1. General information
Clozapine is the first second-generation antipsychotic developed to treat schizophrenia. Clozapine has been used in Europe for several decades. In the mid-1970s, there were reports that the drug could trigger granulocyte deficiency, and the drug was then withdrawn from the market. Until the late 1980s, clozapine was approved for use in the United States, but the FDA restricted its use to refractory schizophrenia, requiring close monitoring during use. In recent years, the FDA has approved clozapine for suicide risk reduction in patients with schizophrenia and schizoaffective disorder who have recurrent suicidal behavior and have been judged to be at chronic risk for suicide.
In clinical practice, clozapine has also been used superindicated in other psychiatric disorders, such as bipolar disorder, schizoaffective disorder, and psychotic depression that do not respond well to other treatments.
2. How is its use managed in the United States?
The use of clozapine requires close monitoring of the patient’s white blood cell status to ensure rapid discontinuation of treatment at the first sign of granulocyte deficiency. In the United States, the four manufacturers of clozapine are required to have a functioning registry that must track patients’ blood counts while they are taking clozapine; pharmacies serve as the link between the patient and their supervising physician and the drug company, and are responsible for reporting the patient’s white blood cell status on a weekly basis. For those patients who have previously discontinued clozapine treatment due to a drop in white blood cell count or granulocyte deficiency, a national database is maintained: these patients should never use clozapine again, regardless of the efforts of the company or the system.
3. What is the recommended starting dose and titration method?
The recommended starting dose of clozapine is 25 mg at bedtime, slowly increasing by 25-50 mg every 4-5 days for the first 2-3 weeks until 200 mg/d. If necessary, titration can be continued up to 300-600 mg/d. At higher doses, splitting the dose to twice a day may help reduce some side effects. In the United States, the median dose of clozapine is close to 600 mg/d, and some patients may require higher doses, but should not exceed 900 mg/d.
For patients with recurrent suicidal behavior, the dose of clozapine is similar to that used in the treatment of schizophrenia and schizoaffective disorder.
4. Important side effects?
The most common and troubling side effects of clozapine include sedation; gastrointestinal discomfort such as nausea, colic, heartburn, and diarrhea; flu-like symptoms; and excessive salivation, especially at night. The drug has a strong anticholinergic effect, which in turn can cause a range of related side effects, including blurred vision, dry mouth, constipation, and difficulty urinating. The elderly are particularly sensitive to anticholinergic adverse reactions. In general, these side effects may disappear as the patient becomes tolerant to the drug.
Sedation: Since clozapine can cause drowsiness and sedation and impair physical coordination and mental alertness, patients should avoid potentially hazardous activities such as driving or operating machinery until they are sure that the side effects do not interfere with their ability to perform these activities.
Weight gain: occurs in most patients using clozapine. For some patients, this side effect is more significant and poses a problem. Stimulation of appetite and excessive eating may be the main cause of weight gain in patients. During treatment with clozapine, weight must be monitored closely; once weight gain occurs, a diet and exercise intervention program should be initiated.
Blood glucose abnormalities: SGAs are often associated with abnormal blood glucose regulation. Clozapine can elevate blood glucose, which in some cases may lead to diabetes mellitus. Although abnormal glucose metabolism and diabetes are often associated with weight gain, some patients may develop diabetes in the absence of significant weight gain. Patients who gain more weight are more susceptible to the metabolic side effects of the drug. Patients taking clozapine, especially those with a family history of diabetes, should be alert to this side effect and monitor their blood glucose regularly while taking the drug.
Orthostatic hypotension: Clozapine can block the compensatory response (vasoconstriction) triggered by postural changes, resulting in a transient drop in blood pressure and triggering dizziness. Patients, especially the elderly and those taking concomitant antihypertensive medications, should be educated not to get up too vigorously to allow the body to gradually adapt to postural changes.
Convulsions: Clozapine can induce convulsions; the risk of convulsions is elevated at higher drug doses and when patients have a history of convulsions or other contributing factors. This side effect is dose-related, with an increased risk at doses >600 mg/d. Patients with a prior history of seizures are not better candidates for clozapine therapy unless their symptoms have been well controlled with anticonvulsant therapy.
Granulocyte deficiency: A major concern with the use of clozapine. In the United States, the incidence of this side effect is about 1.2%. Patients first experience a drop in total white blood cell count, which may fall to almost undetectable levels; granulocyte counts, a type of white blood cell, are also falling, leading to impaired immune function of the body and a greater susceptibility of patients to develop some life-threatening infections.
There is no means to determine which of the patients using clozapine are more susceptible to granulocyte deficiency. Therefore, in the United States, the use of clozapine requires weekly monitoring of white blood cell counts and immediate termination of therapy at the earliest signs of granulocytopenia. The monitoring system requires that a patient’s blood sample be obtained weekly and the pharmacy prescribes only a one-week dose; if the patient has been on the drug for six months without interruption, the monitoring frequency is reduced to every two weeks and the patient can be prescribed a two-week dose each time; if the patient has been on the drug for 12 months without interruption, the monitoring frequency is reduced to every four weeks and the patient can be prescribed a one-month dose.
Myocarditis: Pooled data for patients using clozapine suggest that the drug may be associated with an elevated risk of myocarditis. This side effect, which can be fatal, has symptoms that include mainly chest pain, shortness of breath and palpitations, and usually occurs within one month of the start of clozapine treatment, although there are exceptions. Manufacturers are required to set up labeling to warn clinicians about this side effect and to remind patients using clozapine to report signs and symptoms of myocarditis promptly and to discontinue treatment at the first sign of suspicion.
Malignant syndrome (NMS): fairly rare, but quite serious and potentially fatal if not treated promptly. Compared with classical antipsychotics, the symptoms of NMS associated with clozapine are relatively mild, but early identification and intervention are still important.
5. Safety advantages?
Extrapyramidal reactions (EPS): An advantage of clozapine over classical antipsychotics is that it rarely triggers EPS.
Delayed dyskinesia (TD): Clozapine almost never causes TD; in addition, patients with TD may even benefit from clozapine treatment: it can reverse the symptoms of dyskinesia caused by classical antipsychotics.
6. What is the safety in pregnancy/lactation?
Clozapine is the only commonly used antipsychotic with a safety rating of B for pregnancy. Animal studies are not always predictive in humans, and there are not enough human studies with good control settings. Therefore, weighing the pros and cons of using clozapine remains necessary. Patients who are pregnant or about to become pregnant should discuss this topic with their physician. Some patients may relapse after discontinuation of the medication and may need to be re-dosed or switched to another medication.
Mothers who are breastfeeding should not take clozapine because small amounts of the drug may pass into the fetus through breast milk. If discontinuation of the drug is not practical, then the patient should not begin breastfeeding, and breastfeeding that has begun should be interrupted.
7. What substances should be used with caution in combination?
Clozapine may interact or act synergistically with a number of drugs, which in turn may lead to altered blood levels and adverse consequences.
Carbamazepine: This drug, like other drugs that may cause leukopenia, should not be used in combination with clozapine as it may increase the risk of granulocyte deficiency. In addition, carbamazepine can significantly reduce the blood concentration of clozapine, affecting its efficacy.
Antihypertensive drugs: The risk of upright hypotension may be increased when clozapine is used in combination with antihypertensive drugs;
Antihistamines, sedatives, narcotic analgesics: Central depressant effects may be superimposed and sedative symptoms may be exacerbated, impairing patient function;
SSRIs: fluoxetine, citalopram, fluvoxamine, sertraline, paroxetine may increase the blood concentration of clozapine, which may have enhanced efficacy and side effects. When starting or stopping SSRIs, the dose of clozapine may need to be adjusted accordingly.
Caffeine: Caffeine in coffee, cola, and over-the-counter medications may increase the blood levels of clozapine, thereby increasing the risk of side effects. If these interactions are suspected, caffeine should be avoided.
Ethanol: Alcohol should be avoided with clozapine because it may impair thinking, judgment and coordination.
Tobacco: Polycyclic aromatic hydrocarbons are hepatic enzyme inducers, which can accelerate the metabolism of clozapine and reduce the blood concentration.
8.Overdose safety?
Symptoms of clozapine overdose include confusion, profuse salivation, hypotension, cardiac arrhythmia and convulsions, the regression of which depends on the dose of the drug being digested and the drug combination. Clozapine has a strong anticholinergic effect and patients may experience diarrhea, elevated body temperature, dilated pupils, increased heart rate, delirium, hallucinations, and respiratory failure.
Any suspected drug overdose should be considered an emergency, including clozapine. In addition, attempts should be made to obtain the patient’s leftover drug package to estimate the dose taken by the patient.
9. What should I do if I miss a dose?
If it is early for the next dose, the dose should be made up as soon as possible after the missed dose is realized;
If it is close to the next dosing time, skip the current dose and continue to take the medication routinely. Do not take a “double” dose.