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).
