Abstract
Ligands to the benzodiazepine receptor (BZR) accumulate in hepatic encephalopathy; the benzodiazepine antagonist flumazenil can reverse some manifestations of this condition. This study was designed to explore the effects of flumazenil on cognitive function and anxiety levels in cirrhotic patients without hepatic encephalopathy. Twenty such patients — ten alcoholic, ten nonalcoholics — and ten normal volunteers matched for age and sex were randomly allocated to treatment order (flumazenil or placebo first) in a double-blind cross-over trial. Cognitive function was evaluated with a battery of psychological tests shown previously to be sensitive to the impairment induced by liver disease. Cirrhotic patients performed worse than controls on several tests: digit cancellation, digit symbol substitution, key tapping and Reitan's trail B test. Flumazenil did not reverse these cognitive impairments but it did induce anxiety in nonalcoholic cirrhotics. On one index of memory — delayed word recall — alcoholics performed worse than nonalcoholic cirrhotics. Flumazenil reversed this memory impairment in the alcoholic cirrhotic group. These results suggest that alcohol consumption induces changes at the BZR that are different from changes induced solely by liver impairment.
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References
Arria AM, Tarter RE, Kabene MA, Laird SB, Moss H, Van Thiel DH (1991a) The role of cirrhosis in memory functioning of alcoholics. Alcohol Clin Exp Res 15:932–937
Arria AM, Tarter RE, Starzl TE, Van Thiel DH (1991b) Improvement in cognitive functioning of alcoholics following orthotopic liver transplantation. Alcohol Clin Exp Res 15:956–962
Ball DM, Wilson S, Glue P, Lawson C, Nutt DJ (1992) Alterations in benzodiazepine receptor function underlying panic disorder. In: Burrows GD, Roth M, Noyes R (eds) Handbook of anxiety, vol. 5. Elsevier, Amsterdam, pp 421–435
Bansky G, Meier PJ, Riederer E, Walser H, Ziegler WH, Schmid M (1989) Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology 97:744–750
Basile AS, Harrison PM, Hughes RD, Gu ZQ, Pannell L, McKinney A, Jones EA, Williams R (1994) Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy. Hepatology 19:112–121
Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings Br J Med Psychol 47:211–218
Curran HV (1991) Benzodiazepines, memory and mood: a review. Psychopharmacology 105:1–8
Curran HV, Schiwy W, Lader M (1987) Differential amnesic properties of benzodiazepines: a dose response comparison of two drugs with similar elimination half-lives. Psychopharmacology 92:358–364
Curran HV, Gardiner JM, Java RI, Allen D (1993) Effects of lorazepam upon recollective experience in recognition memory. Psychopharmacology 110:374–378
Dollery C (1991) Flumazenil. In: Dollery C (ed) Therapeutic durgs vol. 1. Churchill Livingstone, London, pp F 50-F 54
File SE, Hitchcott PK (1990) A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomena. Psychopharmacology 101:525–532
File SE, Lister RG, Nutt DJ (1982) The anxiogenic action of benzodiazepine antagonits. Neuropharmacology 21:1033–1037
Frith CD (1967) The effects of nicotine on tapping. Life Sci 6:321–326
Grimm G, Ferenci P, Katzenschlager R, Madl C, Schneeweiss B, Laggner AN, Lenz K, Gangl A (1988) Improvement of hepatic encephalopathy treated with flumazenil. Lancet 2:1392–1394
Guimaraes FS, Zuardi AW, Graeff FG (1987) Effect of chlorimipramine and maprotiline on experimental anxiety in humans. J Psychopharmacol 3:184–192
Higgitt A, Lader M, Fonagy P (1986) The effects of the benzodiazepine antagonists RO-151788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacology 89:395–403
Hills M, Armitage P (1979) The two-period cross-over clinical trial. Br J Clin Pharmacol 8:7–20
Irwin M, Smith TL, Butters N, Brown S, Baird S, Grant I, Schuckit MA (1989) Graded neuropsychological impairment and elevated gamma-glutamyl transferase in chronic alcoholic men. Alcohol Clin Exp Res 13:99–103
Litton JE, Neiman J, Pauli S, Farde L, Hindmarsh T, Halldin C, Sedvall G (1993) PET analysis of [11C] flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls. Psychiatry Res 50:1–13
Mhatre MC, Ticku MK (1992) Chronic ethanol administration alters gamma-aminobutyric acidA receptor gene expression. Mol Pharmacol 42:415–422
Mhatre MC, Pena G, Sieghart W, Ticku MK (1993) Antibodies specific for GABAA receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha-subunit expression in rat brain regions. J Neurochem 61:1620–1625
Nelson H (1982) The national adult reading test. NFER-Nelson, Windsor
Nutt DJ, Glue P, Lawson C, Wilson S (1990) Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 47:917–925
Ohmann C, Stoltzing H, Wins L, Busch E, Thon K (1990) Prognostic scores in oesophageal or gastric variceal bleeding. Scand J Gastroenterol 25:501–512
Olasmaa M, Guidotti A, Costa E, Rothstein JD, Goldman ME, Weber RJ, Paul SM (1989) Edogenous benzodiazepines in hepatic encephalopathy. Lancet 1:491–492
Pomier Layrargues G, Giguere JF, Lavoie J, Perney P, Gagnon S, D'Amour M, Wells J, Butterworth RF (1994) Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology 19:32–37
Reitan RM, Wolfson D (1985) The Halstead-Reitan neuropsychological test battery. Neuropsychology Press, Tucson
Ritson EB, Chick JD, Strang F (1993) Dependence on alcohol and other drugs. In: Kendell RE, Zealley AK (eds) Companion to psychiatric studies, 5th edn. Churchill Livingstone, London, p 369
Scollo-Lavizzari G, Steinman E (1985) Reversal of hepatic coma by benzodiazepine antagonist (RO 15-1788). Lancet 1:1324
Spielberger CD, Gorsuch RL, Lushene RE (1970) Manual for the state-trait anxiety inventory. Consulting Psychologist Press, Palo Alto
Tarter RE, Hegedus AM, Van Thiel DH, Gavaler JS, Schade RR (1986) Hepatic dysfunction and neuropsychological test performance in alcoholics with cirrhosis. J Stud Alcohol 47:74–77
Tarter RE, Van-Thiel DH, Arria AM, Carra J, Moss H (1988) Impact of cirrhosis on the neuropsychological test performance of alcoholics. Alcohol Clin Exp Res 12:619–621
Tarter RE, Moss H, Arria A, Van Thiel D (1990a) Hepatic, nutritional, and genetic influences on cognitive process in alcoholics. In: Spencer JW, Boren JJ (eds) Residual effects of abused drugs on behavior — NIDA research monograph 101. National Institute on Drug Abuse, Rockville, pp 124–135
Tarter RE, Switala JA, Arria A, Plail J, Van Thiel DH (1990b) Subclinical hepatic encephalopathy. Comparison before and after orthotopic liver transplantation. Transplantation 50:632–637
Ticku MK, Mhatre M, Mehta AK (1992) Modulation of GABAergic transmission by ethanol. Adv Biochem Psychopharmacol 47:255–268
Tyrer P (1976) The role of body feelings in anxiety — Maudsley Monograph 23. Oxford University Press, London
Wechsler D (1981) WAIS-R manual. Psychological Corporation, New York
Wilson B, Cockburn J, Baddeley A (1985) The Rivermead behavioural memory test. Thames Valley Test Company, Reading
World Health Organization (1992) The ICD-10 classification of mental nad behavioural disorders. World Health Organization, Geneva
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Kapczinski, F., Sherman, D., Williams, R. et al. Differential effects of flumazenil in alcoholic and nonalcoholic cirrhotic patients. Psychopharmacology 120, 220–226 (1995). https://doi.org/10.1007/BF02246197
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DOI: https://doi.org/10.1007/BF02246197