cns-1261 and Schizophrenia

Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor.. We used [(123)I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction.. Ten healthy controls underwent two single-photon emission tomography scans with [(123)I]CNS-1261. On each occasion, they received a bolus infusion of either ketamine or saline. The Brief Psychiatric Rating Scale (BPRS) was administered at the end of each scan. Predefined regions of interest were used to estimate change in volume of distribution of [(123)I]CNS-1261 following ketamine administration. Two normalised-to-cortex binding indices were also used in order to study effects of ketamine on NMDA receptor availability by region, after correction for global and nonspecific effects.. Ketamine-induced reduction in [(123)I]CNS-1261 volume of distribution in all regions showed the strongest correlation with BPRS negative subscale (p < 0.01). With the normalised-to-cortex measures, NMDA receptor binding in middle inferior frontal cortex showed a significant correlation with BPRS negative subscale (BI1 r = 0.88, BI2 r = 95.9, p < 0.001).. [(123)I]CNS-1261 binding was modulated by ketamine, a drug known to compete for the same site on the NMDA receptor in vitro. Ketamine may induce negative symptoms through direct inhibition of the NMDA receptor, and positive symptoms may arise through a different neurochemical pathway.

Topics: Adult; Brief Psychiatric Rating Scale; Dose-Response Relationship, Drug; Guanidines; Humans; Infusions, Intravenous; Iodine Radioisotopes; Ketamine; Male; Prefrontal Cortex; Psychoses, Substance-Induced; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Single-Blind Method; Tomography, Emission-Computed, Single-Photon

Topics: Analysis of Variance; Antipsychotic Agents; Case-Control Studies; Clozapine; Functional Laterality; Genetic Predisposition to Disease; Guanidines; Hippocampus; Humans; Receptors, N-Methyl-D-Aspartate; Reference Values; Schizophrenia; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

Topics: Algorithms; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Guanidines; Humans; Image Processing, Computer-Assisted; Radiopharmaceuticals; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Tomography, Emission-Computed, Single-Photon

Antipsychotic drugs modulate N-methyl-D-aspartate (NMDA) receptor function in animals. The novel single photon emission tomography (SPET) radiotracer [123I]CNS-1261 binds to the PCP/MK-801 intrachannel site of the NMDA receptor, allowing the noninvasive estimation of NMDA receptor activity in living humans. We used [123I]CNS-1261 to determine whether binding to the NMDA receptor intrachannel PCP/MK-801 site is affected by schizophrenia or by treatment with typical antipsychotics and clozapine in vivo.. Three groups of schizophrenia patients were recruited-drug free (n = 5), typical antipsychotic treated (n = 7), and clozapine treated (n = 9)-as well as a control group of healthy normal volunteers (n = 13). All underwent [123I]CNS-1261 SPET scanning. Total volume of distribution of [123I]CNS-1261 was determined within predefined user-independent regions of interest after alignment of all images to a common template.. There was no apparent difference in total volume of distribution of [123I]CNS-1261 in drug-free patients relative to healthy control subjects. A nonsignificant reduction in total volume of distribution was observed in typical antipsychotic treated patients. A significant decline in total volume of distribution of [123I]CNS-1261 was observed in all examined brain regions in the clozapine-treated patient group relative to healthy control subjects (p < .005).. Clozapine treatment resulted in a global reduction in [123I]CNS-1261 binding to the NMDA receptor intrachannel PCP/MK-801 site in vivo. This supports an effect of the drug on glutamatergic systems that could be exploited for future antipsychotic drug discovery.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Female; Guanidines; Humans; Iodine Radioisotopes; Male; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Tomography, Emission-Computed, Single-Photon