Clozapine - Drug Monograph

Introduction

Clozapine is an atypical antipsychotic medication that represents a significant advancement in the treatment of treatment-resistant schizophrenia. First approved by the FDA in 1989, clozapine remains the gold standard for patients who have failed to respond to conventional antipsychotic therapy. Its unique pharmacological profile and demonstrated efficacy in reducing suicidal behavior in schizophrenia patients distinguish it from other antipsychotic agents.

Mechanism of Action

Clozapine exerts its therapeutic effects through a complex multi-receptor binding profile. It acts as an antagonist at multiple neurotransmitter receptors including:

• Dopamine D1, D2, D3, and D4 receptors
• Serotonin 5-HT2A, 5-HT2C, 5-HT3, and 5-HT6 receptors
• Adrenergic α1 and α2 receptors
• Histamine H1 receptors
• Muscarinic M1 receptors

Unlike typical antipsychotics, clozapine demonstrates relatively weak D2 receptor blockade with stronger 5-HT2A antagonism, resulting in a lower incidence of extrapyramidal symptoms. Its unique receptor profile contributes to its efficacy in treatment-resistant cases and its distinct adverse effect profile.

Indications

FDA-approved indications:

• Treatment-resistant schizophrenia in adults who have failed to respond adequately to at least two different antipsychotic medications
• Reduction of suicidal behavior in patients with schizophrenia or schizoaffective disorder

Off-label uses (with varying evidence):

• Treatment-resistant bipolar disorder
• Parkinson's disease psychosis
• Borderline personality disorder with psychotic features

Dosage and Administration

• Start at 12.5 mg once or twice daily
• Increase gradually by 25-50 mg/day to target dose
• Typical therapeutic range: 300-450 mg/day divided doses
• Maximum recommended dose: 900 mg/day

• Oral administration with or without food
• Divided dosing recommended (bid or tid) to minimize peak concentration effects
• Available as regular tablets and orally disintegrating tablets

• Renal impairment: Use with caution, consider lower doses
• Hepatic impairment: Contraindicated in severe impairment
• Elderly: Initiate at lower doses (6.25-12.5 mg/day)
• Pediatric: Not FDA-approved under 16 years

Pharmacokinetics

Contraindications

• History of clozapine-induced agranulocytosis or severe granulocytopenia
• Myeloproliferative disorders
• Uncontrolled epilepsy
• Severe central nervous system depression or comatose states
• History of clozapine-induced myocarditis or cardiomyopathy
• Concurrent use with other drugs known to cause bone marrow suppression
• Severe hepatic impairment
• WBC count <3,500/mm³ or ANC <2,000/mm³ before initiation

Warnings and Precautions

1. Severe neutropenia (absolute neutrophil count <500/mm³) - risk of 0.8% 2. Seizures - dose-related risk (5% at >600 mg/day) 3. Myocarditis and cardiomyopathy - highest risk in first month 4. Orthostatic hypotension, bradycardia, and syncope

• Increased mortality in elderly patients with dementia-related psychosis
• Neuroleptic malignant syndrome
• Tardive dyskinesia
• Metabolic changes (weight gain, diabetes, dyslipidemia)
• Gastrointestinal hypomotility with severe complications
• Eosinophilia
• QT interval prolongation
• Falls due to sedation and orthostatic hypotension

Drug Interactions

• Benzodiazepines: Increased risk of respiratory depression
• CYP1A2 inhibitors (fluvoxamine, ciprofloxacin): Increase clozapine levels
• CYP1A2 inducers (carbamazepine, smoking): Decrease clozapine levels
• Other bone marrow suppressants: Additive myelosuppression
• Anticholinergic agents: Enhanced anticholinergic effects
• Warfarin: Altered anticoagulant effect

• SSRIs, SNRIs: Potential serotonin syndrome
• Antihypertensives: Enhanced hypotensive effects
• CNS depressants: Additive sedation

Adverse Effects

• Sedation (39%)
• Salivary hypersecretion (31%)
• Tachycardia (25%)
• Constipation (14%)
• Dizziness (12%)
• Weight gain (4-30%)

• Agranulocytosis (0.8%)
• Seizures (1-5%, dose-dependent)
• Myocarditis (0.015-0.188%)
• Cardiomyopathy
• Neuroleptic malignant syndrome
• Severe gastrointestinal hypomotility
• Eosinophilia
• Hepatitis

Monitoring Parameters

• WBC and ANC: Weekly for first 6 months, then every 2 weeks for next 6 months, then monthly
• Temperature: Daily for first 3 weeks, then with fever symptoms

• Cardiovascular: ECG, blood pressure, heart rate regularly
• Metabolic: Weight, BMI, waist circumference, fasting glucose, lipid profile
• Hepatic: Liver function tests periodically
• Renal: Renal function tests
• Therapeutic drug monitoring: Trough levels (350-600 ng/mL therapeutic range)

• Signs of infection (fever, sore throat)
• Cardiac symptoms (chest pain, palpitations)
• Seizure activity
• Bowel function

Patient Education

• Absolute necessity of regular blood monitoring
• Immediate reporting of fever, sore throat, or signs of infection
• Recognition of cardiac symptoms (chest pain, palpitations)
• Importance of not missing doses or stopping abruptly
• Potential for sedation and impaired coordination
• Management of constipation with adequate fluid and fiber intake
• Avoidance of alcohol and CNS depressants
• Smoking cessation counseling (smoking affects drug levels)
• Pregnancy and breastfeeding considerations
• Need for regular metabolic monitoring

• Gradual position changes to prevent dizziness
• Caution with driving or operating machinery
• Healthy diet and exercise to manage weight gain
• Regular dental care for sialorrhea management

References

1. Clozapine REMS Program. FDA Risk Evaluation and Mitigation Strategy. 2021. 2. Miller DD. Review and management of clozapine side effects. Schizophr Res. 2020;216:11-21. 3. Nielsen J, Correll CU, Manu P, et al. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613. 4. Safferman A, Lieberman JA, Kane JM, et al. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull. 1991;17(2):247-261. 5. Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019;381(18):1753-1761. 6. Clozapine prescribing information. FDA Label. 2022. 7. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91. 8. Flanagan RJ, Dunk L. Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol. 2008;23 Suppl 1:27-41.