Usage
Clozapine is an atypical antipsychotic prescribed for:
- Treatment-resistant schizophrenia: In patients who have not responded adequately to standard antipsychotic treatment.
- Reducing the risk of recurrent suicidal behavior: In patients with schizophrenia or schizoaffective disorder judged to be at chronic risk.
Pharmacological Classification: Atypical antipsychotic.
Mechanism of Action: Clozapine has a complex pharmacology, binding to multiple receptors including dopamine D2, serotonin 5-HT2A, 5-HT2C, 5HT6 and 5-HT7, alpha-adrenergic, muscarinic, and histamine H1 receptors. Its unique efficacy in treatment-resistant schizophrenia is thought to be related to its relatively high affinity for serotonin 5-HT2A receptors compared to D2 receptors and the complex interplay between its receptor interactions.
Alternate Names
There are no widely used alternate names for clozapine.
Brand Names: Clozaril, Versacloz.
How It Works
Pharmacodynamics: Clozapine’s antipsychotic effects are likely due to its combined antagonism at dopamine D2 and serotonin 5-HT2A receptors. It impacts other receptors, contributing to its side effect profile, including muscarinic receptors (anticholinergic effects), histamine H1 receptors (sedation, weight gain), and alpha-adrenergic receptors (hypotension).
Pharmacokinetics:
- Absorption: Clozapine is rapidly absorbed orally, with a bioavailability of 60-70%
- Metabolism: Extensively metabolized in the liver, primarily by CYP1A2, with contributions from CYP2C19, CYP2D6, and CYP3A4. The major metabolite is norclozapine (N-desmethylclozapine), which has some pharmacological activity.
- Elimination: Primarily through renal excretion (50%) and fecal excretion (30%), with elimination half-life is usually between 4 to 12 hours depending on the individual and their metabolism.
Mode of Action: Clozapine binds to multiple receptors in the brain, modulating neurotransmission. Its higher affinity for 5-HT2A over D2 is unique among antipsychotics and is thought to be a key factor in its efficacy in treatment-resistant patients.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Clozapine acts as an antagonist at multiple receptors, including dopamine D2, serotonin 5-HT2A, 5-HT2C, 5HT6, and 5HT7, alpha-adrenergic, muscarinic, and histamine H1. It does not directly inhibit enzymes but can impact drug metabolism via CYP1A2 induction.
Elimination Pathways: Clozapine is metabolized primarily by CYP1A2 in the liver and is eliminated through renal and fecal excretion.
Dosage
Standard Dosage
Adults:
- Initial: 12.5 mg once or twice daily.
- Titration: Increase by 25-50 mg/day, if tolerated, to 300-450 mg/day by the end of two weeks.
- Maintenance: Adjust to the lowest effective dose, typically 300-450mg/day. Maximum dose 900 mg/day.
Children:
Safety and efficacy not established in children under 18.
Special Cases:
- Elderly Patients: Start with a lower dose (12.5 mg/day) and titrate more slowly.
- Patients with Renal Impairment: Reduce dose in patients with moderate to severe impairment.
- Patients with Hepatic Dysfunction: Reduce dose and monitor liver function tests.
- Patients with Comorbid Conditions: Consider interactions with other medications and adjust accordingly.
Clinical Use Cases
Clozapine is not indicated for use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in the long-term management of treatment-resistant schizophrenia and reducing suicidal behavior.
Dosage Adjustments
Dose adjustments are necessary for:
- Renal impairment
- Hepatic dysfunction
- Co-administration with CYP1A2 inhibitors (reduce clozapine dose)
- Co-administration with CYP1A2 inducers (increase clozapine dose)
- CYP2D6 poor metabolizers (reduce clozapine dose).
Side Effects
Common Side Effects
- Sedation, drowsiness
- Constipation
- Weight gain
- Hypersalivation (drooling)
- Tachycardia
- Dizziness
- Orthostatic hypotension
Rare but Serious Side Effects
- Agranulocytosis (severely low white blood cell count)
- Myocarditis (inflammation of the heart muscle)
- Seizures
- Ileus (intestinal blockage)
- Severe orthostatic hypotension
Long-Term Effects
- Weight gain and associated metabolic complications
- Tardive dyskinesia (movement disorder)
Adverse Drug Reactions (ADR)
- Agranulocytosis
- Myocarditis
- Seizures
- Neuroleptic malignant syndrome
Contraindications
- History of clozapine-induced agranulocytosis or severe granulocytopenia.
- Uncontrolled epilepsy.
- Myocarditis.
- Severe hepatic impairment.
- Central nervous system (CNS) depression.
- Alcoholic and other toxic psychoses.
- Coma.
- Hypersensitivity to clozapine.
Drug Interactions
- CYP1A2 inhibitors: (e.g., fluvoxamine, ciprofloxacin) increase clozapine levels.
- CYP1A2 inducers: (e.g., carbamazepine, phenytoin) decrease clozapine levels.
- Drugs that prolong the QT interval: Increase risk of arrhythmias.
- Drugs that lower the seizure threshold: Increase the risk of seizures.
- Antihypertensive drugs: May enhance hypotensive effects.
- Central nervous system depressants: May enhance sedation.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: B
- Fetal Risks: While animal studies have not shown evidence of teratogenicity, human data is limited. Use in pregnancy only if clearly needed.
- Breastfeeding: Clozapine is excreted in breast milk. Consider the risks and benefits before breastfeeding.
Drug Profile Summary
- Mechanism of Action: Complex pharmacology, binds to multiple receptors, including dopamine D2 and serotonin 5-HT2A.
- Side Effects: Sedation, constipation, weight gain, hypersalivation, agranulocytosis, myocarditis, seizures.
- Contraindications: History of clozapine-induced agranulocytosis, uncontrolled epilepsy, myocarditis.
- Drug Interactions: CYP1A2 inhibitors and inducers, drugs that prolong the QT interval, drugs that lower seizure threshold.
- Pregnancy & Breastfeeding: Category B; use with caution. Excreted in breast milk.
- Dosage: Initial: 12.5 mg once or twice daily, titrate to 300-450 mg/day, max 900 mg/day.
- Monitoring Parameters: Absolute neutrophil count (ANC), white blood cell count, electrocardiogram (ECG), liver function tests, weight, blood pressure.
Popular Combinations
Clozapine is typically used as monotherapy. In some cases, it may be augmented with other antipsychotics if a full response is not achieved.
Precautions
- General Precautions: Monitor ANC weekly for the first 18 weeks, then less frequently. Monitor ECG, weight, and other parameters regularly.
- Specific Populations: Elderly and renally/hepatically impaired patients require careful dose adjustments.
- Lifestyle Considerations: Avoid alcohol and other CNS depressants. Caution patients about activities requiring alertness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Clozapine?
A: Adults: Initial 12.5 mg once or twice daily, titrate to 300-450 mg/day, max 900 mg/day. Elderly and patients with renal/hepatic impairment: lower initial dose and slower titration.
Q2: What is the most serious side effect of Clozapine?
A: Agranulocytosis, a potentially life-threatening drop in white blood cell count.
A: Primarily by CYP1A2 in the liver.
Q4: What are the contraindications for Clozapine?
A: History of clozapine-induced agranulocytosis, uncontrolled epilepsy, myocarditis, severe hepatic impairment.
Q5: Can Clozapine be used during pregnancy?
A: Only if the potential benefit justifies the potential risk to the fetus.
Q6: What are the common drug interactions with Clozapine?
A: CYP1A2 inhibitors and inducers, drugs that prolong the QT interval, and drugs that lower the seizure threshold.
Q7: What monitoring is required for patients on Clozapine?
A: Regular ANC monitoring, ECG, weight, and other clinical parameters.
Q8: How should Clozapine be discontinued?
A: Gradually taper the dose over 1-2 weeks.
Q9: What if a patient misses a dose of Clozapine?
A: If a dose is missed for more than 48 hours, re-initiate treatment at a low dose (12.5 mg) and titrate up again.
Q10: What is the mechanism behind clozapine-induced orthostatic hypotension?
A: Clozapine blocks alpha-1 adrenergic receptors, leading to vasodilation and a drop in blood pressure upon standing.
