Abstract
Ro 15-1788 is an imidazodiazepine which was initially described as a pure benzodiazepine antagonist lacking in intrinsic actions. Although recent animal work has shown the drug to have differing intrinsic actions depending on the dose, the majority of studies on human subjects conclude that it is a pure antagonist of benzodiazepines. Two oral doses of Ro 15-1788 (30 mg and 100 mg) were compared with 5 mg diazepam and placebo in their intrinsic effects on a range of psychophysiological, performance and subjective measures in 12 healthy adult subjects. At both these doses Ro 15-1788 showed a mixture of agonist (benzodiazepine-like) effects and other non-benzodiazepine-like effects on the variables measured. Although there was no clear-cut dose-response relationship, the results suggested a predominance of benzodiazepine-like effects at the higher dose on physiological measures whilst the lower dose was observed to have greater effects on a number of behavioural and subjective dimensions. The subjective changes were the opposite of those normally found for benzodiazepines.
Similar content being viewed by others
References
Ashton CH (1985) Benzodiazepine overdose: are specific antagonists useful? Br Med J 290:805–806
Ban TA, Prakash R (1983) Anxiolytics: clinical perspectives. In: Malick JB, Enna SJ, Yamamura HI (eds) Anxiolytics: neurochemical, behavioral and clinical and perspectives. Raven Press, New York
Bond A, Lader M (1974) The use of analogue scales in rating subjective feedings. Br J Med Psychol 47:211–218
Bond A, Lader M (1981) Comparative effects of diazepam and buspirone on subjective feedings, psychological tests and the EEG. Int Pharmacopsychiatr 16:212–220
Bond A, Lader M (1982) A comparison of the psychotropic profiles of tofisopam and diazepam. Eur J Clin Pharmacol 22:137–142
Braestrup C, Honore T, Nielsen M, Petersen EN, Jensen LH (1983) Benzodiazepine receptor ligands with negative efficacy: chloride channel coupling. In: Biggio C, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology, Raven Press, New York, pp. 29–36
Crawley JN, Skolnick P, Paul SM (1984) Absence of intrinsic antagonist actions of benzodiazepine antagonists on an exploratory model of anxiety in the mouse. Neuropharmacology 23:531–537
Dantzer R, Perio A (1982) Behavioural evidence for partial agonist property of Ro 15-1788, a benzodiazepine receptor antagonist. Eur J Pharmacol 81:655–658
Darragh A, Lambe R, Scully M, Brick I, O'Boyle C, Downie NW (1981) Investigation in man of the efficacy of a benzodiazepine, antagonist, Ro 15-1788, Lancet July 4:8–10
Darragh A, Lambe R, Kenny M, Brick I, O'Boyle C (1982a) Ro 15-1788 antagonises the central effects of diazepam in man without altering diazepam bioavailability. Br J Clin Pharmacol 14:677–682
Darragh A, Lambe R, Brick I, O'Boyle C (1982b) Antagonism of the central effects of 3-methylclonazepam. Br J Clin Pharmacol 14:871–872
Darragh A, Lambe R, O'Boyle C, Kenny M, Brick I (1983) Absence of central effects in man of the benzodiazepine antagonist Ro 15-1788. Psychopharmacology 80:192–195
Enrich HM, Sonderegger P, Mai N (1984) Actioon of the benzodiazepine antagonist Ro 15-1788 in humans after sleep withdrawal. Neurosci Lett 47:369–373
File SE, Lister RG, Nutt DJ (1982) The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 21:1033–1037
Fink M (1981) Classification of psychoactive drugs: quantitative EEG analysis in man. In: Van Praag HM, Lader MH, Rafaelsen OJ, Sachar EJ (eds) Handbook of biological psychiatry, Part VI Practical applications of psychotropic drugs and the biological treatments Marcel Dekker, Inc New York and Basel
Gaillard JM, Blois R (1983) Effect of the benzodiazepine antagonist Ro 15-1788 on flunitrazepam-induced sleep changes. Br J Clin Pharmacol 15:529–536
Gath I, Wiedenfeld J, Collins GI, Hadad H (1984) Electrophysiological aspects of benzodiazepine antagonists Ro 15-1788 and Ro 15-3505. Br J Clin Pharmacol 18:541–754
Golombok S, Lader M (1984) The psychopharmacological effects of premazepam, diazepam and placebo in healthy human subjects. Br J Clin Pharmacol 18:127–133
Greksch G, Prado de Carvalho L, Venault P, Chapouthier G, Rossier J (1983) Convulsions induced by a submaximal dose of pentyleneleatrazol in mice are antagonised by the benzodiazepine antagonist, Ro 15-1788. Life Sci 32:2579–2584
Grey S, Sartory G, Rachman S (1979) Synchronous and desynchronous changes during fear reduction. Behav Res Ther 17:137–148
Hunkeler W, Mohler H, Pieri L, Pole P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516
Insel TR, Siever LJ (1981) The dopamine system challenge in affective disorder: A review of behavioural and neuroendocrine responses. J Clin Psychopharmacol 1:207–213
Ismail S, Bonetti EP, Ferro A, Hunkeler W, Kapp W, Timm U (1981) The investigational drug brochure — benzodiazepine antagonist Ro 15-1788. Roche report No. 77'177
Itil RM, Schneider SJ, Frederickson JW (1981) The replicability of the psychophysiological effects of diazepam. Biol Psychiatry 16:65–73
Jaffe JH, Clovet DH (1981) Opioid dependence: Links between biochemistry and behaviour. In: Van Praag HM, Lader MH, Rafaelsen OJ, Sachar EJ (eds) Handbook of biological psychiatry, part IV: Brain mechanisms and abnormal behaviour chemistry. Marcel Dekker, Inc, New York
Karniol IG, Dalton J, Lader M (1976) Comparative psychotropic effects of trazodone, imipramine and diazepam in normal subjects. Curr Ther Res 20:337–347
Klotz U, Ziegler G, Reimann IW (1984) Short communications: Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Clin Pharmacol 27:115–117
Lader M (1983) Benzodiazepine withdrawal states. In: Trimble MR (ed) Benzodiazepines divided. Chichester, Wiley
Lang P (1977) Physiological assessment of anxiety and fear. In: Cone J, Hawkins R (eds) Behavioural assessment. Brunner/Mazel, New York, pp 179–195
Laurian S, Gaillard JM, Le PK, Schopf J (;1984) Effects of a benzodiazepine antagonist on the diazepam-induced electrical brain activity modifications. Neuropsychobiology 11:55–58
Lupolover Y, Safran AB, Desangles D, de Weisse C, Meyer JJ, Bousquet A, Assimacopoulos A (1984) Evaluation of visual function in healthy subjects after administration of Ro 15-1788. Eur J Clin Pharmacol 27:505–507
Mohler H, Richards JG (1981) Agonist and antagonist benzodiazepine receptor interaction in vitro.
Nutt DJ, Cowen PJ, Little HJ (1982) Unusual interactions of benzodiazepine receptor antagonists. Nature 295:436–438
O'Boyle C, Lambe R, Darragh A, Taffe W, Brick I, Kenny M (1983) Ro 15-1788 antagonises the effects of diazepam in man without affecting its bioavailability. Br J Anaesth 55:349–356
Pellow S, File SE (1984) Review: multiple sites of action for anxiogenic drugs: behavioural, electrophysiological and biochemical correlations. Psychopharmacology 83:304–315
Petursson H (1982) Clinical and laboratory studies of withdrawal from long-term benzodiazepine treatment. Ph D Thesis, University of London
Pole P, Laurent JP, Scherschlicht R, Haefely W (1981) Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788
Rosenberg HC, Chiu TH (1985) Blood pressure response to Ro 15-1788, a benzodiazepine antagonist. Life Sci 36:781–787
Saletu B, Grünberger J, Linzmeyer L, Fleser R (1980) Anxiolytics and beta-blockers: Evaluation of pharmacodynamics by quantitative EEG, psychometric and physiological variables. Agressologie 22:5–9
Schachter S, Singer J (1962) Cognitive, social and physiological determinants of emotional state. Psychol Rev 69:379–399
Schöpf J, Laurian S, Le PK, Gaillard JM (1984) Intrinsic activity of the benzodiazepine antagonist Ro 15-1788 in man: An electrophysiological investigation. Pharmacopsychiatry 17:79–83
Tyrer PJ (1982) Antianxiety drugs. In: Tyrer PJ (ed) Drugs in psychiatric practice. London, Butterworth
Williams FJ (1949) Experimental designs balanced for the estimation of residual effects of treatments. Aust J Sci Res 2:149–168
Ziegler WH, Schalch E (1983) Antagonism of benzodiazepine-induced sedation in man. Sleep 1982, 6th Eur Congr Sleep Res, Zurich 1982, pp 427–429
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Higgitt, A., Lader, M. & Fonagy, P. The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacology 89, 395–403 (1986). https://doi.org/10.1007/BF02412110
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02412110