Risperidone (Risperdal)
SGA • Last reviewed 2025-09-23
General information
Risperidone (brand name Risperdal) is an atypical second-generation antipsychotic approved for schizophrenia (adults and adolescents ≥13 years), short-term treatment of acute manic or mixed episodes associated with bipolar I disorder (monotherapy in adults and pediatric patients ≥10 years; adjunct to lithium/valproate in adults), and irritability associated with autistic disorder (ages 5–16). It was first approved by the FDA in 1993; oral generics have been available since 2008. Long-acting injectable formulations of risperidone (Risperdal Consta q2wk, Perseris monthly subcutaneous) extend maintenance options for patients requiring depot therapy.
Oral dosage forms include tablets (0.25, 0.5, 1, 2, 3, 4 mg), orally disintegrating tablets (0.5, 1, 2, 3, 4 mg), and an oral solution (1 mg/mL). The usual starting dose for schizophrenia is 1 mg twice daily (or 2 mg once daily), titrated to 4–6 mg/day based on response; effective range is 2–8 mg/day divided once or twice daily. Pediatric schizophrenia (≥13 years) and bipolar mania (≥10 years) typically target 2.5–6 mg/day. For bipolar mania in adults, initiate 2–3 mg once daily and adjust to 1–6 mg/day. Autism-related irritability uses weight-based dosing (0.25–0.5 mg/day start, titrate to 1–2.5 mg/day). Risperidone may be taken with or without food. Therapeutic drug monitoring can be useful; trough plasma concentrations (active moiety risperidone + 9-hydroxyrisperidone) of ~20–60 ng/mL are associated with optimal response.
Risperidone exerts potent antagonism at serotonin 5-HT2A and dopamine D2 receptors, with 5-HT2A blockade exceeding D2 affinity at therapeutic doses. This balance mitigates EPS risk relative to typical antipsychotics while maintaining robust antipsychotic efficacy. Additional antagonism occurs at 5-HT7, α1-adrenergic, and α2-adrenergic receptors, contributing to improvements in mood/cognition but also orthostatic hypotension. Histamine H1 antagonism accounts for sedation and weight gain, while minimal muscarinic activity limits anticholinergic effects. The primary active metabolite, 9-hydroxyrisperidone (paliperidone), shares the parent compound’s receptor profile.
Risperidone is well absorbed orally with peak plasma concentrations in 1–2 hours; ODTs and liquid share similar pharmacokinetics. It is extensively metabolized in the liver by CYP2D6 (major) and CYP3A4 to 9-hydroxyrisperidone, which is active and contributes to total exposure; the parent-to-metabolite ratio depends on CYP2D6 genotype. The terminal half-life of risperidone is 3–20 hours depending on metabolic status, while 9-hydroxyrisperidone has a half-life of ~21 hours. The combined active moiety half-life is ~20 hours, supporting once-daily dosing after stabilization. Approximately 70% of the dose is excreted in urine (35% unchanged or as metabolites), with the remainder in feces.
Dosing & administration
Schizophrenia (adults): initiate 1 mg BID (or 2 mg once daily), increase by 1–2 mg/day to target 4–6 mg/day; maximum 8 mg/day.
Schizophrenia (adolescents ≥13): start 0.5 mg once or twice daily; titrate to 3–6 mg/day.
Bipolar I mania: begin 2–3 mg once daily (monotherapy) or 0.5–1 mg BID (pediatrics); usual range 1–6 mg/day.
Autism-associated irritability (5–16 years): weight-based dosing (see table); typical maintenance 1–2.5 mg/day.
Renal/hepatic impairment: start at 0.5 mg BID and titrate cautiously; reduced clearance increases exposure.
When converting to long-acting injectable (Consta), administer 25–50 mg IM every 2 weeks with oral overlap for the first 3 weeks.
Dose guidance by scenario
- Schizophrenia (adult)
- Start 1 mg BID → 2 mg BID Day 2; maintenance 4–6 mg/day (max 8 mg).
- Schizophrenia (≥13 years)
- Start 0.5 mg once or twice daily; titrate to 3–6 mg/day.
- Bipolar mania (adult)
- 2–3 mg once daily; adjust to 1–6 mg/day.
- Autism irritability (body weight <20 kg)
- Start 0.25 mg/day; may increase to 0.5 mg/day (max 1 mg/day).
- Autism irritability (≥20 kg)
- Start 0.5 mg/day; may increase to 1 mg/day (max 2–2.5 mg/day).
- Renal/hepatic impairment
- Start 0.5 mg BID; titrate slowly to half the usual adult target.
Mechanism of action
Risperidone’s antipsychotic efficacy stems from potent 5-HT2A and D2 receptor antagonism, with serotonin antagonism tempering dopamine blockade and reducing EPS risk. Elevated 5-HT2A/D2 ratio is thought to enhance negative symptom and cognitive outcomes.
Antagonism at α1-adrenergic receptors contributes to orthostatic hypotension; α2 antagonism may improve cognitive function and depressive symptoms. H1 antagonism promotes weight gain and sedation. Minimal muscarinic activity results in low anticholinergic burden.
The active metabolite paliperidone mirrors risperidone’s receptor profile, extending receptor occupancy and clinical duration.
- Potent 5-HT2A and D2 receptor antagonism.
- Affinity for 5-HT7, α1, α2, and H1 receptors (orthostasis, metabolic changes).
- Minimal muscarinic affinity (limited anticholinergic effects).
Metabolism & pharmacokinetics
Oral risperidone reaches peak concentrations in 1–2 hours; the active metabolite peaks at 3–12 hours. Steady-state concentrations are achieved within 2–3 days of dosing.
Extensive hepatic metabolism via CYP2D6 and CYP3A4 produces 9-hydroxyrisperidone; poor CYP2D6 metabolizers exhibit higher parent drug levels but similar total active exposure. Reduced renal clearance in impairment necessitates lower targets.
The combined elimination half-life of the active moiety is ~20 hours, supporting once-daily dosing for maintenance. Risperidone and metabolites are primarily excreted renally (70%) with fecal elimination of the remainder.
- Time to peak concentration (Tmax)
- 1–2 h (risperidone); 3–12 h (9-hydroxyrisperidone)
- Elimination half-life
- 3–20 h (risperidone); ~21 h (9-hydroxyrisperidone); ~20 h (active moiety)
- Protein binding
- ~90% (risperidone); 77% (9-hydroxyrisperidone)
- Renal excretion
- ≈70% (unchanged drug + metabolites)
Drug interactions
CYP2D6 inhibitors (fluoxetine, paroxetine) and CYP3A4 inhibitors (ketoconazole, itraconazole) increase risperidone exposure; dose reduction and monitoring are recommended.
CYP3A4 inducers (carbamazepine, rifampin) decrease plasma levels, risking loss of efficacy—avoid or adjust with monitoring.
QT-prolonging agents (antiarrhythmics, macrolides) add torsades risk; obtain ECGs when coadministered.
Risperidone antagonizes levodopa and dopamine agonists, potentially worsening Parkinsonian symptoms.
Additive CNS depressant effects occur with alcohol, benzodiazepines, and opioids.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP2D6 inhibition | Fluoxetine, paroxetine, quinidine | Reduce risperidone dose; monitor active moiety levels if available. |
| CYP3A4 inhibition | Ketoconazole, itraconazole, ritonavir | Consider dose reduction and monitor for adverse reactions. |
| CYP3A4 induction | Carbamazepine, rifampin | Avoid or increase dose with clinical/EKG monitoring. |
| QT prolongation | Class IA/III antiarrhythmics, macrolides, methadone | ECG at baseline and during therapy. |
| Dopaminergic antagonism | Levodopa, dopamine agonists | Monitor for loss of antiparkinsonian effect. |
Monitoring & safety checks
Weight/BMI and waist circumference
Baseline, 3 months, then annually • Monitor metabolic risk (weight gain common).
Fasting lipids & glucose/A1c
Baseline, 3 months, then annually • Detect dyslipidemia or glucose intolerance.
Prolactin-related symptoms
Each visit • Risperidone frequently elevates prolactin; assess for galactorrhea, menstrual changes.
EPS / tardive dyskinesia screening
Each visit during titration, then periodically • Monitor for Parkinsonism, akathisia, TD.
ECG (QTc) if risk factors present
Baseline and periodically • Dose-related QT prolongation risk.
Educate patients about potential prolactin effects and sexual dysfunction; labs if symptomatic.
Consider switching to another SGA if persistent metabolic or prolactin adverse effects occur.
Discontinuation guidance
Taper over 1–2 weeks when feasible to reduce relapse risk and minimize withdrawal dyskinesia or rebound psychosis.
Cross-titration with another antipsychotic is standard when switching; monitor for additive EPS or sedative effects during overlap.
Special populations
Renal impairment: reduce dose due to decreased clearance of active moiety; therapeutic drug monitoring can aid dosing.
Hepatic impairment: start at 0.5 mg BID and titrate slowly; hepatic dysfunction increases free fraction and exposure.
Geriatric patients: increased sensitivity to orthostasis and sedation; use lower starting doses and slower titration.
Pregnancy/Lactation: limited controlled data; use if benefits outweigh risks. Neonates exposed in third trimester require monitoring for EPS or withdrawal.
Pediatrics: approved for schizophrenia (≥13), bipolar mania (≥10), autism irritability (5–16); monitor growth, metabolic parameters, and prolactin.
Key adverse effects
Common: somnolence, fatigue, dizziness, weight gain, akathisia, EPS, hyperprolactinemia (galactorrhea, gynecomastia).
Metabolic: weight gain, dyslipidemia, hyperglycemia (less than clozapine/olanzapine but clinically relevant).
Serious: tardive dyskinesia, neuroleptic malignant syndrome, QT prolongation/torsades, seizures (rare), blood dyscrasias.
LAI availability
Clozapine does not have an FDA-approved long-acting injectable formulation. Related LAI options for the treatment class are listed below.
References
- Risperdal (risperidone) Prescribing Information — Janssen Pharmaceuticals (2022)
- AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2017 — Pharmacopsychiatry (2017) DOI: 10.1007/s00213-017-4813-7
- Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a network meta-analysis — The Lancet (2017) DOI: 10.1016/S0140-6736(17)32455-2
- Risperidone in autism spectrum disorder: meta-analysis of randomized controlled trials — European Child & Adolescent Psychiatry (2015) DOI: 10.1007/s00787-015-0682-7
- Therapeutic drug monitoring of risperidone: active moiety concentration and response — Clinical Psychopharmacology and Neuroscience (2012) DOI: 10.3109/13880209.2012.691431
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.