Abstract
This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT2 receptor blockade as shown by displacement of radioligand binding (Ki: 0.16 nM), activity on isolated tissues (EC50:0.5 nM), and antagonism of peripherally (ED50: 0.0011 mg/kg) and centrally (ED50:0.014 mg/kg) acting 5-HT2 receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT2 receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D2 receptor antagonist as indicated by displacement of radioligand binding (Ki: 1.4 nM), activity in isolated striatal slices (IC50: 0.89 nM), and antagonism of peripherally (ED50: 0.0057 mg/kg in dogs) and centrally acting D2 receptor agonists (ED50: 0.056–0.15 mg/kg in rats). Risperidone shows all effects common to D2 antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4–10 times less potent than haloperidol as a central D2 antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT2 antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D2 antagonism; synergism of combined 5-HT2/D2 antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D2 receptors and at D2 receptors from various rat brain regions. The binding affinity for D4 and D3 receptors is 5 and 9 times weaker, respectively, than for D2 receptors; interaction with D1 receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H1 and α-adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D2 antagonist with predominant 5HT2 antagonistic activity and optimal pharmacokinetic properties.
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References
Ålander T, Anden N-E, Grabowska-Anden M (1980) Metoclopramide and sulpiride as selective blocking agents of pre- and postsynaptic dopamine receptors. Naunyn Schmiedebergs Arch Pharmacol 312:145–150
Ansoms C, De Backer-Dierick C, Vereecken JTLM (1977) Sleep disorders in patients with severe mental depression. Double-blind placebo-controlled evaluation of the value of pipamperone. Acta Psychiatr Scand 55:116–122
Ashby CR Jr, Miabe Y, Edwards E, Wang RY (1991) Comparison of the effects of various typical and atypical antipsychotic drugs on the suppressant action of 2-methylserotonin on medial prefrontal cortical cells in the rat. Synapse 8:155–161
Awouters FHL, Niemegeers CJE, Megens AAHP, Meert TF, Janssen PAJ (1988) The pharmacological profile of ritanserin, a very specific central serotonin S2-antagonist. Drug Dev Res 15:61–73
Awouters FHL, Niemegeers CJE, Megens AAHP, Janssen PAJ (1990) Functional interaction between serotonin-S2 and dopamine D2-neurotransmission as revealed by selective antagonism of hyperreactivity to tryptamine and apomorphine. J Pharmacol Exp Ther 254:945–951
Balsara JJ, Jadhav JH, Cnadorkar AG (1979) Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy. Psychopharmacology 62:67–69
Bergman J, Madras B, Spealman RD (1991) Behavioral effects of D1 and D2 dopamine receptor antagonists in squirrel monkeys. J Pharmacol Exp Ther 258:910–917
Blum PS, Davis CB (1988) Effect of risperidone (R 64 766) on presynaptic dopamine receptors in the neostriatum of the rat. Janssen Biological Research Report 010, N 64755
Bogdanov MB, Gainetdinov RR, Kudrin VS, Medvedev OS, Val'dman AV (1991) Microdialysis study of effects of atypical neuroleptics and anxiolytics on striatal dopamine release and metabolism in conscious rats. Bull Exp Biol Med 111:655–658
Borison RL, Diamond A, Pathiraja A, Meibach RC (1991) Clinical profile of risperidone in chronic schizophrenia. In: Kane JM (ed) Risperidone: major progress in antipsychotic treatment. Oxford Clinical Communications, Oxford, pp 31–36
Borison RL, Diamond A, Pathiraja A, Meibach RC (1992) Clinical overview of risperidone. In: Meltzer HY (ed) Novel antipsychotic drugs. Raven, New York, pp 233–239
Bowden CR, Voina SJ (1988) Effects of R 64 766, haloperidol hydrochloride and clozapine on fasting plasma prolactin, insuline, corticosterone and glucose concentrations in normal rats. Janssen Biological Research Report 004, N 59594
Bowden CR, Voina SJ, Woestenborghs R, De Coster R, Heykants J (1992) Stimulation by risperidone of rat prolactin secretion in vivo and in cultured pituitary cells in vitro. J Pharmacol Exp Ther 262:699–706
Bunney BS, Walters JR, Roth RH, Aghajanian GK (1973) Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J Pharmacol Exp Ther 185:560–571
Burt DR, Enna ST, Creese I, Snyder SH (1975) Dopamine receptor binding in the corpus striatum of mammalian brain. Proc Natl Acad Sci USA 72:4655–4695
Canton H, Verrièle L, Colpaert FC (1990) Binding of typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites. Eur J Pharmacol 191:93–96
Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–144
Chouinard G, Jones B, Remington G, Bloom D, Addington D, MacEwan GW, Labelle A, Beauclair L, Arnott WA (1993) Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 13:25–40
Civelli O, Bunzow JR, Grandy DK, Zhou Q-Y, Van Tol HHM (1991) Molecular biology of the dopamine receptors. Eur J Pharmacol 207:277–286
Colpaert FC, Niemegeers CJE, Janssen PAJ (1982) A drug discrimination analysis of lysergic acid diethlylamide (LSD): in vivo agonist and antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, a LSD-antagonist. J Pharmacol Exp Ther 221:206–214
Connell P (1958) Amphetamine psychosis. Maudsley Monograph no. 5, Oxford University Press, New York
Corbet R, Hartman H, Kerman LL, Woods AT, Strupczewski JT, Helsley GC, Conway PC, Dunn RW (1993) Effects of atypical antipsychotic agents on social behavior in rodents. Pharmacol Biochem Behov 45:9–17
Corrodi H, Fuxe K, Lidbrink P (1972) Interaction between cholinergic and catecholaminergic neurons in rat brain. Brain Res 43:397–416
Costall B, Fortune DH, Naylor RJ, Marsden CD, Pycock C (1975) Serotonergic involvement with neuroleptic catalepsp. Neuropharmacology 14:859–868
Crow TJ, Deakin JFW, Longden A (1977) The nucleus accumbenspossible site of antipsychotic action of neuroleptic drugs? Psychol Med 7:213–221
D'Aubioul J, Van Gerven W, Wouters L, Xhonneux R (1985) Cardiovascular and behavioural effects of R 64 766 (0.08 mg.kg−1, orally) in conscious dogs. Janssen Preclinical Research Report R 64 766/1, N 43655
D'Aubioul J, Van Gerven W, Wouters L, Xhonneux R (1986) The effects of R 64 766 (0.31 mg.kg−1, orally) on ECG, heart rate and behaviour in conscious dogs. Janssen Preclinical Research Report R 64 766/7, N 51935
D'Aubioul J, Van Gerven W, Wouters L, Xhonneux R (1989) Cardiovascular and behavioural effects of R 64 766 (0.08 mg.kg−1, orally) in conscious dogs, chronically medicated with the compound. Janssen Preclinical Research Report R 64 766/20, N 64850
Deberdt R (1974) A multicentric evaluation of pimozide (OrapR) in patients who usually would take tranquilizers. Acta Psychiatr Belg 74:653–660
Deberdt R (1976) Pipamperone (Dipiperon) in the treatment of behaviour disorders. A large-scale multicentre evaluation. Acta Psychiatr Belg 76:157–166
De Chaffoy de Courcelles D (1988) Effect of risperidone (R 64 766) on the activation of signal transducing system coupled to the human platelet serotonin-S2 receptor. Janssen Preclinical Research Report R 64 766/17, N 59993
De Coster R, Coussement W, Van Cauteren H, Goeminne N (1991) Effects of daily oral administration of risperidone for 6 weeks on serum prolactin, LH and testosterone levels in rats. Janssen Preclinical Research Report R 64 766/33, N 84177
De Veaugh-Geiss J, McBain S, Cooksey P, Bell JM (1991) The effects of a novel 5-HT3 antagonist, ondansetron, in schizophrenia: results from uncontrolled trials. In: Meltzer HY (ed) Novel antipsychotic drugs. Raven, New York, pp 225–232
Devaud LL, Hollingsworth EB (1991) Effects of the 5-HT2 receptor antagonist, ritanserin, on biogenic amines in the rat nucleus accumbens. Eur J Pharmacol 192:427–429
Dugovic C, Wauquier A, Janssen PAJ (1989) Differential effects of the new antipsychotic risperidone on sleep and wakefulness in the rat. Neuropharmacology 28:1431–1433
Dugovic C, Van Wassenhove JJH, Van Den Broeck W, Clincke GHC (1992) Comparative study on the effects of haloperidol, bromperidol, and risperidone on sleep-wakefulness and ECoG power spectra in the rat. Janssen Preclinical Research Report R 64 766, N 91966
Ellenbroek B (1988) The paw test: an animal model with predictive validity. In: Animal models for schizophrenia and neuroleptic drug action (Chapter 7). Ph. D. Thesis, Krips Repro Meppel, pp 230–275
Gerlach J, Thorsen K, Fog R (1975) Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenia patients. Psychopharmacologia 40:341–350
Grandy DK, Zhang Y, Bouvier C, Zhou Q-Y, Johnson RA, Allen L, Buck K, Bunzow JR, Salon J, Civelli O (1991) Multiple human D5 dopamine receptor genes: a functional receptor and two pseudogenes. Physiol Pharmacol Phys 88:9175–9179
Heinrich K, Lehman E (1989) Therapy with fluspirilene in neuroleptoanxiolysis. In: Ayd FJ (ed) 30 Years Janssen Research in psychiatry. Ayd Medical Communications, Baltimore, pp 24–36
Heinrich K, Klieser E, Lehmann E, Kinzler E (1991) Experimental comparison of the efficacy and compatibility of risperidone and clozapine in acute schizophrenia. In: Kane JM (ed) Risperidone: major progress in antipsychotic treatment. Oxford Clinical Communications, Oxford, pp 37–39
Hiatt JF, Floyd TC, Katz PH, Feinberg I (1985) Further evidence of abnormal non-rapid-eye-movement sleep in schizophrenia. Arch Gen Psychiatry 42:797–802
Hicks PB (1990) The effect of serotonergic agents on haloperidol-induced catalepsy. Life Sci 47:1609–1615
Hommer DW, Zahn TP, Dickar D, Van Kammer DP (1984) Prazosin, a specific alpha1-noradrenergic receptor antagonist, has no effect on symptoms but increases autonomic arousal in schizophrenic patients. Psychiatry Res 11:193–204
Hrib NJ, Jurcak JG, Huger FP, Errico CL, Dunn RW (1991) Synthesis and biological evaluation of a series of substitutedN-alkoxyimides and -amides as potential antipsychotic agents. J Med Chem 34:1068–1072
Jaffe JH (1985) Drug addiction and drug abuse. In: Goodman LS, Gilman A (eds) The pharmacological basis of therapeutics (7th ed). MacMillan, New York, pp 532–581
Janowski D, Davis J (1974) Dopamine, psychomotor stimulants and schizophrenia: effects of methylphenidate and the stereoisomers of amphetamine in schizophrenics. In: Usdin E (ed) Neuropsychology of monoamines and their regulatory enzymes. Raven, New York, pp 317–324
Janssen PAJ (1987) The development of new antipsychotic drugs: towards a new strategy in the management of chronic psychoses. J Drug Ther Res 12:324–328
Janssen PAJ, Awouters FHL (1993) Is it possible to predict the clinical effects of neuroleptics from animal data? V. From haloperidol and pipamperone to risperidone. Arzneimittelforschung (in press)
Janssen PAJ, Niemegeers CJE, Verbruggen, FJ (1962) A propos d'une méthode d'investigation de modifier le compartement agressif inné du rat blanc vis-à-vis de la souris blanche. Psychopharmacology 3:114–123
Janssen PAJ, Niemegeers CJE, Schellekens KHL (1965a) Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from animal data? Part 1: neuroleptic activity spectra for rats. Arzneimittelforschung 15:104–117
Janssen PAJ, Niemegeers CJE, Schellekens KHL (1965b) Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from animal data? Part 2: neuroleptic activity spectra for dogs. Arzneimittelforschung 15:1196–1206
Janssen PAJ, Niemegeers CJE, Schellekens KHL, Lenaerts FM (1967) Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from animal data? Part 4: an improved experimental design for measuring the inhibitory effects of neuroleptic drugs on amphetamine- or apomorphine-induced ‘chewing’ and ‘agitation’ in rats. Arzneimittelforschung 17:841–854
Janssen PAJ, Niemegeers CJE, Awouters F, Schellekens KHL, Megens AAHP, Meert TF (1988) Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244:685–693
Janssens WJ, Schuurkes JAJ, Ghoos ECR, Van Nueten JM (1988) The pharmacological profile of risperidone (R 64 766) on peripheral tissues. Janssen Preclinical Research Report R 64 766/18, N 62360
Korsgaard S, Gerlach J, Christensson E (1985) Behavioral aspects of serotonin-dopamine interaction in the monkey. Eur J Pharmacol 118:245–252
Kusumi I, Koyama T, Yamashita I (1991) Effect of various factors on serotonin-induced Ca2+ response in human platelets. Life Sci 48:2405–2412
Largent BL, Gundlach AL, Snyder SH (1986) Discrimination of sigma and phencyclidine receptor binding sites in brain with (+)-[3H]-SKF10,047, (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H]-1-(1-(2-thienyl)cyclohexyl)piperidine. J Pharmacol Exp Ther 238:739–748
Lavrijsen K, Van Houdt J, Van Dyck D, Heykants J (1989) Study on the induction and/or inhibition potential of risperidone towards drug-metabolizing enzymes in the liver of male Wistar rats. Janssen Preclinical Research Report R 64 766/21, N 69384
Lavrijsen K, Meuldermans W, Heykants J (1993) In vitro inhibition study in human liver microsomes to investigate the interaction potential of various drugs with the metabolism of risperidone. Janssen Preclinical Research Report R 64 766/FK 1257
Leysen JE, Niemegeers CJE (1985) Neuropleptics. In: Lajtha A (ed) Handbook of neurochemistry, vol 9. Plenum, New York, pp 331–361
Leysen JE, Pauwels PJ (1990) Central and peripheral 5-HT2 receptors: role in physiological versus pathological conditions. In: Paoletti R et al. (eds) Serotonin: From cell biology to pharmacology and therapeutics, Kluwer, Dordrecht
Leysen JE, Niemegeers CJE, Tollenaere JP, Laduron, PM (1978) Serotonergic component of neuroleptic receptors. Nature 272:168–171
Leysen JE, De Chaffoy de Courcelles D, De Clerck F, Niemegeers CJE, Van Nueten JM (1984) Serotonin-S2 receptor binding sites and functional correlates. Neuropharmacology 23:1493–1501
Leysen JE, Gommeren W, Van Gompel P, Wynants J, Janssen PFM, Laduron PM (1985) Receptor-binding properties in vitro and in vivo of ritanserin. A very potent and long acting serotonin-S2 antagonist. Mol Pharmacol 27:600–611
Leysen JE, Gommeren W, Eens A, De Chaffoy De Courcelles D, Stoof JC, Janssen PAJ (1988) Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 247:661–670
Leysen JE, Gys L, Heylen L, Gommeren W (1991) In vitro receptor binding and neurotransmitter uptake inhibition profile of R 64 766, R 76 477, R 78 543 and R 78 544. Janssen Preclinical Research Report R 64 766/28, R 76 477/, R 78 543/, R 78 544/, N 79120
Leysen JE, Janssen PMF, Gommeren W, Wynants J, Pauwels PP, Janssen PAJ (1992) In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone. Mol Pharmacol 41:494–508
Leysen JE, Gommeren W, Wynants J, Mertens J, Luyten WHML, Pauwels PJ, Ewert M, Seeburg P (1993a) Comparison of in vitro binding properties of a series of dopamine antagonists and agonists for cloned human dopamine D2S and D2L receptors and for D2 receptors in rat striatal and mesolimbic tissues, using [125I]2′-iodospiperone. Psychopharmacology 110:27–36
Leysen JE, Janssen PMF, Schotte A, Luyten WHML, Megens AAHP (1993b) Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology 112[Suppl]: S40-S54
Magnusson O, Fowler CJ, Mohringe B, Wijkström A, Ögren S-O (1988) Comparison of the effects of haloperidol, remoxipride and raclopride on “pre”-and postsynaptic dopamine receptors in the rat brain. Naunyn Schmiedebergs Arch Pharmacol 337:379–384
Maj J, Mogilnicka E, Przewlocka B (1975) Antagonistic effect of cyproheptadine in neuroleptic-induced catalepsy. Pharmacol Biochem Behav 3:25–37
Malsch U (1987) Behandlung von Schlafstörungen bei älteren Patienten. Therapiewoche 37:2484–2487
Mc Lellan AT, Woody GE, O'Brien CP (1979) Development of psychiatric illness in drug abusers. N Engl J Med 301:1310–1314
Meert TF (1991) Application of drug discrimination with drugs of abuse to develop new therapeutic agents. Proceedings of the International Drug Discrimination Symposium, Noordwijkerhout, The Netherlands, June 25–27, 1990. In: Glennon RA et al. (eds) Drug discrimination: applications to drug abuse research. Research Monograph 116, National Institute on Drug Abuse, Rockville, Maryland, USA, pp 307–323
Meert TF, Awouters F (1991) Serotonin 5-HT2 antagonists: a preclinical evaluation of possible therapeutic effects. In: Idzikowski C, Cowen PJ (eds) Serotonin, sleep and mental disorders. Wrightson Biomedical Publishing Ltd., Petersfield, pp 65–76
Meert TF, Niemegeers CJE, Awouters F, Janssen PAJ (1988) Partial and complete blockade of 5-hydroxytryptophan (5-HTP)-induced head twitches in the rat: a study of ritanserin (R 55 667), risperidone (R 64 766), and related compounds. Drug Dev Res 13:237–244
Meert TF, de Haes P, Janssen PAJ (1989) Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology 97:206–212
Meert TF, de Haes P, Vermote PCM, Janssen PAJ (1990) Pharmacological validation of ritanserin and risperidone in the drug discrimination test procedure in the rat. Drug Dev Res 19:353–373
Megens AAHP, Awouters FHL (1993) In vivo pharmacological profile of 9-hydroxyrisperidone, the major metabolite of the novel antipsychotic risperidone: comparison with risperidone and haloperidol. Janssen Preclinical Research Report R 64 766, N 96295
Megens AAHP, Canters LLJ (1988) Absence of gastrointestinal motor stimulating or inhibiting properties of risperidone in the phenol red and charcoal tests in rats. Janssen Preclinical Research Report R 64 766/19, N 62363
Megens AAHP, Niemegeers CJE (1990) Comparative pharmacology of risperidone, its major metabolite R 76 477(+, −) and the corresponding enantiomers R 78 543(+) and R 78 544(−) in rats and dogs. Janssen Preclinical Research Report R 64 766/23, N 74694
Megens AAHP, Awouters FHL, Niemegeers CJE (1988a) Differential effects of the new antipsychotic risperidone on large and small motor movements in rats: a comparison with haloperidol. Psychopharmacology 95:493–496
Megens AAHP, Awouters FHL, Niemegeers CJE (1988b) Complementary study on the pharmacology of risperidone in mice and rats. Janssen Preclinical Research Report R 64 766/16, N 62321
Megens AAHP, Awouters FHL, Niemegeers CJE (1989) Interaction of haloperidol and risperidone (R 64 766) with amphetamine-induced motility changes in rats. Drug Dev Res 17:23–33
Megens AAHP, Awouters FHL, Meert TF, Schellekens KHL, Niemegeers CJE, Janssen PAJ (1992a) Pharmacological profile of the new potent neuroleptic ocaperidone (R 79 598). J Pharmacol Exp Ther 260:146–159
Megens AAHP, Niemegeers CJE, Awouters FHL (1992b) Antipsychotic profile and side-effect liability of haloperidol, risperidone and ocaperidone as predicted from their differential interaction with amphetamine in rats. Drug Dev Res 26:129–145
Megens AAHP, Niemegeers CJE, Awouters FHL (1992c) Behavioral disinhibition and depression in amphetaminized rats: a comparison of risperidone, ocaperidone and haloperidol. J Pharmacol Exp Ther 260:160–167
Megens AAHP, Vermeire J, Artois K, Hens K, Awouters FHL (1993a) The new antipsychotic risperidone is devoid of local irritating and anesthetic activity on rabbit cornea and fails to affect nerve conduction from rat tail. Janssen Preclinical Research Report R 64 766, N 94702
Megens AAHP, Hendrickx H, Awouters FHL (1993b) Risperidone is devoid of interaction with the convulsant pentylenetetrazole in rats. Janssen Preclinical Research Report R 64 766, N 94704
Meltzer HY, Nash JF (1991) Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43:587–604
Meltzer HY, Stahl SM (1976) The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 2:19–76
Meltzer HY, Matsubara S, Lee J-C (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246
Mertens C (1991) Long-term treatment of chronic schizophrenic patients with risperidone. In: Kane JM (ed) Risperidone: major progress in antipsychotic treatment. Oxford Clinical Communications, Oxford, pp 44–48
Niemegeers CJE (1989) Serotonin receptor antagonists: pharmacology of risperidone. In: Ayd FJ (ed) 30 Years Janssen Research in psychiatry, Chapter 11. Ayd Medical Communications, Baltimore, Maryland, pp 99–107
Niemegeers CJE, Janssen PAJ (1975) Differential antagonism to amphetamine-induced oxygen consumption and agitation by psychoactive drugs. In: Fielding S, Lal H (eds) Industrial pharmacology. Part II. antidepressants. Futura, New York, pp 125–141
Niemegeers CJE, Janssen PAJ (1979) A systematic study of the pharmacological activities of dopamine antagonists. Life Sci 24:2201–2216
Niemegeers CJE, Awouters F, Janssen PAJ (1990) Serotonin involvement in the action of antipsychotic drugs. In: Paoletti R, Vanhoutte PM (eds) Proceedings of the International Symposium on serotonin: from cell biology to pharmacology and therapeutics. Kluwer, Dordrecht, pp 531–541
Perregaard J, Arnt J, Bogeso KP, Hyttel J, Sánchez C (1992) Non-cataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles. J Med Chem 35:1092–1101
Persyko I (1972) Psychiatric adverse reaction to methysergide. J Nerv Ment Dis 154:299–301
Povlsen UJ, Noring U, Fog R, Gerlach J (1985) Tolerability and therapeutic effect of clozapine. Acta Psychiatr Scand 71:176–185
Reyntjens A, Gelders YG, Hoppenbrouwers MLJA, Van Den Bussche G (1986) Thymostenic effects of ritanserin (R 55 667), a centrally acting serotonin S2 receptor blocker. Drug Dev Res 8:205–211
Richelson E (1984) Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J Clin Psychiatry 45:331–336
Rogerson R, Butler JK (1971) Assessment of low dosage haloperidol in anxiety states. Br J Psychiatry 119:169–170
Roth BL, Ciaranello RD, Meltzer HY (1992) Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. J Pharmacol Exp Ther 260:1361–1365
Saller CF, Czupryna MJ, Salama AI (1990) 5-HT2 receptor blockade by ICI169,369 and other 5-HT2 antagonists modulates the effects of D2 dopamine receptor blockade. J Pharmacol Exp Ther 253:1162–1170
Schenk JO, Morocco MT, Ziemba VA (1991) Interactions between the argininyl moieties of neurotensin and the catechol protons of dopamine. J Neurochem 57:1787–1795
Schotte A, de Bruyckere K, Janssen PFM, Leysen JE (1989) Receptor occupancy by ritanserin and risperidone measured using ex vivo autoradiography. Brain Res 500:295–301
Schotte A, Janssen PAJ, Megens AAHP, Leysen JE (1993) Occupancy of central neurotransmitter receptors by risperidone, clozapine, and haloperidol, measured ex vivo by quantitative autoradiography. Brain Res 631:191–202
Sedvall G (1975) Receptor feedback and dopamine turnover in CNS. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, vol 6. Plenum, New York, pp 127–177
Seeman P, Chau-Wong M, Tedesco J, Wong K (1975) Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad USA 72:4370–4380
Simpson GM, Varga E (1974) Clozapine, a new antipsychotic agent. Curr Ther Res 16:679–686
Sleight AJ, Wouter K, Bigg DCH (1993) Binding of antipsychotic drugs at α1A- and α1B-adrenoceptors: risperidone is selective for the α1B-adrenoceptor. Eur J Pharmacol 238:407–410
Snyder SH, Greenberg D, Yamamura HI (1974) Antischizophrenic drugs: affinity for muscarinic cholinergic receptor sites in the brain predicts extrapyramidal effects. J Psychiatr Res 11:91–95
Sokoloff P, Martres M-P, Giros B, Bouthenet M-L, Schwartz J-C (1992) The third dopamine receptor (D3) as a novel target for antipsychotics. Biochem Pharmacol 43:659–666
Stevens JR (1973) An anatomy of schizophrenia. Arch Gen Psychiatry 29:177–189
Svensson TH, Nomikos GG, Andersson JL (1993) Modulation of dopaminergic neurotransmission by 5HT2 antagonism. In: Paoletti R, Saxena P, Vanhoutte P (eds) 2nd Serotonin from Cell Biology to Pharmacology and Therapeutics. Kluwer, Dordrecht, The Netherlands (in press)
Tedeschi DH, Tedeschi RE, Fellows EJ (1961) Central serotonin antagonist activity of a number of phenothiazines. Arch Int Pharmacodyn Ther 132:172–179
Ugedo L, Grenhof J, Svensson TH (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology 98:45–50
Van Beijsterveldt LEC, Geerts RJF, Leysen JE, Megens AAHP, Van den Eynde HMJ, Meuldermans WEG, Heykants JJP (1993) The regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology (in press)
Van Cauteren H, Lampo A, Megens A, Meuldermans W (1992) Expert report on the toxicological, pharmacodynamic and pharmacokinetic documentation on risperidone. Janssen Research Expert Report on R 64 766, N 84308
Van de Water A, Wouters L, Xhonneux R, Reneman RS (1985) The cardiac and haemodynamic effects of cumulative intravenous administrations of R 64 766 in closed-chest anaesthetized mongrel dogs. Janssen Preclinical Research Report R 64 766/2, N 45495
Van de Water A, Xhonneux R, De Clerck F (1992) Analysis of the effects of risperidone on the electrocardiogram and the overall behaviour of awake Beagle dogs: a randomised, placebo-controlled comparison with chlorpromazine. Janssen Preclinical Research Report R 64 766, N 91564
Wilk S, Watson E, Stanley ME (1975) Differential sensitivity of two dopaminergic structures in rat brain to haloperidol and to clozapine. J Pharmacol Exp Ther 195:265–270
Woolley DW (1962) The biochemical bases of psychoses or the serotonin hypothesis about mental diseases. Wiley, New York, p 131
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Megens, A.A.H.P., Awouters, F.H.L., Schotte, A. et al. Survey on the pharmacodynamics of the new antipsychotic risperidone. Psychopharmacology 114, 9–23 (1994). https://doi.org/10.1007/BF02245439
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DOI: https://doi.org/10.1007/BF02245439