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Drugs

, Volume 48, Issue 2, pp 253–273 | Cite as

Risperidone

A Review of its Pharmacology and Therapeutic Potential in the Treatment of Schizophrenia
  • Susan Grant
  • A. Fitton
Drug Evaluation

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.

Keywords

Haloperidol Risperidone Negative Symptom Extrapyramidal Symptom Brief Psychiatric Rate Scale 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Susan Grant
    • 1
  • A. Fitton
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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