What are the uses, mechanism of action, and side effects of Clozapine?

Clozapine: Uses, Mechanism of Action, and Side Effects

Clozapine is an atypical antipsychotic medication primarily used for treatment-resistant schizophrenia after at least two trials of other antipsychotic medications have failed. 1

Mechanism of Action

• Clozapine's exact mechanism of action is unknown, but its therapeutic efficacy in schizophrenia is believed to be mediated through antagonism of dopamine type 2 (D2) and serotonin type 2A (5-HT2A) receptors 2
• Unlike typical antipsychotics that primarily block dopamine receptors, clozapine has a complex receptor binding profile with high affinity for multiple neurotransmitter systems 2, 3
• Demonstrates binding affinity to multiple receptors with varying strengths (Ki values in nM): histamine H1 (1.1), adrenergic α1A (1.6), serotonin 5-HT6 (4), serotonin 5-HT2A (5.4), muscarinic M1 (6.2), serotonin 5-HT7 (6.3), serotonin 5-HT2C (9.4), dopamine D4 (24), and others 2
• Has relatively weak binding affinity for dopamine D2 receptors (Ki 160 nM) compared to typical antipsychotics, which explains its low risk of extrapyramidal side effects 2, 3
• Causes little to no prolactin elevation, unlike many other antipsychotics 2
• Affects EEG patterns by increasing delta and theta activity and slowing dominant alpha frequencies 2

Clinical Uses

• Primary indication: Treatment-resistant schizophrenia, defined as persistent moderate to severe delusions or hallucinations despite trials of at least two other antipsychotic medications (one or both should be an atypical agent) 1, 4
• High-risk suicidal patients with schizophrenia or schizoaffective disorder 4
• Superior efficacy for both positive and negative symptoms in treatment-resistant schizophrenia 5, 6
• May reduce symptoms of hostility and violence 6
• Can improve social and occupational functioning and quality of life 6
• May reduce affective symptoms, hospitalizations, and secondary negative symptoms 6
• Has been used to treat tardive dyskinesia and other movement disorders 3

Side Effects and Monitoring

Serious Side Effects

• Agranulocytosis: Requires mandatory blood monitoring through the Clozapine REMS Program 2, 5

  • Regular monitoring of absolute neutrophil count (ANC) is required 1
  • For hospice patients, monitoring may be reduced to once every 6 months 2

• Seizures: Risk is dose-dependent and may require dosage reduction 2, 5

  • Clozapine lowers the seizure threshold in a dose-dependent manner 3

• Myocarditis and Cardiomyopathy: Rare but potentially fatal 2, 4

  • Cardiovascular monitoring is essential, especially during initiation

• Gastrointestinal Hypomotility: Can lead to severe complications 2

Common Side Effects

• Sedation/Drowsiness: Affects approximately 39% of patients 2
• Hypersalivation: Very common (31-48% of patients) 2
• Tachycardia: Occurs in about 25% of patients 2
• Orthostatic Hypotension: Particularly concerning in elderly patients 2
• Constipation: Affects 14-25% of patients 2
• Weight Gain: Common metabolic side effect 2, 5
• Dizziness/Vertigo: Reported in 19-27% of patients 2
• Fever: May occur in approximately 5% of patients 2
• Metabolic Effects: Hyperglycemia, diabetes mellitus, and dyslipidemia 2

Monitoring Requirements

• Baseline and regular monitoring of complete blood counts with ANC 1
• Cardiovascular monitoring (blood pressure, heart rate, ECG) 2
• Metabolic monitoring (weight, glucose, lipids) 2
• Seizure precautions and monitoring 2
• Documentation of target symptoms and treatment response 1
• Documentation of suspected side effects 1

Pharmacokinetics

• Oral bioavailability of approximately 27% 3
• Peak plasma concentration occurs at approximately 2.5 hours after dosing 2
• Highly protein-bound (approximately 97%) 2
• Almost completely metabolized by liver enzymes (primarily CYP1A2, CYP2D6, and CYP3A4) 2
• Mean elimination half-life of 8 hours after single dose, increasing to 12-14 hours with multiple dosing 2, 3
• Can be administered with or without food 2
• Approximately 50% excreted in urine and 30% in feces 2

Clinical Pearls and Pitfalls

• Underutilization: Despite being considered the gold standard for treatment-resistant schizophrenia, clozapine is significantly underutilized (only 4.4% of schizophrenia patients in the US) 4
• Dosage Adjustment: May be necessary for patients with renal or hepatic impairment and for CYP2D6 poor metabolizers 2
• Abrupt Discontinuation: Monitor carefully for recurrence of psychotic symptoms and cholinergic rebound (profuse sweating, headache, nausea, vomiting, diarrhea) 2
• Drug Interactions: Caution with other highly protein-bound drugs due to potential interactions 2
• Mortality Benefit: Despite serious side effects, clozapine has been associated with the lowest mortality of any antipsychotic drug in large epidemiologic studies, mainly due to reduced suicide risk 4
• Therapeutic Trials: Require sufficient dosages over a period of 4-6 weeks before determining efficacy 1

Clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia despite its side effect profile. With proper monitoring and management of side effects, the benefits often outweigh the risks for appropriate patients.