Risperidone
Risperidone
Generic Name
Risperidone
Mechanism
- Dopamine D2 receptor antagonism: ↓ postsynaptic D₂ activity → decreases positive schizophrenia symptoms.
- Serotonin 5‑HT₂A receptor antagonism: reduces negative symptoms and improves mood.
- Partial agonism at 5‑HT₁A and antagonism at 5‑HT₂C: modulate anxiety and impulsivity.
- Glutamatergic modulation via NMDA receptors: emerging evidence of indirect effects.
- Net effect: balanced dopamine/serotonin blockade with fewer extrapyramidal side effects compared to typical antipsychotics.
Pharmacokinetics
| Parameter | Key Points |
| Absorption | Oral bioavailability ~35 % (first‑pass hepatic metabolism). Bile‑acid formulation improves absorption in children. |
| Distribution | Protein‑bound ~83 % (mainly to albumin). Crosses the blood‑brain barrier. |
| Metabolism | Extensive hepatic metabolism by CYP‑2D6 and CYP‑3A4 → active metabolite p‑chloro‑benzoate (CBZ‑H), ~4‑fold higher potency. |
| Elimination | Renal excretion of unchanged drug (30 %) and metabolites (70 %). Half‑life: *oral* 3–4 h; *LAI* 3–4 weeks. |
| Drug interactions | Inhibits/induces CYP‑2D6, CYP‑3A4 → caution with fluoxetine, paroxetine, carbamazepine, phenytoin. |
| Special populations |
• Elderly: increased sensitivity, risk of orthostatic hypotension, extrapyramidal symptoms. • Renal impairment: minor adjustment; primary concern is metabolite accumulation. • Hepatic impairment: avoid in severe liver disease. |
Indications
- Schizophrenia (adult, adolescent ≥12 y).
- Bipolar I disorder: maintenance or acute mania.
- Autistic disorder: irritability, aggression, and self‑injurious behavior (approved in children ≥5 y).
- Delusional or chemical psychoses as off‑label adjunct.
Contraindications
- Absolute contraindications: hypersensitivity to risperidone or any excipient; concurrent use of other CNS depressants with risk of additive sedation.
- Warnings:
- Acute akathisia, tardive dyskinesia (especially with prolonged use).
- Extrapyramidal symptoms (EPS); monitor for dystonia.
- Metabolic syndrome: weight gain, hyperglycemia, dyslipidemia.
- QTc prolongation: monitor ECG in patients with cardiac disease or concomitant QT‑prolonging drugs.
- Hyperprolactinemia: gynecomastia, galactorrhea, menstrual irregularities.
- Neuroleptic malignant syndrome: rare but life‑threatening.
- Precautions:
- Pregnancy: Category C; limited data on fetal toxicity.
- Breast‑feeding: excreted in milk; risk of neurotoxicity in infants – avoid or discontinue.
- Drug‑drug interactions with anticholinergics may mask akathisia.
Dosing
| Population | Starting Dose | Titration | Maintenance | Maximum | LAI | |
| Adults | 1–2 mg PO BID | 0.5 mg increments BID/qd for 1–2 weeks | 1–4 mg/day (often 1.5–3 mg) | 6 mg/day | 25 mg/imp | _ 1 week after first injection, then 25 mg/imp every 4 weeks |
| Adolescents (≥12 y) | 0.5–1 mg/day | 0.5‑1 mg increments weekly | 1–3 mg/day | 6 mg/day | – | |
| Children (5–11 y) | 0.25 mg PO daily (5 mg/m² in pediatrics) | 0.25‑0.5 mg weekly | 0.5–1.5 mg/day | 2 mg/day | – | |
| Bipolar mania | 1–2 mg PO BID | Increase to 2–3 mg BID, then 2–3 mg/day × 12–24 h | 2–4 mg/day | 6 mg/day | – | |
| Autistic irritability | 0.5–1 mg/day | Weekly increment 0.5 mg | 2–4 mg/day | 6 mg/day | – |
• Long‑acting injectable (LAI): 25 mg/imp intramuscular once every 4 weeks after a loading dose of 25 mg/imp on day 1, 25 mg/imp on day 29, then 25 mg/imp/4 wk.
• Switching: Match oral dose *CYP‑2D6* conversion ratio (oral 1 mg ≈ LAI 25 mg/imp at steady state).
Adverse Effects
| Category | Common (≥10 %) | Serious (≤1 %) |
| Neurologic | Akathisia, dizziness, blurred vision | Tardive dyskinesia, neuroleptic malignant syndrome (NMS) |
| Endocrine | Hyperprolactinemia – menstrual irregularity, galactorrhea | Gynecomastia, decreased libido |
| Metabolic | Weight gain, hyperlipidemia, impaired glucose tolerance | New‑onset diabetes |
| Cardiac | QTc prolongation (mild) | Sudden cardiac death (rare) |
| Gastro‑intestinal | Dry mouth, constipation | Severe orthostatic hypotension |
| Respiratory | None typical | Respiratory depression (rare, with CNS depressants) |
Monitoring
- Baseline
- CBC, electrolytes, liver & renal function tests.
- Weight, BMI, fasting glucose, lipid panel.
- Blood pressure & heart rate; ECG if QTc risk.
- During therapy
- Weight & metabolic markers: every 3–6 months.
- Blood pressure: at each visit.
- Prolactin: if symptoms; baseline for patients on antidepressants.
- Neuropsychiatric: assess EPS with BARS or SAS scales quarterly.
- LAI: monitor injection site reaction, serum trough levels (if therapeutic failure).
- Special
- Pregnancy: serial ultrasounds (if retained).
- Ethnicity: CYP‑2D6 poor metabolizers (African ancestry) – start lower oral dose.
Clinical Pearls
- CYP‑2D6 Genotyping: Poor metabolizers require an oral starting dose of ~0.5 mg BID instead of 1 mg.
- LAI Conversion: 25 mg intramuscular in 1 mL equals ~1 mg oral dose at steady state. Use the LAI conversion factor 25 mg/imp ≈ 1 mg/day’s steady‑state oral effect.
- Adjunctive Atypicals: Co‑prescribing olanzapine with risperidone can potentiate weight gain; use clozapine or quetiapine if metabolic syndrome is present.
- Extrapyramidal Symptoms: AKATHISIA appears early (within 1–2 weeks). Offer low‑dose benztropine or propranolol before dose escalation.
- Sodium Valproate: simultaneous use reduces risperidone metabolism; avoid over‑dosage.
- Pediatric Note: Bile‑acid formulation is critical for children 200 mg/dL or fasting triglycerides >150 mg/dL.
- Discontinuation: Gradual taper over 4–6 weeks to avoid rebound mania/hallucinations; monitor for withdrawal EPS.
- Pregnancy and Breastfeeding: Discuss risks; many clinicians choose to stop or switch to haloperidol for pregnancy, but no definitive data support risperidone safety.
- Electronic Medical Records (EMR) Alerts: Use an alert threshold of >6 mg/day or weight gain >7 % in 3 months to flag patients for metabolic monitoring.
*References: U.S. FDA labeling, NICE guidelines 2019, and *Board Review: Pharmacology* (MedlinePlus, 2023).