Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

https://jamanetwork.com/journals/PSYCH/articlepdf/496531/archpsyc_51_3_004.pdf

Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.

Objective: Agents that antagonize the N-methyl-D-aspartic acid (NMDA) receptor, such as phencyclidine and ketamine, produce an acute psychotic state in normal individuals that resembles some symptoms of schizophrenia. The aim of this study was to determine which brain regions are involved in NMDA receptor-mediated psychosis. Method: Positron emission tomography with [18F]fluorodeoxyglucose was used to determine cerebral metabolic activity in 17 healthy volunteers while an acute psychotic state was induced simultaneously by the administration of subanesthetic doses of ketamine. Results: Ketamine produced focal increases in metabolic activity in the prefrontal cortex and an acute psychotic state. A change in one psychotic symptom, conceptual disorganization, was significantly related to prefrontal activation. Conclusions: These data suggest that the prefrontal cortex may be involved in mediating NMDA receptor-induced psychosis. (Am J Psychiatry 1997; 154:805‐811)

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/ajp.154.6.805

Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers.

Psychological deficit in schizophrenia. ii. interference and activation.

Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia A dysfunction in NMDA-dopaminergic interactions has been proposed as a mechanism for these behavioral effects In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine We found that the percent decreases (mean +/- SD) in specific 11C-raclopride binding from baseline for ketamine (112 +/- 89) was greater than for saline (19 +/- 37) (t = 24, df = 13, P = 0003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations Ketamine-related binding changes were not significantly different than the decreases in percent change (mean +/- SD) in specific 11C-raclopride binding caused by amphetamine (155 +/- 62) (t = 13, df = 19, P = 021) Ketamine-induced changes in 11C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed

M. Devault

Papers

A NEW DRUG CAUSING SYMPTOMS OF SENSORY DEPRIVATION Neurological, Electroencephalographic and Pharmalogical Effects of Sernyl