Clozapine

Clozapine is an atypical antipsychotic medication used primarily for treatment-resistant schizophrenia. It was the first atypical antipsychotic introduced, in the 1970s, and remains unmatched in efficacy for some patients with severe schizophrenia unresponsive to other medications.

Some key points about clozapine:

• It is effective for reducing positive and negative symptoms in schizophrenia, especially in treatment-resistant cases. Up to 30-60% of patients show significant improvement on clozapine after failing other antipsychotics.

• It has a low risk of extrapyramidal side effects like Parkinsonism and tardive dyskinesia due to weak blocking effects on dopamine D2 receptors and additional serotonin 5-HT2A antagonism.

• However, it frequently causes sedation, dizziness, sialorrhea (excessive salivation), tachycardia, and weight gain due to potent antihistamine effects. It can also lower blood pressure and cause gastrointestinal issues in some patients.

• Clozapine requires weekly to biweekly blood monitoring for the first 6 months due to the risk of agranulocytosis, a dangerous drop in white blood cell count. Ongoing monitoring at longer intervals is needed lifelong.

• Common doses range from 100 to 900 mg/day, with lower initiation doses and gradual upward titration based on response and tolerability. The average therapeutic dose is 300 mg/day.

• Clozapine can be sedating at high doses, so is often taken as a single bedtime dose or with a higher nighttime dose. It may require hospital admission for initial titration.

• Significant interactions can occur with other drugs, including benzodiazepines, antihypertensives, and substances that induce or inhibit the CYP1A2 and CYP3A4 enzymes which metabolize clozapine.

• Clozapine can also increase risks of seizure, myocarditis, hyperglycemia, and other medical issues. Ongoing monitoring of weight, blood pressure, blood sugar, lipids, etc. is important during long term treatment.

• Due to risks and monitoring requirements, clozapine is usually only initiated when other antipsychotic trials have been unsuccessful in treating severe psychotic symptoms. Benefit must be considerable to warrant its safety profile and high cost.

In summary, clozapine is the most effective antipsychotic for treatment-resistant schizophrenia but has a significant side effect burden and safety risks that require close clinical management. Newer agents provide safer alternatives when possible, but for some patients clozapine remains the gold standard. Ongoing research aims to develop antipsychotics that match the efficacy of clozapine with improved tolerability.