Risperidone

Generic Name: Risperidone
Brand Names: Risperdal, Risperdal Consta, Perseris (US), Rispolept (Europe)
Drug Class: Atypical antipsychotic (Second-generation antipsychotic)
Formulations:
– Oral tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg
– Orally disintegrating tablets (ODTs): 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg
– Oral solution: 1 mg/mL
– Long-acting intramuscular injection (Risperdal Consta): 12.5 mg, 25 mg, 37.5 mg, 50 mg
– Extended-release subcutaneous injection (Perseris, US only): monthly depot

Route of Administration: Oral, Intramuscular (IM), Subcutaneous (SC)

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Approved Therapeutic Indications

Risperidone is an antipsychotic agent approved for treating several psychiatric disorders in adults and pediatric patients, depending on the indication and formulation.

Adults:

1. Schizophrenia (oral and depot formulations)

2. Bipolar I Disorder – manic or mixed episodes, as monotherapy or adjunct to mood stabilizers

3. Irritability associated with autistic disorder (in children and adolescents)

4. Schizoaffective disorder (off-label or region-dependent approval)

Pediatric (US FDA-approved):

• Schizophrenia: ages 13–17

• Bipolar disorder (acute mania): ages 10–17

• Irritability in autism spectrum disorder (ASD): ages 5–16

Off-label (region- and case-specific):

• Tourette syndrome

• Conduct disorder

• Dementia-related aggression (not FDA-approved due to mortality risk)

• Generalized anxiety disorder (as augmentation)

• Borderline personality disorder (BPD) adjunct

• Delusional parasitosis

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Mechanism of Action

Risperidone acts through dopamine and serotonin receptor antagonism, classifying it as a second-generation (atypical) antipsychotic.

1. D2 Receptor Antagonism – in mesolimbic pathway reduces positive symptoms (hallucinations, delusions)

2. 5-HT2A Receptor Antagonism – modulates dopamine release in different brain regions, improving negative and cognitive symptoms

3. Alpha-1 adrenergic antagonism – may cause orthostatic hypotension

4. Histamine H1 antagonism – contributes to sedation and weight gain

5. Alpha-2 adrenergic and partial muscarinic activity – minor contributions to side effects

This dual receptor antagonism contributes to reduced extrapyramidal symptoms (EPS) at lower doses compared to typical antipsychotics.

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Dosage and Administration

Oral (Adults):

• Schizophrenia:

  • Start: 1–2 mg/day in 1–2 divided doses

  • Target: 4–6 mg/day

  • Max: 16 mg/day (rarely used due to dose-dependent side effects)

• Bipolar Mania:

  • Initial: 2–3 mg once daily

  • Titrate as needed (max 6 mg/day typically)

Pediatrics:

• Autism-related irritability (5–16 yrs):

  • Start: 0.25–0.5 mg/day

  • Maintenance: 0.5–2.5 mg/day depending on weight

• Schizophrenia/Bipolar (13–17 yrs):

  • Start: 0.5–1 mg/day

  • Target: 2–6 mg/day

Risperdal Consta (Long-acting IM Injection):

• 25–50 mg every 2 weeks

• Requires oral risperidone overlap for 3 weeks after first injection

• Not suitable for acute symptom control

Perseris (Extended-release SC injection – US):

• 90–120 mg once monthly

• Used in adults with schizophrenia

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Pharmacokinetics

• Absorption (oral): Well absorbed, peak at 1 hour (oral), 4–6 weeks (IM depot)

• Bioavailability: 70% oral solution; slightly lower in tablets

• Protein Binding: ~90%

• Metabolism: Hepatic via CYP2D6 → active metabolite 9-hydroxyrisperidone (paliperidone)

• Half-Life:

  • Oral: 3–20 hours (parent and metabolite)

  • IM depot: ~3–6 days

  • Perseris: up to 4–6 weeks

• Elimination: Urine (~70%), feces (~14%)

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Contraindications

• Hypersensitivity to risperidone or any components

• IM injections contraindicated in patients with bleeding disorders

• Dementia-related psychosis in elderly (boxed warning – increased risk of death)

• Severe hepatic or renal dysfunction without dose adjustment

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Black Box Warning

Elderly Patients with Dementia-Related Psychosis:
– Increased risk of death (cardiac events, infections)
– Risperidone is not approved for dementia-related behavioral disturbances

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Warnings and Precautions

1. Tardive Dyskinesia (TD):

   • Involuntary, irreversible facial and limb movements with long-term use

2. Neuroleptic Malignant Syndrome (NMS):

   • Life-threatening; symptoms include hyperthermia, rigidity, mental status changes, autonomic dysfunction

3. Metabolic Changes:

   • Weight gain

   • Hyperglycemia/diabetes mellitus

   • Dyslipidemia

4. Hyperprolactinemia:

   • Due to potent D2 blockade

   • Galactorrhea, gynecomastia, menstrual irregularities, sexual dysfunction

5. Orthostatic Hypotension:

   • From alpha-1 blockade; caution in elderly or volume-depleted patients

6. Seizures:

   • Use cautiously in patients with seizure history

7. Cognitive and Motor Impairment:

   • Sedation, somnolence, impaired judgment

8. Leukopenia, Neutropenia, Agranulocytosis:

   • Monitor CBC if preexisting leukopenia or during suspected adverse events

9. Suicide Risk:

   • Monitor high-risk patients carefully

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Adverse Effects

Very Common (≥10%):

• Sedation

• Extrapyramidal symptoms (dose-dependent)

• Weight gain

• Increased appetite

• Fatigue

• Hyperprolactinemia

• Insomnia

• Anxiety

• Headache

• Dizziness

Common (1–10%):

• Nausea, vomiting, constipation

• Hypersalivation

• Tachycardia

• Orthostatic hypotension

• Akathisia

• Sexual dysfunction

Serious / Rare (<1%):

• Neuroleptic malignant syndrome

• Tardive dyskinesia

• Seizures

• QT prolongation

• Sudden cardiac death

• Agranulocytosis

• Priapism

• Severe allergic reactions

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Drug Interactions

1. CYP2D6 inhibitors (e.g., fluoxetine, paroxetine):
   – Increase plasma concentration of risperidone → lower starting dose

2. CNS depressants (e.g., alcohol, benzodiazepines):
   – Additive sedation and respiratory depression risk

3. Antihypertensives:
   – May potentiate hypotensive effect

4. Dopamine agonists (e.g., levodopa, bromocriptine):
   – Antagonized by risperidone

5. QT-prolonging drugs (e.g., macrolides, antiarrhythmics):
   – Increased arrhythmia risk

6. Valproate, carbamazepine:
   – Carbamazepine lowers risperidone levels via CYP3A4 induction
   – Valproate interaction variable; monitor levels

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Monitoring Parameters

• Baseline and Periodic:
  – Weight and BMI
  – Blood glucose and HbA1c
  – Lipid profile
  – Prolactin levels (if symptomatic)
  – CBC (in case of hematologic symptoms)
  – ECG (if cardiac risk factors present)
  – Liver and renal function
  – Extrapyramidal symptoms (AIMS scale)
  – Tardive dyskinesia monitoring in long-term use
  – Suicide risk evaluation

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Use in Special Populations

• Pregnancy: Category C (US); limited human data, potential risk of extrapyramidal/neonatal withdrawal in 3rd trimester

• Lactation: Excreted in breast milk; caution advised

• Geriatrics: Increased risk of stroke and death in dementia patients

• Renal/Hepatic Impairment: Lower initial doses recommended

• Children: Approved for schizophrenia, bipolar mania, and autism-related irritability (age- and weight-specific dosing)

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Patient Counseling Points

• Take with or without food; maintain consistent timing

• Do not stop abruptly without medical advice

• Report symptoms like tremors, muscle stiffness, abnormal movements

• Monitor for changes in mood, suicidal thoughts

• Avoid alcohol or sedative drugs unless advised

• Watch for symptoms of high blood sugar (e.g., increased thirst, urination)

• Regular check-ups for weight, blood glucose, and lipids

• Long-acting injection (Consta): needs oral overlap for 3 weeks

• Do not drive or operate machinery until effects are known

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Comparison to Other Atypical Antipsychotics

Drug	EPS Risk	Sedation	Weight Gain	Prolactin ↑	QT Prolong
Risperidone	Moderate	Moderate	Moderate	High	Moderate
Olanzapine	Low	High	Very High	Moderate	Low
Aripiprazole	Low	Low	Low	Low	Low
Quetiapine	Low	High	High	Low	Low
Paliperidone	Moderate	Moderate	Moderate	High	Moderate

Storage and Handling

• Store at 20–25°C (68–77°F)

• Protect oral solution from light and use within 6 months of opening

• Injection powder and suspension must be used as per manufacturer’s instructions

• Keep out of reach of children

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Global Brand Availability

• Risperdal (Janssen) – oral and IM

• Risperdal Consta – biweekly injection

• Rispolept (EU/Asia)

• Perseris – monthly subcutaneous injection (US only)

• Multiple generics available in all formulations