indication

For the treatment of schizophrenia in adults and in adolescents, ages 13 to 17, and for the short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents ages 10 to 17. May also be used to manage symptoms of inappropriate behavior due to aggression and/or psychosis in patients with severe dementia.

pharmacology

Risperidone is an atypical antipsychotic medication. It is most often used to treat delusional psychosis (including schizophrenia), but risperidone is also used to treat some forms of bipolar disorder and psychotic depression. It also has shown some success in treating symptoms of Asperger's Syndrome and autism. Risperidone is now the most commonly prescribed antipsychotic medication in the United States.

mechanism of action

Blockade of dopaminergic D2 receptors in the limbic system alleviates positive symptoms of schizophrenia such as hallucinations, delusions, and erratic behavior and speech. Blockade of serotonergic 5-HT₂ receptors in the mesocortical tract, causes an excess of dopamine and an increase in dopamine transmission, resulting in an increase in dopamine transmission and an elimination of core negative symptoms. Dopamine receptors in the nigrostriatal pathway are not affected by risperidone and extrapyramidal effects are avoided. Like other 5-HT₂ antagonists, risperidone also binds at alpha(1)-adrenergic receptors and, to a lesser extent, at histamine H1 and alpha(2)-adrenergic receptors.

toxicity

Symptoms of overdose include drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. LD₅₀=82.1mg/kg (orally in mice).

biotransformation

Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone, which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent.

absorption

Well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

half life

20-24 hours

route of elimination

Risperidone is extensively metabolized in the liver.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.

drug interactions

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Carbamazepine: Decreases the effect of risperidone

Donepezil: Possible antagonism of action

Fluoxetine: The SSRI, fluoxetine, increases the effect and toxicity of risperidone.

Galantamine: Possible antagonism of action

Indinavir: Increased risk of extrapyramidal symptoms

Itraconazole: Increases the level of risperidone

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Paliperidone: Paliperidone is the active metabolite of risperidone, 9-OH-risperidone. Concomitant therapy may increase the adverse effects of paliperidone due to additive paliperidone exposure. Consider alternate therapy.

Paroxetine: The SSRI, paroxetine, increases the effect and toxicity of risperidone.

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Risperidone, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Risperidone. Consider alternate therapy or monitor for therapeutic/adverse effects of Risperidone if Terbinafine is initiated, discontinued or dose changed.

Tetrabenazine: May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Trimethobenzamide: Trimethobenzamide and Risperidone, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Risperidone, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Risperidone, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).