will be given to schizophrenic patients while they are being treated with neuroleptic medications. In addition, the effects of ketamine on metabolic rate and blood flow will be examined. The present study will be amended to a previously approved Positron Emission Tomography (PET) protocol (93-M-0 1121) for the PET/ketamine study.
