Clozapine exerts its therapeutic effects through its action on multiple neurotransmitter systems in the brain. Its key mechanisms include:

1. Dopamine Receptor Antagonism:
   • Clozapine has a high affinity for dopamine D4 receptors and a lower affinity for D2 receptors compared to other antipsychotics.
   • This selective dopamine receptor blockade contributes to its efficacy in reducing positive symptoms (e.g., hallucinations, delusions) with a lower risk of extrapyramidal side effects (EPS).
2. Serotonin Receptor Antagonism:
   • Clozapine strongly blocks serotonin 5-HT2A receptors, which is thought to improve negative symptoms (e.g., social withdrawal, apathy) and cognitive symptoms of schizophrenia.
   • This action also contributes to its mood-stabilizing effects.
3. Other Receptor Interactions:
   • Clozapine has affinity for adrenergic α1 and α2 receptors, histamine H1 receptors, and muscarinic M1 receptors, which contributes to its side effect profile (e.g., sedation, orthostatic hypotension, anticholinergic effects).
4. Neuroprotective Effects:
   • Clozapine’s ability to modulate glutamate and GABA neurotransmission may provide neuroprotective benefits.

Clozapine is approved for specific clinical conditions, including:

1. Treatment-Resistant Schizophrenia:
   • Clozapine is indicated for patients with schizophrenia who have not responded adequately to at least two other antipsychotics.
2. Reduction of Suicidal Behavior:
   • Clozapine is used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
3. Off-Label Uses:
   • Treatment of severe bipolar disorder (particularly in treatment-resistant cases).
   • Parkinson’s disease psychosis (in cases where other treatments have failed).

The dosage of clozapine varies depending on the indication, patient response, and tolerability. The following dosing guidelines are based on the British National Formulary (BNF) and clinical pharmacology references:

1. Schizophrenia:
   • Adults: Start with 12.5 mg once or twice daily, increasing gradually by 25–50 mg daily to a target dose of 300–450 mg daily in divided doses. The maximum dose is 900 mg daily.
   • Elderly: Lower starting doses (12.5 mg once daily) and slower titration are recommended.
2. Reduction of Suicidal Behavior:
   • Adults: Similar dosing as for schizophrenia, with careful monitoring for side effects.

Important Considerations:

• Clozapine must be titrated slowly to minimize the risk of side effects, particularly hypotension and seizures.
• Regular monitoring of white blood cell (WBC) and absolute neutrophil count (ANC) is mandatory due to the risk of agranulocytosis.
• Clozapine is available in oral tablets and orally disintegrating tablets.

Clozapine is associated with a range of side effects, some of which can be serious. Common side effects include:

1. Central Nervous System:
   • Sedation, dizziness, and headache.
   • Seizures, particularly at higher doses.
2. Cardiovascular:
   • Tachycardia, orthostatic hypotension, and myocarditis (rare but serious).
3. Gastrointestinal:
   • Constipation, nausea, and hypersalivation (sialorrhea).
4. Metabolic Effects:
   • Weight gain, hyperglycemia, and dyslipidemia, which increase the risk of metabolic syndrome and type 2 diabetes.
5. Hematological:
   • Agranulocytosis (a potentially life-threatening reduction in WBC count).

Serious Side Effects:

• Agranulocytosis: Requires immediate discontinuation of clozapine and close monitoring.
• Myocarditis: Presents with symptoms like chest pain, fever, and shortness of breath.
• Seizures: Risk increases with higher doses.
• Neuroleptic Malignant Syndrome (NMS): A rare but life-threatening condition characterized by fever, muscle rigidity, and autonomic instability.

Clozapine requires careful monitoring and adherence to specific precautions to ensure patient safety:

1. Hematological Monitoring:
   • Regular monitoring of WBC and ANC is mandatory before starting treatment and throughout therapy. Clozapine is contraindicated in patients with a history of agranulocytosis or severe neutropenia.
2. Cardiovascular Monitoring:
   • Baseline and periodic monitoring of cardiac function is recommended, particularly for signs of myocarditis.
3. Metabolic Monitoring:
   • Regular monitoring of weight, blood glucose, and lipid levels is essential to detect and manage metabolic side effects.
4. Pregnancy and Lactation:
   • Clozapine should be used during pregnancy only if the potential benefits outweigh the risks. It is excreted in breast milk, so breastfeeding is generally not recommended.
5. Elderly Patients:
   • Lower doses and slower titration are recommended due to increased sensitivity to side effects.

Clozapine has a significant potential for drug interactions due to its metabolism via cytochrome P450 enzymes (primarily CYP1A2). Key interactions include:

1. CYP1A2 Inhibitors:
   • Fluvoxamine and ciprofloxacin can increase clozapine levels, increasing the risk of toxicity.
2. CYP1A2 Inducers:
   • Smoking and carbamazepine can decrease clozapine levels, reducing its efficacy.
3. Other Antipsychotics:
   • Concurrent use with other antipsychotics may increase the risk of side effects.
4. Benzodiazepines:
   • Enhanced sedation and respiratory depression.
5. Other Interactions:
   • Warfarin: Altered anticoagulant effect.
   • Lithium: Increased risk of seizures and neurotoxicity.

Clozapine is the generic name for this medication. It is marketed under various brand names, depending on the country and manufacturer. Some examples include:

• Clozaril (a well-known brand in the United States and other regions).
• Denzapine.
• Zaponex.
• Fazaclo (orally disintegrating tablets).