Pharmacology

Risperidone is a benzisoxazole derivative with the chemical designation 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2.

Pharmacodynamics. The exact mechanism of action of risperidone is unknown. The antipsychotic activity is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2A) antagonism. It also inhibits adrenergic beta-1 and beta-2, and histaminergic H1 receptors. Risperidone has low to moderate affinity for 5-HT1C, 5-HT1D, and 5-HT1A receptors, weak affinity for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity for cholinergic muscarinic or beta-1 and beta-2 adrenergic receptors.

Pharmacokinetics. Risperidone is well-absorbed and extensively metabolized in the liver by cytochrome P450IID6 to a major active metabolite, 9-hydroxyrisperidone, which is the predominant circulating species and is approximately as effective as risperidone with respect to receptor binding. Therefore, the clinical effect of the drug likely results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are proportional to the dose. The absolute oral bioavailability of risperidone is 70%. Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.

Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occur at about 1 hour. Peak 9-hydroxyrisperidone level occurs at about 3 hours in extensive metabolizers and 17 hours in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone is about 21 hours in extensive metabolizers and 30 hours in poor metabolizers. The plasma binding of 9-hydroxyrisperidone is 77%.

A long-acting injectable form of risperidone is also available. After a single intramuscular injection, there is a small initial release of the drug followed by a lag period of 3 weeks when the main release of the drug starts, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the injection. Therefore, oral antipsychotics are continued during the first 3 weeks of treatment to maintain therapeutic levels until the main release of the risperidone injection site has begun. RBP-7000 is a long-acting formulation of risperidone designed for once-monthly subcutaneous injection for the treatment of schizophrenia. A model simulation study has shown that 90 mg of RBP-7000, in comparison with 25 mg of long-acting risperidone, reached effective concentrations immediately after the first administration (16). Results of a systematic review of randomized clinical trials comparing depot risperidone with other treatments for patients with schizophrenia and/or schizophrenia-like psychoses concluded that it is uncertain whether depot risperidone is any more effective in controlling the symptoms of schizophrenia, but it can improve patient compliance in clinical practice (24).

Therapeutic drug monitoring. Monitoring of the total concentration of risperidone and its metabolite 9-hydroxyrisperidone using mass spectrometry and liquid chromatography, which correlate with the dose, is useful for individualization of pharmacotherapy (03).

Pharmacogenetics. A randomized controlled trial has shown that polymorphism of the serotonin transporter promoter gene is a useful biomarker of intolerance to selective serotonin reuptake inhibitors, such as risperidone in patients with dementia (10). Both the genotyping of DRD2 and the monitoring of plasma drug concentrations may be useful for improving clinically dominant symptoms of schizophrenia with risperidone rather than drug concentration monitoring alone (31). A genotyping study showed that in treatment of autism spectrum disorders with risperidone, a CYP2D6 phenotype may be associated with response to treatment as well as development of adverse drug reactions in poor metabolizers (32). Although there are increased adverse effects in poor metabolizers, they are mostly not significant, and routine genotyping for screening is not recommended (05). The role of CYP2D6 genotyping in practice needs to be clarified by further studies. The search for a genetic biomarker to predict the response of schizophrenic patients to risperidone has revealed that single-nucleotide polymorphism rs2133450 inside the GRM7 gene is an indicator of poor response (23). A systematic review and metaanalysis of association between dopamine receptor gene polymorphisms and effects of risperidone treatment has shown that DRD2 affects risperidone treatment and DRD1 had no significant effect, whereas DRD3 might be associated with an improvement in negative symptoms of schizophrenia (17).

Clinical trials

Over the past 15 years, over 100 clinical trials have evaluated risperidone in various conditions, starting with schizophrenia. The earlier clinical trials showed that risperidone is comparable to haloperidol as an antipsychotic, but it has a safer profile regarding extrapyramidal syndromes. Many of the subsequent clinical trials were conducted to demonstrate long-term effects or compare efficacy and safety with other atypical antipsychotics.

A randomized, double-blind, placebo-controlled study in adolescents aged 13 to 17 years with acute exacerbation of schizophrenia showed that doses of risperidone 1 to 3 mg/day and 4 to 6 mg/day were both well tolerated and effective (11). The 1 to 3 mg/day dose was optimal.

A randomized, double-blind, placebo-controlled clinical trial has demonstrated the superior efficacy as well as safety of risperidone ISM^®, a long-acting formulation, in the monthly treatment of acute schizophrenia as compared to placebo (07).

Indications

Risperidone is indicated for the treatment of schizophrenia. The efficacy was established in short-term (6 to 8 weeks) controlled trials of schizophrenic inpatients. Risperidone is now approved for irritability associated with autistic disorder in children and adolescents including symptoms of aggression, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The long-acting injectable formulation of risperidone is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder and for the treatment of schizophrenia.

Risperidone is also approved for use in bipolar disorder and autism with severe behavioral disorders.

Off-label uses

Contraindications

Risperidone is contraindicated in patients with a known hypersensitivity to the product.

Goals and duration of treatment

Risperidone controls both the negative and positive symptoms of schizophrenia. The efficacy in delaying relapse was demonstrated in schizophrenic patients who had been clinically stable for at least 4 weeks before initiation of treatment with risperidone and who were then observed for relapse during a period of 1 to 2 years. The long-term usefulness of the drug for individual patients over extended periods should be periodically reevaluated. A retrospective study has shown that long-acting injection of risperidone is well-tolerated and over half the patients continued treatment for 1 year or more (29).

Dosing

In early, short-term clinical trials, oral risperidone was generally administered at 1 mg twice a day initially, with increases in increments of 1 mg twice a day on the second and third day, as tolerated, to a target dose of 3 mg twice a day by the third day. In later clinical trials, total daily risperidone doses of up to 8 mg on a daily regimen were also shown to be safe and effective. The recommended dosage of injectable risperidol is 25 mg intramuscularly every 2 weeks.

Special considerations

In patients with moderate to severe renal disease, clearance of risperidone and its active metabolite decreases by 60% compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease.

In subjects with liver disease, the mean free fraction of risperidone in plasma is increased by about 35% because of the diminished concentration of both albumin and a1-acid glycoprotein. Risperidone doses should be reduced in patients with liver disease.

Pediatric. A prospective observational study on antipsychotic-naive children/adolescent patients under 18 years of age on risperidone therapy showed statistically significant increases in body mass index total cholesterol and prolactin, as well as other cardiometabolic changes (20). In another study, risperidone treatment in children and adolescents with autism spectrum disorders disturbed glucose homeostasis and endocrine regulation, particularly that of leptin, in a dose- and duration-dependent manner (27). Therefore, periodic clinical and laboratory evaluations should be done during risperidone treatment in this age group.

Geriatric. In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in elderly patients. A population-based retrospective study of elderly patients showed the use of risperidone was associated with a lower risk of extrapyramidal symptoms compared to first-generation agents (28).

Pregnancy. The teratogenic potential of risperidone has been studied in rats, but there are no conclusive results that can be transposed to human beings. There are no adequate well-controlled studies of teratogenesis in pregnant women exposed to risperidone. Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It has been demonstrated that risperidone and 9-hydroxyrisperidone are excreted in human breast milk. Therefore, women receiving risperidone should not breast feed.

Anesthesia. A case of severe hypotension during a spinal anesthetic for cesarean delivery might have been a result of the alpha-adrenergic antagonism of risperidone (30). This was refractory to conventional treatment with ephedrine and intravenous fluids but responded to large doses of phenylephrine.

Interactions

Inhibitors of cytochrome P450IID6 such as quinidine can interfere with conversion of risperidone to 9-hydroxyrisperidone in poor metabolizers.

Adverse effects

There is no decline in cognitive function with long-term risperidone treatment in children and adolescents with disruptive behavior disorder (21). Treatment with long-acting risperidone is associated with a lower rate of emergent persistent tardive dyskinesias than conventional antipsychotics. A prospective study of extrapyramidal symptoms in different risperidone maintenance treatment paradigms found that symptoms were tolerable and differentially decreased depending on the dose paradigm over 1 year (04). Risperidone has been reported to induce rabbit syndrome, an antipsychotic-induced rhythmic motion of the mouth and lips, resembling the chewing motion of a rabbit (25).

Neuroleptic malignant syndrome has been reported in association with antipsychotic drugs. Risperidone and 9-hydroxyrisperidone appear to have a potential for proarrhythmic effects, as they lengthen the QT interval in some patients. Antipsychotic drugs exhibit anticholinergic side effects and can worsen myasthenia gravis coexisting in a schizophrenic patient. Long-acting injectable risperidone should be avoided in patients with schizophrenia (01). In a case with atypical presentation of neuroleptic malignant syndrome without hyperthermia, the cause was considered to be dose related (06). On recovery after discontinuation, rechallenge was done with a lower dose of risperidone, and there was no recurrence of neuroleptic malignant syndrome at 3-year follow-up. Acute laryngeal dystonia, a rare and lethal form of extrapyramidal reaction, has been reported in a young woman with schizophrenia on risperidone who presented to an emergency department with a sensation of choking and respiratory distress, mimicking a panic attack (02). The patient improved as the dose of risperidone was tapered before discontinuation and replacement with another antipsychotic.

Other adverse effects include cognitive impairment, seizures, dysphagia, movement disorders, and priapism. For a complete list of adverse effects, see the Physicians' Desk Reference.

Management. Risperidone may be reduced in dose or discontinued in case of adverse effects. Management of some of the adverse effects, such as neuroleptic syndrome, is discussed in other articles in MedLink Neurology.