What is Risperidone (atypical antipsychotic medication)?

What is Risperidone?

Risperidone is an atypical antipsychotic medication that acts primarily through combined dopamine D2 and serotonin 5-HT2A receptor antagonism, used to treat schizophrenia, bipolar mania, and irritability associated with autistic disorder. 1

Chemical Classification and Mechanism

• Risperidone belongs to the benzisoxazole derivative class of atypical antipsychotics, with the molecular formula C23H27FN4O2 and molecular weight of 410.49 1

• The drug's therapeutic activity results from combined concentrations of risperidone and its major active metabolite, 9-hydroxyrisperidone, which has similar pharmacological activity to the parent compound 1

• It demonstrates high affinity (Ki of 0.12 to 7.3 nM) for serotonin 5-HT2, dopamine D2, α1 and α2 adrenergic, and H1 histaminergic receptors 1

Pharmacokinetics

• Risperidone has 70% absolute oral bioavailability with rapid absorption, reaching peak plasma concentrations at approximately 1 hour after oral administration 1

• The active metabolite 9-hydroxyrisperidone reaches peak concentrations at about 3 hours in extensive metabolizers and 17 hours in poor metabolizers 1

• Steady-state concentrations are achieved in 1 day for extensive metabolizers and approximately 5 days for poor metabolizers 1

• The drug is extensively metabolized in the liver through hydroxylation by CYP 2D6 enzyme, with plasma protein binding of 90% for risperidone and 77% for 9-hydroxyrisperidone 1

FDA-Approved Indications

• Schizophrenia in adults and adolescents aged 13-17 years 2, 3

• Bipolar mania as monotherapy for short-term treatment of acute manic and mixed episodes associated with bipolar I disorder in children and adolescents aged 10-17 years 2, 3

• Irritability associated with autistic disorder in children and adolescents aged 5-16 years 2, 3

Clinical Evidence in Specific Populations

Children and Adolescents with Intellectual Disability

• Multiple randomized controlled trials demonstrate risperidone's efficacy for disruptive behaviors, aggression, and irritability in children with intellectual disability at mean doses of 1.16-2.9 mg/day over 4-6 weeks 4

• Common side effects in this population include somnolence (51%), headache (29%), vomiting (20%), weight gain (15%), transient tiredness (58%), and hypersalivation 4

• Due to its side effect profile, risperidone should be considered only after assessing whether nonpharmacological interventions could address irritability and aggression 4

ADHD in Intellectual Disability

• Risperidone demonstrated improvements in hyperactivity as a secondary outcome in children with intellectual disability and disruptive behavior disorders 4

• When added to stimulant medication, risperidone provided better control of hyperactivity than stimulant alone without increasing adverse events 4

• Despite potential efficacy for ADHD, methylphenidate remains the first-line agent due to risperidone's side effect profile 4

Critical Safety Considerations

Metabolic Effects

• Atypical antipsychotics cause significant metabolic disturbances, with weight gain representing the most common significant problem, which may be extreme 5

• Hyperglycemia and diabetes mellitus, including cases with ketoacidosis or hyperosmolar coma, have been reported with risperidone use 1

• Patients require fasting blood glucose testing at baseline and periodic monitoring during treatment, with vigilance for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, weakness) 1

• Dyslipidemia with undesirable alterations in cholesterol and triglycerides occurs with atypical antipsychotic treatment 1

Neurological Adverse Effects

• Risperidone carries the highest risk among atypical antipsychotics for extrapyramidal symptoms including acute dystonia, laryngeal dystonia, akathisia, and drug-induced Parkinsonism 5

• Tardive dyskinesia occurs in 5% of young patients per year, characterized by rapid involuntary facial movements and extremity or truncal movements 5

• Neuroleptic malignant syndrome, though rare (0.02% to 3% incidence), is potentially lethal and consists of mental status changes, fever, hypertonicity, and autonomic dysfunction 5

• Antipsychotic medications lower the seizure threshold in a dose-dependent manner, though seizures remain rare (<1%) at therapeutic doses 5

Cardiovascular Effects

• Orthostatic hypotension is a common side effect requiring caution in patients with cardiovascular or cerebrovascular disease 5, 6

• Minor electrocardiogram changes have been associated with atypical antipsychotics, with concerns that youth may be more susceptible to cardiac effects 5

Monitoring Requirements

• Baseline and follow-up laboratory tests including renal and liver function, complete blood counts, and electrocardiograms as indicated 5

• Regular monitoring for extrapyramidal symptoms and tardive dyskinesia, particularly with long-term use 5, 6

• The Abnormal Involuntary Movement Scale (AIMS) should be performed at least every 3 to 6 months after starting therapy 6

• Weekly blood cell counts during first 6 months if using clozapine (though this applies to clozapine specifically, not risperidone), then every 2 weeks thereafter 5

Cognitive Effects

• Atypical antipsychotics including risperidone show consistent benefits in fine motor function, memory, and executive function compared to typical antipsychotics, causing fewer cognitive difficulties 5, 6