Abstract
Evidence from histological and pharmacological challenge studies indicates that N-methyl-D-aspartate (NMDA) receptor hypofunction may play an important role in the pathophysiology of schizophrenia. Our goal was to characterize effects of NMDA hypofunction further, as related to schizophrenia-associated neuropsychological impairment. We administered progressively higher doses of ketamine (target plasma concentrations of 50, 100, 150, and 200 ng/ml) to 10 psychiatrically healthy young men in a randomized, single-blind, placebo-controlled design and assessed oculomotor, cognitive, and symptomatic changes. Mean ketamine plasma concentrations approximated target plasma concentrations at each infusion step. Verbal recall, recognition memory, verbal fluency, pursuit tracking, visually guided saccades, and fixation all deteriorated significantly during ketamine infusion; lateral gaze nystagmus explained some, but not all, of the smooth pursuit abnormalities. We concluded that ketamine induces changes in recall and recognition memory and verbal fluency reminiscent of schizophreniform psychosis. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities characteristic of schizophrenia. These findings help delineate the similarities and differences between schizophreniform and NMDA–blockade-induced cognitive and oculomotor abnormalities.
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References
Akbarian S, Sucher NJ, Bradley D, Tafazzoli A, Trinh D, Hetrick WP, Potkin SG, Sandman CA, Bunney WE Jr, Jones EG . (1996): Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J Neurosci 16: 19–30
Bartha R, Williamson PC, Drost DJ, Malla A, Carr TJ, Cortese L, Canaran G, Rylett RJ, Neufeld RW . (1997): Measurement of glutamate and glutamine in the medial prefrontal cortex of never treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch Gen Psychiat 54: 959–965
Benes FM, McSparren J, San-Giovanni JP, Vincent SL . (1991): Deficits in small interneurons in cingulate cortex of schizophrenic and schizoaffective patients. Arch Gen Psychiat 48: 996–1001
Benes FM, Sorensen I, Vincent SL, Bird ED, Sathi M . (1992): Increased density of glutamate-immunoreactive vertical processes in superficial laminae in cingulate cortex of schizophrenic brain. Cereb Cortex 2: 502–512
Benes FM . (1995): Altered glutamatergic and GABAergic mechanisms in the cingulate cortex of the schizophrenic brain. Arch Gen Psychiat 52: 1015–1018
Benton AL, Hamsher K, Varney NR, Spreen O . (1983): Contributions to Neuropsychological Assessment. New York, Oxford University Press.
Bosco G, Casabona A, Perciavalle V . (1994): Non-N-methyl-D-Aspartate receptors mediate neocerebellar excitation at accessory oculomotor nuclei synapses of the rat. Arch Ital Biol 132: 215–227
Brier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D . (1997): Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiat 154: 805–811
Byrd LD, Standis LJ, Howell LL . (1987): Behavioral effects of phencyclidine and ketamine alone and in combination with other drugs. Eur J Pharmacol 144: 331–341
Clementz BA, McDowell JE, Zisook S . (1994): Saccadic system functioning among schizophrenia patients and their first-degree biological relatives. J Abnorm Psychol 103: 277–287
Clementz BA, McDowell JE . (1994): Smooth pursuit in schizophrenia. Abnormalities of open and closed-loop responses. Psychophysiology 31: 79–86
Conti F, Minelli A, DeBiasi S, Melone M . (1997): Neuronal and glial localization of NMDA receptors in the cerebral cortex. Mol Neurobiol 13: 1–18
Corssen G, Domino EF . (1966): Dissociative anesthesia. Further pharmacologic studies and first clinical experience with phencyclidine derivative CI-581. Anesth Analges 45: 29–40
Domino EF, Domino SE, Smith RE, Domino LE, Goulet JR, Domino KE, Zsigmond EK . (1984): Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther 36: 645–653
Fukushima J, Morita N, Fukushima K, Chiba T, Tanaka S, Yamashita I . (1990): Voluntary control of saccadic eye movements in patients with schizophrenic and affective disorders. J Psychiat Res 24: 9–24
Funahashi S, Chafee MV, Goldman-Rakic PS . (1993): Prefrontal neuronal activity in rhesus monkeys performing a delayed antisaccade task. Nature 365: 753–756
Ginski MJ, Witkin JM . (1994): Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists. Psychopharmacol Berl 114: 573–582
Glass PS, Jacobs JR, Smith RL, Ginsberg B, Quill TJ, Bai SA, Reves JG . (1990): Pharmacokinetic model-driven infusion of fentanyl: Assessment of accuracy. Anesthesiology 73: 1082–1090
Godaux E, Cheron G, Mettens P . (1990): Ketamine induces failure of the oculomotor neural integrator in the cat. Neurosci Lett 116: 162–167
Grawe RW, Levander S . (1995): Smooth pursuit eye movements and neuropsychological impairments in schizophrenia. Acta Psychiat Scand 92: 108–114
Grove WM, Clementz BA, Iacono WG, Katsanis J . (1992): Smooth pursuit ocular motor dysfunction in schizophrenia: Evidence for a major gene. Am J Psychiat 149: 1362–1368
Hartvig P, Valtysson J, Antoni G, Westerberg G, Langstrom B, Ratti-Moberg E, Oye I . (1994): Brain kinetics of the (R) and (S)-[N-methyl-11C] ketamine in the rhesus monkey studied by positron emission tomography, PET. Nucl Med Biol 21: 927–934
Hartvig P, Valtysson J, Linder K, Kristensen J, Karlsten R, Gustafsson LL, Persson J, Svensson JO, Oye I, Antoni G, Westerberg G, Langstrom B . (1995): Central nervous system effects of subdissociative doses of (S) ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers. Clin Pharmacol Ther 58: 165–173
Holzman PS, Kringlen E, Matthysse S, Flanagan SD, Lipton RB, Cramer G, Levin S, Lange K, Levy DL . (1988): A single dominant gene can account for eye-tracking dysfunctions and schizophrenia in offspring of discordant twins. Arch Gen Psychiat 45: 641–647
Ishimaru M, Kurumaji A, Toru M . (1994): Increases in strychnine-insensitive glycine binding sites in cerebral cortex of chronic schizophrenics: Evidence for glutamate hypothesis. Biol Psychiat 35: 84–95
Jansen KL, Dragunow M, Faull RL, Leslie RA . (1991): Autoradiographic visualization of [3H]DTG binding to sigma receptors, [3H]TCP binding sties, and L-[3H]glutamate binding to NMDA receptors in human cerebellum. Neurosci Lett 125: 143–146
Kharasch ED, Labroo R . (1992): Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology 77: 1201–1207
Kruger-Theimer E . (1968): Continuous intravenous infusion and multicompartment accumulation. Eur J Pharmacol 4: 317–324
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charnew DS . (1994): Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiat 51: 199–214
Lahti AC, Koffel B, LaPorte D, Tamminga CA . (1995): Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13: 9–19
LaPorte DJ, Lahti AC, Koffel B, Tamminga CA . (1996): Absence of ketamine effects on memory and other cognitive functions in schizophrenia patients. J Psychiat 30: 321–330
Lear E, Suntay R, Pallin IM, Chiron AE . (1959): Cyclohexamine (CI-400). A new intravenous agent. Anesthesiology 20: 330–334
Litman RE, Hommer DW, Radant A, Clem T, Pickar D . (1994): Quantitative effects of typical and atypical neuroleptics on smooth pursuit eye tracking in schizophrenia. Schizophr Res 12: 107–120
Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R . (1959): Study of a new schizophrenomimetic drug—sernyl. Arch Neurlol Psychiat 81: 363–369
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Brier A . (1996): NMDA receptor function and human cognition. The effects of ketamine in healthy volunteers. Neuropsychopharmacology 14: 301–307
Mettens P, Cheron G, Godaux E . (1994): Involvement of the N-methyl-D-aspartate receptors of the vestibular nucleus in the gazeholding system of the cat. Neurosci Lett 174: 209–212
O'Driscoll GA, Alpert NM, Matthysse SW, Levy DL, Rauch SL, Holzman PS . (1995): Functional neuroanatomy of antisaccade eye movements investigated with positron emission tomography. Proc Natl Acad Sci USA 92: 925–929
Olney JW, Farber NB . (1995): Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiat 52: 998–1007
Radant AD, Hommer DW . (1992): A quantitative analysis of saccades and smooth pursuit during visual pursuit tracking: A comparison of schizophrenics with normals and substance abusing controls. Schizophr Res 6: 225–235
Rashbass C . (1961): The relationship between saccadic and smooth pursuit tracking eye movements. J Physiol (Lond) 159: 326–338
Ross DE, Thaker GK, Holcomb HH, Cascella NG, Medoff DR, Tamminga CA . (1995): Abnormal smooth pursuit eye movements in schizophrenic patients are associated with cerebral glucose metabolism in oculomotor regions. Psychiat Res 58: 53–67
Ross RG, Hommer D, Breiger D, Varley C, Radant A . (1994): Eye movement task related to frontal lobe functioning in children with attention deficit disorder. J Am Acad Child Adolesc Psychiat 33: 869–874
Roy-Byrne P, Radant A, Wingerson D, Cowley DS . (1995): Human oculomotor function: Reliability and diurnal variation. Biol Psych 38: 92–97
Roy-Byrne PP, Uhde TW, Holcomb HH, King AK, Thompson K, Weingartner H . (1987): Effects of diazepam on cognitive processess in normal subjects. Psychopharmacology 91: 30–33
Schreiber H, Rothmeier J, Becker W, Jrugens R, Born J, Stolz-Born G, Westphal KP, Kornhuber HH . (1995): Comparative assessment of saccadic eye movements, psychomotor and cognitive performance in schizophrenics, their first-degree relatives and control subjects. Acta Psychiat Scand 91: 195–201
Schuttler J, Kloos S, Schwilden H, Stoeckel H . (1988): Total intravenous anaesthesia with propofol and alfentanil by computer-assisted infusion. Anaesthesia 43: 2–7
Shafer SL, Vervel JR, Aziz N, Scott JC . (1990): Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology 73: 1091–1102
Simpson MD, Slater P, Royston MC, Deakin JF . (1991): Alterations in phencyclidine and sigma binding sites in schizophrenic brains. Effects of disease process and neuroleptic medication. Schizophr Res 6: 41–48
Ulas J, Weihmuller FB, Brunner LC, Joyce JN, Marshall JF, Cotman CW . (1994): Selective increase of NMDA sensitive glutamate binding in the striatum of Parkinson's disease, Alzheimer's disease, and mixed Parkinson's disease/Alzheimer's disease patients: An autoradiographic study. J Neurosci 14: 6317–6324
Verma A, Moghaddam B . (1996): NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats. Modulation by dopamine. J Neurosci 16: 373–379
Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J . (1997): Differential psychopathology and patterns of cerebral glucose utilisation produces by (S) and (R) ketamine in healthy volunteers using positron emission tomography (PET). Eur J Neuropsychopharmacol 7: 25–38
Watanabe M, Mishina M, Inoue Y . (1994): Distinct distributions of five NMDA receptor channel subunit mRNAs in the brainstem. J Comp Neurol 343: 510–531
Acknowledgements
This work was performed at the Psychopharmacology Laboratory, Department of Psychiatry, Harborview Medical Center and Core Laboratory, Department of Anesthesiology, University of Washington, Seattle, Washington. It was supported in part by NIH grants MH49413 (PPR), and AA09635 (DSC) and a Merit Review Award from the Veteran's Affairs Research Service (EDK). Presented in part at the Western Pharmacology Society 1996 Meeting, the society of Biological Psychiatry Annual Scientific Program (1996), and the Annual Meeting of the American College of Neuropsychopharmacology (1995). The data on symptomatic ratings was included in a paper under review in Anesthesiology.
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Radant, A., Bowdle, T., Cowley, D. et al. Does Ketamine-Mediated N-methyl-D-aspartate Receptor Antagonism Cause Schizophrenia-like Oculomotor Abnormalities?. Neuropsychopharmacol 19, 434–444 (1998). https://doi.org/10.1016/S0893-133X(98)00030-X
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DOI: https://doi.org/10.1016/S0893-133X(98)00030-X
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