Several lines of evidence suggest that deficits in glutamatergic function may play a role in the pathophysiology of schizophrenia. Ketamine is an FDA approved anesthetic agent. It is a specific noncompetitive antagonist of the NMDA-type glutamate receptor and is currently being used by several research groups in subanesthetic doses to probe glutamatergic function. The purpose of this study is to examine the effects of subanesthetic doses of ketamine on metabolic rate with FDG/PET, behavior, neuroendocrine parameters and neuropsychologic function in schizophrenic patients and healthy controls. We have found that ketamine (.12mg/kg bolus followed by .65mg/kg hourly infusion) impaired memory and these effects were independent of effects on attention (Malhotra et al 1995). We are now in the data analysis phase of comparing the cognitive, symptomatic, neuroendocrine effects of ketamine between neuroleptic-free schizophrenic patients, neuroleptic- treated schizophrenic patients and healthy controls.The PET study examining the cerebral metabolic effects of ketamine in healthy volunteers (N=17) has been completed. We found highly focal activation of the prefrontal cortex suggesting for the first time that prefrontal NMDA receptors mediate ketamine-induced psychosis. We have also scanned neuroleptic-free schizophrenia patients and schizophrenic patients treated with clozapine (N=7) and found a more diffuse pattern of ketamine-induced metabolic activity. One line of investigation we are pursing to explain this apparent control-patient difference is through examination of the allelic sequence of the NMDA receptor in controls and patients which will test the hypothesis that schizophrenic patients have a mutation in this receptor that causes differential metabolic effects.
