Ketamine-Induced Exacerbation of Psychotic Symptoms and Cognitive Impairment in Neuroleptic-Free Schizophrenics

The N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. We administered subanesthetic doses of the NMDA receptor antagonist ketamine in a double-blind, placebo–controlled design to 13 neuroleptic-free schizophrenic patients to investigate if schizophrenics will experience an exacerbation of psychotic symptoms and cognitive impairments with ketamine. We also examined whether schizophrenics experienced quantitative or qualitative differences in ketamine response in comparison to normal controls. Schizophrenics experienced a brief ketamine-induced exacerbation of positive and negative symptoms with further decrements in recall and recognition memory. They also displayed greater ketamine-induced impairments in free recall than normals. Qualitative differences included auditory hallucinations and paranoia in patients but not in normals. These data indicate that ketamine is associated with exacerbation of core psychotic and cognitive symptoms in schizophrenia. Moreover, ketamine may differentially affect cognition in schizophrenics in comparison to normal controls.

[1]  D. Lodge,et al.  The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate , 1983, British journal of pharmacology.

[2]  H. Meltzer,et al.  Comparison of Ketamine and Thiopental in Healthy Volunteers: Effects on Mental Status, Mood, and Personality , 1984, Anesthesia and analgesia.

[3]  H. Lehmann,et al.  Observations on the Action of Sernyl — A New Psychotropic Drug , 1961, Canadian Psychiatric Association journal.

[4]  D. J. Smith,et al.  The interaction of ketamine with the opiate receptor. , 1980, Life Science.

[5]  Carol A. Tamminga,et al.  Subanesthetic Doses of Ketamine Stimulate Psychosis in Schizophrenia , 1995, Neuropsychopharmacology.

[6]  M. Herkenham,et al.  Altered metabolic activity in the cerebral cortex of rats exposed to ketamine , 1983, The Journal of comparative neurology.

[7]  J. Olney,et al.  Glutamate receptor dysfunction and schizophrenia. , 1995, Archives of general psychiatry.

[8]  T. Schorn,et al.  Are there long-term effects of ketamine on the central nervous system? , 1980, British journal of anaesthesia.

[9]  O. Paulsen,et al.  The chiral forms of ketamine as probes for NMDA receptor functions in humans , 1991 .

[10]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[11]  Herbert Weingartner,et al.  NMDA Receptor Function and Human Cognition: The Effects of Ketamine in Healthy Volunteers , 1996, Neuropsychopharmacology.

[12]  S. Kothary,et al.  Low dose intravenous infusion technique with ketamine , 1980, Anaesthesia.

[13]  A. Trevor,et al.  Inhibition of mammalian brain acetylcholinesterase by ketamine. , 1974, Biochemical pharmacology.

[14]  J. Olney,et al.  Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. , 1989, Science.

[15]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[16]  G. Rosenbaum,et al.  Comparison of sernyl with other drugs: simulation of schizophrenic performance with sernyl, LSD-25, and amobarbital (amytal) sodium; I. Attention, motor function, and proprioception. , 1959, A.M.A. archives of general psychiatry.

[17]  G. Rosenbaum,et al.  Comparison of phencyclidine hydrochloride (Sernyl) with other drugs. Simulation of schizophrenic performance with phencyclidine hydrochloride (Sernyl), lysergic acid diethylamide (LSD-25), and amobarbital (Amytal) sodium; II. Symbolic and sequential thinking. , 1962, Archives of general psychiatry.

[18]  J. Overall,et al.  The Brief Psychiatric Rating Scale , 1962 .

[19]  S. J. Young,et al.  Phencyclidine-induced psychosis. , 1978, The American journal of psychiatry.

[20]  L. Standish,et al.  Behavioral effects of phencyclidine and ketamine alone and in combination with other drugs. , 1987, European journal of pharmacology.

[21]  M. Buchsbaum,et al.  Effects of serotonin on memory impairments produced by ethanol. , 1983, Science.

[22]  J. Rapoport,et al.  Acquisition and retrieval of information in amphetamine-treated hyperactive children , 1982, Psychiatry Research.

[23]  G. Rosenbaum,et al.  Study of a new schizophrenomimetic drug; sernyl. , 1959, A.M.A. archives of neurology and psychiatry.

[24]  A. Crane,et al.  Local Changes in Cerebral Glucose Utilization during Ketamine Anesthesia , 1982, Anesthesiology.

[25]  J. Grafman,et al.  Forms of memory failure. , 1983, Science.

[26]  S. Rothman.  Noncompetitive N-methyl-D-aspartate antagonists affect multiple ionic currents. , 1988, The Journal of pharmacology and experimental therapeutics.

[27]  D. J. Smith,et al.  Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines , 1981, Neuropharmacology.

[28]  H. Beech,et al.  The effect of 1-arylcylohexylamine (sernyl) on twelve normal volunteers. , 1960, The Journal of mental science.