Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
[(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.
Stone
James M
JM
Institute of Psychiatry, King's College London, London, UK. j.stone@iop.kcl.ac.uk
Erlandsson
Kjell
K
Arstad
Erik
E
Squassante
Lisa
L
Teneggi
Vincenzo
V
Bressan
Rodrigo A
RA
Krystal
John H
JH
Ell
Peter J
PJ
Pilowsky
Lyn S
LS
D000328:Adult; D010054:Brief Psychiatric Rating Scale; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007649:Ketamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging* / Q000187:drug effects*; D011605:Psychoses, Substance-Induced / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced* / Q000000981:diagnostic imaging*; D016037:Single-Blind Method; D015899:Tomography, Emission-Computed, Single-Photon
C417904:CNS 1261; D006146:Guanidines; D007457:Iodine Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine