European Neuropsychopharmacology 7 (1997) 25–38 Differential psychopathology and patterns of cerebral glucose utilisation produced by ( S )- and ( R )-ketamine in healthy volunteers using positron emission tomography (PET) a, b c a a * F.X. Vollenweider , K.L. Leenders , I. Øye , D. Hell , J. Angst a ¨ ¨ Psychiatric University Hospital Zurich, Research Department, P .O. Box 68, CH-8029 Zurich, Switzerland b Paul Scherrer Institute, PET Department, CH-5232 Villigen, Switzerland c Oslo University School of Medicine, Department of Pharmacology, P .O. Box 1057 Blindern, 0316 Oslo 3, Norway Received 11 March 1996; accepted 16 July 1996 Abstract Until recently, racemic ketamine ( S-ketamine / R-ketamine550:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S )- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S )-ketamine binds with a 3–4 time higher affinity to the PCP binding site of the NMDA receptor than ( R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where ( S )-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure ( S )- and ( R)-ketamine 18 enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [ F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of ( S )-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The ( S )-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.  1997 Elsevier Science B.V. All rights reserved. Keywords: Model psychosis; Schizophrenia; Glutamate; (S )- and (R)-ketamine enantiomeres; N-Methyl-D-aspartate (NMDA) receptor; 18 Sigma receptor; Cerebral glucose metabolism; Frontal cortex; PET (Positron emission tomography); [ F]Fluorodeoxyglucose (FDG) 1. Introduction strong support for a glutamate deficiency hypothesis in schizophrenia (Anis et al., 1983). The glutamate hypoth- Phencyclidine (PCP) and its congener ketamine are two esis is further supported by the finding of a decreased anesthetics that can uniquely produce a psychosis-like glutamate concentration in cerebrospinal fluid of schizo- mental state in normal humans, including both positive and phrenics (Kim et al., 1980), alterations in cortical and negative symptoms of schizophrenia (Luby et al., 1959; subcortical NMDA receptor densities (Deakin et al., 1989; Domino et al., 1965). At subanesthetic doses, ketamine Kornhuber et al., 1989; Simpson et al., 1992; Ishimaru et primarily blocks the PCP binding site of the N-methyl-D- al., 1994), and reduced glutamate release in postmortem aspartate (NMDA)-sensitive glutamate receptor giving schizophrenic brain preparations (Sherman et al., 1991). Moreover, pharmacological models of schizophrenia incor- * Corresponding author. Fax: 141 1 3843396; Tel: 141 1 3832111. porating the thalamic filter theory propose that blockade of 0924-977X / 97 / $17.00  1997 Elsevier Science B.V. All rights reserved PII S0924-977X(96)00042-9