Abstract
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.
References
Allen RM, Young SJ (1978): Phencyclidine–induced psychosis. Am J Psychiatry 135:1081–1084
Anis NA, Berry SC, Burton NR, Lodge D (1983): The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N–methyl–aspartate. Br J Pharmacol 79:565–575
Ban TA, Lohrenz JJ, Lehmann HE (1961): Observations on the action of sernyl—a new psychotropic drug. Can J Psychiatry 6:150–157
Byrd LD, Standish LJ, Howell LL (1987): Behavioral effects of phencyclidine and ketamine alone and in combination with other drugs. Eur J Pharmacol 144:331–341
Cohen BD, Rosenbaum G, Luby ED, Gottlieb JS (1962): Comparison of phenylcyclidine hydrochloride (Sernyl) with other drugs. Arch Gen Psychiatry 6:395–397
Cohen ML, Chan SL, Bhargava HN, Trevor AJ (1974): Inhibition of mammalian brain acetylcholinesterase by ketamine. Biochem Pharmacol 23:1647–1652
Crosby G, Crane AM, Sokoloff L (1982): Local changes in cerebral glucose utilization during ketamine anesthesia. Anesthesiologist 56:437–443
Davies BM, Beech HR (1960): The effect of 1-arylcyclohexylamine (Sernyl) on twelve normal volunteers. J Ment Sci 106:912–924
Hammer RP, Herkenham M (1983): Altered metabolic activity in the cerebral cortex of rats exposed to ketamine. J Comp Neurol 220:396–404
Javitt DC, Zukin SR (1991): Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers Jr MB, Charney DS (1994): Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214
Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995): Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19
Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R (1959): Study of a new schizophrenomimetic drug-sernyl. Arch Neurol Psychiatry 81:363–369
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A (1996): NMDA receptor function and human cognition: The effects of ketamine in healthy volunteers. Neuropsychopharmacology 14:301–307
Moretti RJ, Hassan SZ, Goodman LI, Meltzer HY (1984): Comparison of ketamine and thiopental in healthy volunteers: Effects on mental status, mood, and personality. Anesth Analg 63:1087–1096
Olney JW, Labruyere J, Price MT (1989): Pathological changes induced in cerebrocortical neurons by phenylcyclidine and related drugs. Science 244:1360–1362
Olney JW, Farber NB (1995): Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007
Overall JE, Gorham DR (1962): The brief psychiatric rating scale. Psychol Rep 10:799–812
Oye I, Hustveit O, Moberg ER, Pausen O, Skoglund LA (1991): The chiral forms of ketamine as probes for NMDA receptor function in humans. In Kameyama T, Nabeshima T, Domino EF (eds), NMDA Receptor Related Agents: Biochemistry, Pharmacology, and Behavior. Ann Arbor, Michigan, NPP Books, pp 381–389
Pandit SK, Kothary SP, Kumar SM (1980): Low dose intravenous infusion technique with ketamine. Anaesthesia 35:669–675
Rosenbaum G, Cohen BD, Luby ED, Gottlieb JS, Yelen D (1959): Comparison of Sernyl with other drugs. A. M. A. Arch Gen Psychiatry 1:651–666
Rothman S (1988): Noncompetitive N-methyl-D-aspartate antagonists affect multiple ionic currents. J Pharmacol Exp Ther 246:137–142
Schorn TOF, Whitman JG (1980): Are there long-term effects of ketamine on the central nervous system? Br J Anaesth 52:967–968
Smith DJ, Azzaro AJ, Zaldivar SB, Palmer S, Lee HS (1981): Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines. Neuropharmacology 20:391–396
Smith DJ, Pekoe GM, Martin LL, Coalgate B (1980): The interaction of ketamine with the opiate receptor. Life Sci 26:789–795
Spitzer RL, Williams JBW, Gibbon M, First MB (1990): Structured clinical interview for DSM–III–R–patient edition (SCID-P, Version 1.0). Washington, DC: American Psychiatric Press
Weingartner HJ, Hommer D, Lister RG, Thompsom K, Wolkowitz O (1992): Selective effects of triazolam on memory. Psychopharmacology 106:341–345
Weingartner H, Grafman J, Boutelle W, Kayne W, Martin PR (1983a): Forms of memory failure. Science 221:380–382
Weingartner H, Rudorfer MV, Buchsbaum MS, Linnoila M (1983b): Effects of serotonin on memory impairments produced by ethanol. Science 221:472–473
Weingartner H, Langer D, Grice J, Rapoport J (1982): Acquisition and retrieval of information in amphetamine-treated hyperactive children. Psychiatry Res 6:21–29
Acknowledgements
The authors thank John J. Bartko for consultation with the statistical analyses, the staff of the 4East Nursing Unit for providing expert clinical care, and Marilyn Duncan for editorial assistance.
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Experimental Therapeutics Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
- Anil K Malhotra
- , Debra A Pinals
- , Caleb M Adler
- , Igor Elman
- , Allan Clifton
- , David Pickar
- & Alan Breier
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Correspondence to Anil K Malhotra.
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