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 anesthetic agent approved by the Food and Drug Administration. 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 intravenous bolus, with subsequent administration as needed to maintain anesthesia. Ketamine is a noncompetitive NMDA-receptor antagonist and has been used in subanesthetic doses to probe glutamatergic function in healthy subjects, schizophrenic patients, and chronic pain patients. In the present study, we proposed to examine the effects of ketamine on behavioral, neuroendocrine, and neuropsychological parameters in neuroleptic-free schizophrenic patients and matched controls, using a double-blind, counterbalanced, 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 amend a previously approved positron emission tomography protocol (93-M-01121) for the PET/ketamine study.
