Clozapine is usually used only in patients that have not responded to other anti-psychotic treatments due to its danger of causing agranulocytosis as well as the costs of having to have blood tests continually during treatment. It is, however, one of the most effective anti-psychotic treatment choices. Patients are monitored weekly for the first six months. If there are no low counts the patient can be monitored every two weeks for an additional six months. Afterwards, the patient may qualify for every four-week monitoring. Clozapine has numerous severe side effects including agranulocytosis, and seizures, and has been associated with myocarditis and diabetes though those relationships have not been confirmed. Additionally, it also often causes less serious side effects such as hypersalivation and weight gain.
Clozapine is an atypical antipsychotic drug primarily prescribed to patients who are unresponsive to or intolerant of conventional and other atypical neuroleptics. It is used principally in treating treatment-resistant schizophrenia, a term used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics. It has been shown to be more effective in reducing symptoms of schizophrenia than the older typical antipsychotics, with more pronounced effects in those who have responded poorly to other medication. The relapse rate is lower and patient acceptability is better. There is some evidence clozapine may reduce propensity for substance abuse in schizophrenic patients.
There has been one case report of successful use of clozapine in isolated increase in creatine kinase (in absence of neuroleptic malignant syndrome) in a patient with schizophrenia where other atypical antipsychotics were not successful.
A number of case reports indicate that clozapine can be an effective treatment for schizophrenia while at the same time diminishing some symptoms associated with Parkinson's, such as the tremor and dyskinesia. Unlike typical antipsychotics such as haloperidol and some atypical antipsychotics such as risperidone, clozapine does not produce Parkinsonian symptoms, even at high doses. This is in part because it binds relatively weakly to the D2 dopamine receptor, compared to most other antipsychotics. Clozapine is not approved by the Food and Drug Administration (FDA) for the treatment of behavior problems in older adults with dementia.
Clozapine carries a black box warning for drug-induced agranulocytosis. Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment; the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.
Clozapine induced agranulocytosis can be transient.
Myocarditis is a sometimes fatal side effect of clozapine, which usually develops within the first month of commencement. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness. Signs of cardiac failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate.
While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for the hypersalivation.
Abrupt withdrawal may lead to cholinergicrebound effects, severe movement disorders as well as severe psychotic decompensation. It has been recommended that patients, families, and caregivers are aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.
Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.
When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine.Patients should be monitored for “decreased therapeutic effects of clozapine if carbamazepine” is started or increased. If carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. The study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis.
Published case reports have stated that the use of benzodiazepines and clozapine concomitantly can result in severe adverse reaction such as respiratory arrest, cardiac arrest and sudden death.
Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in schizophrenia subjects concurrently taking ciprofloxacin.Thus, the prescribing information for clozapine recommends “reducing the dose of clozapine by one-third of original dose” when ciprofloxacin and other CYP1A2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose.
Clozapine is a dibenzodiazepine that is structurally related to loxapine. It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 188.9 mg/L (25 °C). Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).
Clozapine is a partial antagonist  at the 5-HT1A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.
A direct interaction of clozapine with the GABAB receptor has also been shown. GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.
Norclozapine (N-desmethylclozapine), clozapine's chief active metabolite
The absorption of clozapine is almost complete, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).
Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and feces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.
Clozapine and norclozapine plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimization.
Clozapine was developed by Sandoz in 1961, and trials took place in 1972, when it was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany, and Finland in 1975. Early testing was performed in the United States around the same time. 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 and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular hematological monitoring to detect granulocytopenia, before agranulocytosis develops. In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior. In 2005 FDA approved criteria to allow reduced blood monitoring frequency.
As of 2014, three pharmaceutical companies market this drug: Novartis Pharmaceuticals (manufacturer), Mylan Laboratories and Teva Pharmaceuticals (market generic clozapine). In India the drug is manufactured by Sun Pharmaceuticals.
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