Abstract
Synopsis
Risperidone, a benzisoxazol derivative, is a novel antipsychotic agent which combines potent serotonin (5-hydroxytryptamine) 5-HT2 and dopamine D2 receptor antagonism. Development of the drug was stimulated by reports that the selective serotonin 5-HT2 antagonist ritanserin improved the negative symptoms of schizophrenia and decreased extrapyramidal symptoms when combined with haloper-idol. The relatively low incidence of extrapyramidal symptoms with risperidone may reflect a preferential action on mesolimbic rather than nigrostriatal dopaminergic pathways.
Recent clinical investigation suggests that risperidone is of at least comparable efficacy to haloperidol and perphenazine in improving the symptoms of acute and chronic schizophrenia on short term administration. Advantages offered by risperidone over haloperidol include a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects and possibly greater efficacy against the negative symptoms of schizophrenia. If these benefits prove to be maintained during long term therapy, risperidone is likely to make a significant contribution to the treatment of schizophrenia.
Pharmacodynamic Properties
Risperidone shows high affinity for central serotonin 5-HT2, adrenergic-α1 and -α2, histamine Hi, and dopamine D2 receptors in vitro and for serotonin 5-HT2, adrenergic-oci and dopamine D2 receptors in vivo. In the rat, risperidone increased dopamine turnover in the striatum, nucleus accumbens, olfactory tubercle and frontal cortex at doses in excess of those required for 50% occupancy of central dopamine D2 receptors ex vivo, suggesting possible modulation of dopamine turnover by serotonin 5-HT2 receptor blockade.
Risperidone exhibits central serotonin 5-HT2 and neostriatal dopamine D2 antagonistic activity, but is devoid of anticholinergic activity, in several in vivo animal models. It is also effective in animal behavioural models considered predictive of antipsychotic activity (e.g. suppression of apomorphine- and amphetamine-induced stereotypy and conditioned avoidance behaviour). In healthy volunteers, risperidone produced an alteration in sleep architecture similar to that seen with the selective serotonin 5-HT2 antagonist ritanserin, while in patients with chronic schizophrenia risperidone 5 to 10 mg/day restored sleep patterns and improved sleep efficiency, showing a more pronounced ameliorative effect than haloperidol. Following multiple dose (4-week) administration, risperidone produced marked and sustained increases in serum prolactin levels in schizophrenic patients; there was no evidence of tolerance to this effect. The cardiovascular effects of risperidone reflect its oc-adrenergic antagonistic activity, comprising a dose-related decrease in blood pressure and reflex tachycardia on single, but not multiple, dose administration. Patients with schizophrenia appear to be more tolerant of the hypotensive effect of risperidone than healthy volunteers.
Pharmacokinetic Properties
Risperidone undergoes extensive metabolism (hydroxylation and oxidative N-de-alkylation), and its major metabolite, 9-hydroxy-risperidone, displays similar pharmacological activity to the parent compound. Oxidative metabolism of risperidone is subject to genetic polymorphism. The oral bioavailability of risperidone varies from 66% (extensive metabolisers) to 82% (slow metabolisers). Peak plasma risperidone concentrations of 3 to 8 μu/L were achieved within 2 hours of single oral dose administration of risperidone 1 mg to extensive metabolisers. Plasma concentrations of risperidone, 9-hydroxy-risperidone and the active moiety (risperidone + 9-hydroxy-risperidone) were linearly related to dosage (< 25 mg/day) in schizophrenic patients.
Risperidone and its metabolites are extensively distributed throughout the body. Plasma protein binding of risperidone is approximately 90% and the volume of distribution is 1.2 L/kg. Risperidone is primarily excreted via the urinary route, with approximately 70% of the administered dose being recovered in the urine and 15% in the faeces over a 1-week period postdose. Plasma elimination half-lives (t1/2β) of risperidone and 9-hydroxy-risperidone in extensive metabolisers are 2.8 and 20.5 hours, respectively, with a t1/2β for the active moiety of approximately 24 hours. In poor metabolisers t1/2β of risperidone is extended to approximately 16 hours, whereas that of the active moiety is unchanged. Renal clearance of risperidone is reduced in patients with impaired renal function.
Therapeutic Use
Short term (4 to 8 weeks) noncomparative studies in patients with chronic schizophrenia have demonstrated marked improvements in general symptoms [Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions (CGI) scale] with risperidone < 25 mg/day, and a reduced incidence of extrapyramidal symptoms and antiparkinson drug requirements in comparison with prior antipsychotic therapy. These effects appeared to be maintained on long term (< 12 months) follow-up. Addition of risperidone 2 to 6 mg/day to existing antipsychotic therapy tended to produce a greater improvement in negative symptoms [Scale for Assessment of Negative Symptoms (SANS)] than the addition of placebo.
Recent findings from several short term (8 weeks) multicentre studies in patients with predominantly chronic schizophrenia suggest that risperidone 4 to 8 mg/day is of at least comparable efficacy to haloperidol 10 to 20 mg/day in alleviating the positive symptoms of the disease, and that it may confer the advantage over haloperidol of a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects, and possibly greater efficacy against the negative symptoms of schizophrenia. Risperidone 5 to 15 mg/day has demonstrated similar antipsychotic efficacy to perphenazine 16 to 48 mg/day on short term administration to patients with acute exacerbation of chronic schizophrenia.
Tolerability
The more commonly reported adverse effects of risperidone in recent clinical trials included sedation (30% of patients), insomnia (26%), agitation (22%), extrapyramidal symptoms (17%), dizziness (14%), anxiety (12%) and rhinitis (10%).
The incidence of extrapyramidal symptoms is linearly related to dosage (1 to 16 mg/day); at therapeutic dosages of 4 to 8 mg/day the incidence is comparable to that seen with placebo and significantly less than that associated with haloperidol 10 or 20 mg/day. Tardive dyskinesia has rarely been reported on long term (>12 months) risperidone therapy.
Risperidone produces oc-adrenergically mediated hypotension; however, the use of conservative dose titration schedules and divided doses minimises the risk of clinically important hypotension. Significant and dose-related weight gain (1.2 to 2.2 kg over 8 weeks) has been reported with risperidone 2 to 16 mg/day.
Dosage and Administration
Titration of risperidone dosage is recommended, starting at 1 mg orally twice daily, and increasing to 3mg twice daily over 3 days; the dosage may then be individualised. The optimum therapeutic dosage is 4 to 8 mg/day; dosages above 10 mg/day do not appear to confer greater clinical efficacy but are associated with a higher incidence of extrapyramidal symptoms.
For elderly patients and those with impaired renal function a starting dosage of 0.5mg twice daily, increased in 0.5mg aliquots to a total dosage of 1 or 2mg twice daily, is recommended.
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References
Carlsson A. Antipsychotics, neurotransmitters and schizophrenia. Am J Psychiatry 1978; 135: 164–73
Losonczy MF, Davidson M, Davis KL. The dopamine hypothesis of schizophrenia. Psychopharmacology 1987; 70: 715–26
Niemegeers CJE, Leysen JE. The pharmacological and biochemical basis of neuroleptic treatment in schizophrenia. Pharm Weekbl — Sei 1982; 4: 71–8
Zemlan FP, Hitzemann RJ, Hirschowitz J, et al. Down-regulation of central dopamine receptors in schizophrenia. Am J Psychiatry 1985; 142: 1334–7
Reynolds GP. Developments in the drug treatment of schizophrenia. Trends Pharmacol Sciences 1992; 13: 116–21
DeLisi LE, Neckers LM, Weinberger DR, et al. Increased whole blood serotonin concentrations in chronic schizophrenic patients. Arch Gen Psychiatry 1981; 38: 647–50
Lerer B, Ran A, Blacker M, et al. Neuroendocrine responses in chronic schizophrenia: evidence for serotonergic dysfunction. Schizophr Res 1988; 1: 405–10
Meitzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology 1992; 99: S18–S27
Richelson E. Neuroleptic affinities for human brain receptors and their use in predicting adverse effects. J Clin Psychiatry 1984; 45: 331–6
Ceulemans DL, Gelders YG, Hoppenbrouwers M-L, et al. Effect of serotonin antagonism in schizophrenia: a pilot study with setoperone. Psychopharmacology 1985; 85: 329–32
Bersani G, Grispini A, Marini S, et al. Neuroleptic-induced extrapyramidal side effects: clinical perspectives with ritanserin (R 55667), a new selective 5-HT2 receptor blocking agent. Curr Ther Res 1986; 40: 492–9
Gelders YG. Thymosthenic agents, a novel approach in the treatment of schizophrenia. Br J Psychiatry 1989; 155 Suppl. 5: 33–6
Leysen JE, Janssen PMF, Gommeren W, et al. 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 1992; 41: 494–508
Leysen JE, Gommeren W, Eens A, et al. Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 1988; 247: 661–70
Bolden C, Cusack B, Richelson E. Antagonism by antimuscari-nic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther 1992; 260: 576–80
Schotte A, de Bruyckere K, Janssen PFM, et al. Receptor occupancy by ritanserin and risperidone measured using ex vivo autoradiography. Brain Res 1989; 500: 295–301
Nyberg S, Farde L, Eriksson L, et al. 5-HT2 and D2 dopamine receptor occupancy in the living human brain: a PET study with risperidone. Psychopharmacology 1993; 110: 265–72
Kerwin RW, Busatto GF, Pilowsky LS, et al. Dopamine D2 receptor occupancy in vivo and response to the new antipsychotic risperidone. Br J Psychiatry 1993; 163: 833–40
Westerink BHC. The effects of drugs on dopamine biosynthesis and metabolism in the brain. In: Horn AS, et al., editors. Theneurobiology of dopamine. London: Academic Press, 1979: 251–90
Sailer CF, Czupryna MJ, Salama AI. 5-HT2 receptor blockade by ICI 169,369 and other 5-HT2 antagonists modulates the effects of D-2 dopamine receptor blockade. J Pharmacol Exp Ther 1990; 253: 1162–70
Lappalainen J, Hietala J, Koulu M, et al. Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects. Eur J Pharmacol 1990; 190: 403–7
Meert TF, Niemegeers CJE, Awouters F, et al. Partial and complete blockade of 5-hydroxytrytophan (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 1988; 13: 237–44
Janssen PAJ, Niemegeers CJE, Awouters F, et al. Pharmacology of risperidone (R 64 766), a new antipsychotic with seroto-nin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 1988; 244: 685–93
Czyrak A, Jaros T, Moryl E, et al. Pharmacological effects of zotepine and other antipsychotics on the central 5-HT2 receptors. Pharmacopsychiatry 1993; 26: 53–8
Niemegeers CJE, Janssen PAJ. Differential antagonism to amphetamine-induced oxygen consumption and agitation by psychoactive drugs. In: Fielding S, Lai H, editors. Industrial pharmacology. Part II. Antidepressants. Mt Kisco, New York: Dutura Publishing Co., 1975: 125–41
Niemegeers CJE, Lenaerts FM, Artois KSK, et al. Interaction of drugs with apomorphine, tryptamine and norepinephrine. A new ‘in vivo’ approach: the ATN test in rats. Arch Int Phar-macodyn Thér 1977; 227: 238–53
Megens AAHP, Niemegeers CJE, Awouters FHL. Behavioral disinhibition and depression in amphetaminized rats: a comparison of risperidone, ocaperidone and haloperidol. J Pharmacol Exp Ther 1992; 260: 160–7
Moore NA, Tye NC, Axton MS, et al. The behavioral pharmacology of olanzapine, a novel ‘atypical’ antipsychotic agent. J Pharmacol Exp Ther 1992; 262: 545–51
Meert TF, de Haes P, Janssen PAJ, et al. Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology 1989; 97: 206–12
Meert TF, De Haes PLAJ, Vermote PCM, et al. Pharmacological validation of ritanserin and risperidone in the drug discrimination test procedure in the rat. Drug Dev Res 1990; 19: 353–73
Kuribara H, Tadokoro S. Correlation be ween antiaversive activities of antipsychotic drugs in rats and daily clinical doses. Pharmacol Biochem Behav 1981; 14: 181–92
Bergman J, Madras BK, Spealman RD. Behavioral effects of Di and D2 dopamine receptor antagonists in squirrel monkeys. J Pharmacol Exp Ther 1991; 258: 910–7
Casey DE. Serotonergic and dopaminergic aspects of neuroleptic-induced extrapyramidal syndromes in nonhuman primates. Psychopharmacology 1993; 112: S55–9
Meitzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-l, D-2 and serotonin pKi values. J Pharmacol Exp Ther 1989; 251: 238–46
Tandon R, Shipley JE, Taylor S, et al. Electroencephalographic sleep abnormalities in schizophrenia: relationship to positive/negative symptoms and prior neuroleptic treatment. Arch Gen Psychiatry 1992; 49: 185–94
Ganguli R, Reynolds CF, Kupfer DJ. Electroencephalographic sleep in young, never-medicated schizophrenics. Arch Gen Psychiatry 1987; 44: 36–44
Idzikowski C, Mills FJ, Glennard R. 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep. Brain Res 1986; 378: 164–8
Reyntjens A, Gelders YG, Hoppenbrouwers M-L, et al. Thy-mostenic effects of ritanserin (R 55667), a centrally acting serotonin-S2 receptor blocker. Drug Dev Res 1986; 8: 205–11
Dugovic C, Wauquier A, Janssen PAJ. Differential effects of the new antipsychotic risperidone on sleep and wakefulness in the rat. Neuropharmacology 1989; 28: 1431–3
Idzikowski C, Burton S, James R. The effects of risperidone on human sleep. Hum Psychopharm 1991; 6: 182–3
De Buck R, Hoffmann G, De Smet S, et al. A Polysomnographie study in young chronic schizophrenic patients treated with risperidone [abstract]. 17th Congress of Collegium Internationale Neuro-Psychopharmacologicum; 1990 Sept 10; Kyoyo, 32
Claus A, Bollen J, De Cuyper H, et al. Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study. Acta Psychiatr Scand 1992; 85: 295–305
Tuomisto J, Mannisto P. Neurotransmitter regulation of anterior pituitary hormones. Physiol Rev 1985; 37: 249–332
Bowden CR, Voina SJ, Woestenborghs R, et al. Stimulation by risperidone of rat prolactin secretion in vivo and in cultured pituitary cells in vitro. J Pharmacol Exp Ther 1992; 262: 699–706
Huang M-L, Van Peer A, Woestenborghs R, et al. Pharmacoki-netics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54: 257–68
Bersani G, Bresa GM, Meco G, et al. Combined serotonin-5HT2 and dopamine-D2 antagonism in schizophrenia: clinical, extrapyramidal and neuroendocrine response in a preliminary study with risperidone (R 64 766). Hum Psychopharm 1990; 5: 225–31
Mesotten F, Suy E, Pietquin M, et al. Therapeutic effect and safety of increasing doses of risperidone (R 64 766) in psychotic patients. Psychopharmacology 1989; 99: 445–9
Ishigooka J, Wakatabe H, Murasaki M, et al. Phase I Study of risperidone, a new antipsychotic drug of benzisoxazol derivative. Rinsho Hyoka 1991; 19: 93–163
Desseilles M, Antoine J, Pietquin M, et al. Risperidone in psychotic patients: an open dose-finding study [in French]. Psychiatry Psychobiol 1990; 5: 319–24
Gelders YG, Heylen SLE, Vanden Bussche G, et al. Pilot clinical investigation of risperidone in the treatment of psychotic patients. Pharmacopsychiatry 23: 206–11
Reid E, Wilson ID, editors. Methodological surveys in biochemistry and analysis. Cambridge: Royal Society of Chemistry, 1990; Vol. 20, 241–6
Le Moing JP, Edouard S, Levron JC. Determination of risperidone and 9-hydroxyrisperidone in human plasma by high-performance liquid chromatography with electrochemical detection. J Chromatogr 1993; 614: 333–9
Woestenborghs R, Lorreyne W, Van Rompaey F, et al. Determination of risperidone and 9-hydroxyrisperidone in plasma, urine and animal tissues by high-performance liquid chromatography. J Chromatogr 1992; 583: 223–30
Vanden Bussche G, Heykants J, De Coster R. Pharmacokinetic profile and neuroendocrine effects of the new antipsychotic risperidone [abstract]. Psychopharmacology 1988; 96 Suppl.: 334
van Beijsterveldt LEC, Geerts RJF, Leysen JE, et al. The regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat. Psychopharmacology 1994; 114: 53–62
Mannens G, Meuldermans W, Snoeck E, et al. Plasma protein binding of risperidone and its distribution in blood. Psychopharmacology 1994; 114: 566–72
Mannens G, Huang M-L, Meuldermans W, et al. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos 1993; 21: 1134–41
Brsen K, Gram LF. Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 1989; 36: 537–47
Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clinical Psychopharmaco 1993; 13: 25–40
Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151: 825–35
Müller-Spahn F, for the International Risperidone Research Group. Risperidone in the treatment of chronic schizophrenic patients: an international double-blind parallel-group study versus haloperidol. Clin Neuropharmacol 1992; 15 Suppl. 1, Pt A: 90A–1A
Borison RL, Diamond BI, Pathiraja A, et al. Risperidone- clin-ical efficacy and safety in schizophrenia. Psychopharmaco Bull 1992; 28: 213–8
De Cuyper HJA. Risperidone in the treatment of chronic psychotic patients: an overview of the double-blind comparative studies. In: Ayd FJ, editor. 30 years of Janssen Research in psychiatry. Baltimore: Ayd Medical Communications, 1989: 115–22
Casteláo JF, Ferreira L, Gelders YG, et al. The efficacy of the D2 and 5-HT2 antagonist risperidone (R-64-766) in the treatment of chronic psychosis. An open dose-finding study. Schizophr Res 1989; 2: 411–5
Fujii Y, Yamashita I, Yamauchi T, et al. Efficacy and safety of risperidone in the treatment of chronic schizophrenic inpatients. Evaluation of efficacy using PANSS [in Japanese]. Rinsho Seishin Igaku 1993; 22: 101–16
Ishigooka J. Clinical experience with risperidone in Japan — a multicentre early phase II study. In: Kane JM, editor. Risperidone: major progress in antipsychotic treatment. Oxford: Oxford Clinical Communications, 1991: 40–3
Mertens C. Long-term treatment of chronic schizophrenic patients with risperidone. In: Kane JM, editor. Risperidone: major progress in antipsychotic treatment. Oxford: Oxford Clinical Communications, 1991: 44–8
Möller HJ, Pelzer E, Kissling W, et al. Efficacy and tolerability of a new antipsychotic compound (risperidone): results of a pilot study. Pharmacopsychiatry 1991; 24: 185–9
Silver H, Nassar A. Fluvoxamine improved negative symptoms in treated chronic schizophrenia- an add-on, double-blind, placebo-controlled study. Biol Psychiatry 1992; 31: 698–704
Silver H, Blacker M, Weiler MP, et al. Treatment of chronic schizophrenia with cyproheptadine: a double-blind placebo-controlled study. Biol Psychiatry 1991; 30: 523–5
Roose K, Gelders Y, Heylen S. Risperidone (R64 766) in psychotic patients: a first clinical therapeutic exploration. Acta Psychiatr Belg 1988; 88: 233–41
Hillert A, Maier W, Wetzel H, et al. Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome- a functional approach. Pharmacopsychiatry 1992; 5: 213–7
Meco G, Bedini L, Bonifati V, et al. Risperidone in the treatment of chronic schizophrenia with tardive dyskinesia. Curr Ther Res 1989; 46: 876–83
Cesková E, Svestka J. Double-blind comparison of risperidone and haloperidol in schizophrenic and schizoaffective psychoses. Pharmacopsychiatry 1993; 26: 121–4
Min SK, Rhee CS, Kim C-E, et al. Risperidone versus haloperidol in the treatment of chronic schizophrenic patients: a parallel group double-blind comparative trial. Yonsei Med J 1993; 34: 179–90
Hyberg OJ, Fensbo C, Remvig J, et al. Risperidone versus perphenazine in the treatment of chronic schizophrenic patients with acute exacerbations. Acta Psychiatr Scand 1993; 88: 395–402
Heinrich K, Klieser E, Lehmann E, et al. Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double blind, randomized trial. Prog Neuro-psycho Biol Psychiatry 1994; 18: 129–37
Rifkin A, Quitkin F, Kan J, et al. Are prophylactic antiparkinson drugs necessary: a controlled study of procyclidine withdrawal. Arch Gen Psychiatry 1978; 35: 483–9
Van Putten T. Why do schizophrenic patients refuse to take their drugs?. Arch Gen Psychiatry 1974; 31: 67–72
Silver H, Kogan H, Zlotogorski D. Postural hypotension in chronically medicated schizophrenics. J Clinical Psychiatry 1990; 51: 459–62
Brown K, Levy H, Brenner C, et al. Overdose of risperidone. Ann Emerg Med 1993; 22: 1908–10
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Various sections of the manuscript reviewed by: R.L. Borison, Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia, USA; A. Claus, University Psychiatric Centre St Kamillus, Catholic University of Leuven, Bierbeek, Belgium; D. Copolov, Mental Health Research Institute, Royal Park Hospital, Parkville, Victoria, Australia; A. Hillert, Psychiatric Clinic, University of Mainz, Mainz, Germany; Ishigooka, Department of Psychiatry, Kitasato University School of Medicine, Kanagawa, Japan; J.M. Kane, Department of Psychiatry, Hillside Hospital, Long Island Jewish Medical Center, Glen Oaks, New York, USA; MM. Lader, Institute of Psychiatry, University of London, London, England; B. Lerer, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; R.G. McCreadie, Crichton Royal Hospital, Dumfries, Scotland; C. Mertens, Psychiatric Centre Sleidinge, Sleidinge, Belgium; H-J. Möller, Department of Psychiatry, University of Bonn, Bonn, Germany; G.P. Reynolds, Department of Biomedical Science, University of Sheffield, Sheffield, England; B.L. Roth, Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; P. Seeman, Departments of Pharmacology and Psychiatry, University of Toronto, Toronto, Ontario, Canada; H. Silver, Flugelman (Mazra) Psychiatric Hospital, Doar Na Ashrat, Israel; /. Svestka, Department of Psychiatry, Masaryk University, Brno, Czech Republic; R. Tandon, Department of Psychiatry, University of Michigan Medical Center, Ann Arbor, Michigan, USA
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Grant, S., Fitton, A. Risperidone. Drugs 48, 253–273 (1994). https://doi.org/10.2165/00003495-199448020-00009
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DOI: https://doi.org/10.2165/00003495-199448020-00009