• Treatment of schizophrenia in patients who do not respond to or cannot tolerate standard antipsychotic medications.
• Treatment of psychosis associated with Parkinson’s disease.

Clozapine is considered an “atypical” antipsychotic because its interaction with dopamine receptors and its effects on dopamine-related behaviors are different from those of typical antipsychotic drugs. It affects dopamine binding at D1, D2, D3, and D5 receptors and has a particularly strong affinity for the D4 receptor. This suggests that Clozapine acts more on limbic dopamine receptors than on striatal ones, which may explain its lower risk of causing extrapyramidal side effects. In addition, Clozapine works as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors.

Schizophrenia: Adult over 16 years, 12.5 mg once or twice (elderly 12.5 mg once) on first day then 25-50 mg (elderly 25-37.5 mg) on second day then increased gradually (if well tolerated) in steps of 25-50 mg daily (elderly max. increment 25 mg daily) over 14-21 days up to 300 mg daily in divided doses (larger dose at night, up to 200 mg daily may be taken as a single dose at bedtime); if necessary may be further increased in steps of 50-100 mg once (preferably) or twice weekly; usual dose 200-450 mg daily (max. 900 mg daily)

Psychosis in Parkinson's disease: Adult over 16 years, 12.5 mg at bedtime then increased according to response in steps of 12.5 mg up to twice weekly; usual dose range 25-37.5 mg at bedtime, usual maximum 50 mg daily; exceptionally, dose may be increased further in steps of 12.5 mg weekly to maximum 100 mg daily in 1-2 divided doses.

Clozapine has several important drug interactions. The risk of myelosuppression may increase when it is used together with other myelosuppressive agents. It may also interact with other central nervous system (CNS) active drugs or alcohol, enhancing their effects. The use of benzodiazepines or other psychotropic medications with Clozapine can lead to orthostatic hypotension. Since Clozapine is highly protein-bound, it can be displaced by other highly protein-bound drugs, or it may displace them, such as warfarin and digoxin. Additionally, cimetidine may reduce the plasma levels of Clozapine.

Although the combined use of Carbamazepine and Clozapine is generally not recommended, stopping Carbamazepine may increase Clozapine levels in the blood. A lower dose of Clozapine is advised when used with drugs like fluvoxamine, paroxetine, and sertraline. Clozapine may enhance the effects of antihypertensive drugs and increase the activity of other anticholinergic agents. The use of adrenaline should usually be avoided due to the risk of reversal of its effects caused by Clozapine’s alpha-adrenergic blockade. When used with drugs metabolized by cytochrome P450 2D6, or with inhibitors of this enzyme such as quinidine, dose adjustments of Clozapine or the interacting drugs may be necessary.

Clozapine is contraindicated in severe heart disease; significant renal impairment; history of neutropenia or agranulocytosis; bone marrow disorders; paralytic ileus; alcoholic or toxic psychosis; circulatory collapse; drug intoxication; coma; severe CNS depression; uncontrolled epilepsy; and during breastfeeding.

Common side effects of Clozapine include constipation, mild dizziness or lightheadedness, drowsiness, mild headache, excessive salivation, nausea or vomiting, and unusual weight gain. Less commonly, patients may experience abdominal discomfort, heartburn, or dry mouth.

There are no sufficient studies on the use of Clozapine in pregnant women. Animal studies do not show significant harmful effects on the fetus. Clozapine may be used during pregnancy if the physician considers it necessary. However, studies in animals indicate that Clozapine is excreted into breast milk; therefore, women taking Clozapine should avoid breastfeeding.

Clozapine should not be stopped suddenly; instead, the dose should be gradually reduced over 1–2 weeks. If abrupt discontinuation is necessary (such as in cases of leukopenia, myocarditis, or cardiomyopathy), patients should be closely monitored for the return of psychosis and signs of cholinergic rebound, including headache, nausea, vomiting, and diarrhea. Elderly patients are more vulnerable to adverse effects such as agranulocytosis, cardiovascular complications, anticholinergic effects, and tardive dyskinesia. There is a serious risk of agranulocytosis, which can be life-threatening. Regular monitoring of white blood cell (WBC) counts is essential—weekly for the first 6 months, then every two weeks if stable, and weekly again for 4 weeks after stopping therapy. Caution is required when used with other bone marrow–suppressing drugs, and eosinophilia may occur, sometimes requiring interruption of treatment.

Sedation and cognitive or motor impairment are common with Clozapine, which may affect tasks requiring alertness such as driving or operating machinery. It should be used cautiously in patients at risk of seizures, including those with a history of seizures, head injury, brain damage, alcoholism, or use of drugs that lower the seizure threshold. Clozapine may cause mild, temporary fever, especially in the first few weeks, but it can also lead to severe reactions such as neuroleptic malignant syndrome (NMS). The risk of extrapyramidal symptoms with Clozapine is generally very low.

Clozapine may produce anticholinergic effects and should be used carefully in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, dry mouth, visual disturbances, constipation, or a history of bowel obstruction. It may also cause high blood sugar levels, sometimes severe, leading to complications such as ketoacidosis, coma, or death. Therefore, caution is needed in patients with diabetes or glucose regulation disorders, and blood sugar levels should be monitored. It should also be used cautiously in patients with liver disease, as hepatitis has been reported.

Clozapine can cause orthostatic hypotension and increased heart rate, so caution is necessary in patients prone to low blood pressure or those with cardiovascular or cerebrovascular disease. The combined use of psychotropic drugs or benzodiazepines may increase the risk of severe heart and lung complications.

Serious cardiac conditions such as myocarditis, pericarditis, pericardial effusion, cardiomyopathy, and congestive heart failure have been associated with Clozapine. Fatal cases of myocarditis have been reported, especially during the first month of treatment, although later cases can also occur. Symptoms such as shortness of breath, fatigue, chest pain, palpitations, swelling, or unexplained fever should be carefully evaluated. Clozapine must be discontinued if myocarditis is suspected and should not be restarted in such cases. It should also be stopped in confirmed cardiomyopathy unless benefits outweigh risks. Rare cases of blood clots, including pulmonary embolism and stroke, have also been reported.

Clozapine overdose typically causes disturbances in consciousness, ranging from drowsiness and confusion to delirium and coma. Common physical effects include rapid heartbeat (tachycardia), low blood pressure (hypotension), breathing difficulties or respiratory failure, and excessive salivation. In some cases, complications such as aspiration pneumonia and irregular heart rhythms may occur. Seizures have been reported but are relatively uncommon. Fatal cases have been documented, usually at doses exceeding 2500 mg, although some patients have survived even after ingesting more than 4 grams.

Treatment of Clozapine overdose is mainly supportive and focuses on stabilizing the patient. Maintaining a clear airway and ensuring proper oxygen supply and ventilation are critical. Activated charcoal, with or without sorbitol, may be administered and can be as effective or more effective than inducing vomiting or gastric lavage. Continuous monitoring of heart function and vital signs is essential, along with symptomatic and supportive care. Patients should be observed for several days due to the risk of delayed complications. Epinephrine should be avoided when managing hypotension, and quinidine or procainamide should not be used for treating arrhythmias. There is no specific antidote for Clozapine overdose, and methods like forced diuresis, dialysis, hemoperfusion, or exchange transfusion are generally ineffective. Clinicians should also consider the possibility of multiple drug ingestion.

Atypical neuroleptic drugs

Store at a temperature not exceeding 30°C. Protect from light and keep out of reach of children.