Clozapine (trade names Clozaril®; Leponex®), approved by the FDA in 1989, was the first of the atypical antipsychotics. Clozapine is the only FDA approved medication indicated for treatment-resistant schizophrenia and for reducing the risk of suicidal behaviour in patients with schizophrenia.
Clozapine was developed by Sandoz in 1961, and introduced in Europe ten years later. In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer. Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA approved its use only for treatment-resistant schizophrenia, and required regular haematological monitoring to detect granulocytopenia, before agranulocytosis develops. In December of 2002, clozapine was also approved for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.
Clozapine is yellow crystalline solid with melting point 183-184 °C. It is insoluble in water, soluble in acetone, very well soluble in chloroform. Chemical name is 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine, C18H19ClN4.
The effectiveness of clozapine as an antipsychotic is thought to be mediated by antagonism at dopamine receptors. Compared to typical antipsychotics, with their strong affinity for D2 receptors, clozapine has a relatively low affinity (about 100X less than haloperidol) for the D2 receptor subtype, and this difference in affinity (more specifically the fast dissociation constant that results in lower affinity) is theorized to be responsible for the "atypicality" of clozapine. Clozapine also displays antagonism at 5-HT2, alpha adrenergic, H1, and cholinergic receptors. The role of antagonism of these neurotransmitter systems is clinical profile of clozapine is unknown, however serotonergic antagonism may play a contributing role in the "atypicality" of this antipsychotic. Alpha adrenergic, histaminic and cholinergic antagonism may play contribute to the side effect profile of clozapine.
The elimination half-life of clozapine is about 12 hours. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to effect the bioavailability of clozapine. Clozapine is extensively hepatically metabolized and eliminated in the urine and feces.
Clozapine is metabolize via the cytochrome P450 system in humans to polar metabolites suitable for elimination. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents which induce (e.g. cigarette smoke) or inhibit (e.g. theophylline, ciprofloxacin) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine.
Clozapine is contraindicated in individuals with uncontrolled epilepsy, myeloproliferative disease, or agranulocytosis with prior clozapine treatment.
Clozapine carries a black box warning for drug induced agranulocytosis. Agranulocytosis occurs in about 1% of patients who take clozapine during the first 6 months of treatment, and decreases to about 0.01% thereafter. Patients who have experienced agranulocytosis with prior treatment of clozapine should not receive clozapine again. Clozapine also carries black box warnings for seizures, myocarditis, and "other adverse cardiovascular and respiratory effects."
Lowering of the seizure threshold may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for orthostasis and other adverse cardiovascular side effects. Common side effects with clozapine treatment include: constipation, drooling, muscle-stiffness, sedation, tremors, orthostasis,hyperglycemia and weight-gain. The risks of extrapyramidal symptoms and tardive dyskinesias are much less with clozapine when compared to the typical antipsychotics (also known as conventional antipsychotics or conventional neuroleptics).
Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics. Indeed, there are case reports of clozapine-induced hyperglycemia and diabetes. Additionally there are case reports of clozapine-induced diabetic ketoacidosis. There is data showing that clozapine can decrease insulin sensitivity. Clozapine should be used with caution in patients who are diagnosed with diabetes or in patients at risk for developing diabetes. All patients receiving clozapine should have their fasting blood glucose monitored.
In addition to hyperglycemia, weight gain may be experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggests that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. Research has indicated that clozapine may cause a deficiency of selenium.
Patient's who take clozapine are advised to have a blood cell count every week, for the first 6 months of therapy. After this they should continue to conduct said count every 2 weeks. If the number of white blood-cells drops notably, one should consult with a hematologist. If you are using clozapine and have a sore throat, or fever, then you should inform your doctor.
More recently, a regular echocardiogram is also recommended to detect myocarditis.
The manufacturers of both the brand and generic clozapine are required by the FDA to track white blood cells counts for patients receiving clozapine, and pharmacies are required to obtain a copy of the CBC prior to dispensing the medication to the patient. The purpose of the monitoring system is to prevent rechallenge with clozapine in patients with a history of clozapine-induced agranulocytosis and to detect leukopenic events among patients taking clozapine.
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