Clozapine Toxicity: How to Identify and Treat It

What Is Clozapine?

Clozapine is an antipsychotic drug used to treat mental conditions like schizophrenia (a severe mental disorder affecting a person's behavior, thoughts, and feelings), schizoaffective disorder, recurrent suicidal behavior, etc. Clozapine is frequently used in the case of schizophrenia patients who do not respond to therapy with other antipsychotic drugs. Clozapine works by aiding in restoring the neurotransmitter balance in the brain. An antipsychotic medication called Clozapine helps to regulate the amount of dopamine and other chemicals in the brain. When dopamine activity is excessive, Clozapine decreases it and alleviates symptoms like hallucinations and suicidal behavior. Although Clozapine can be helpful for certain patients, there are also health hazards associated with drug usage. In particular, Clozapine can reduce the number of neutrophils, a kind of white blood cell that helps the body fight infections. Other side effects of the drug include myocarditis (inflammation of the heart muscles), seizures (electrical disturbance in the brain), metabolic syndrome (a set of medical conditions that increases the risk of various diseases), etc.

Why Is Clozapine Used?

Although Clozapine is FDA (The United States Food and Drug Administration) approved, it is not frequently used because of the various side effects associated with the disease and the risk of Clozapine toxicity. However, the drug can be used in the following conditions when other antipsychotic drugs fail to show any effective results:

• Schizophrenia: A mental condition characterized by an inability to interpret reality and altered thinking, behavior, and expressions.

• Suicidal Behavior: People who have attempted suicide are prone to attempt suicide or cause injury to themselves again.

How Should Clozapine Be Taken?

• Clozapine is available in oral suspension, tablets, and disintegrated tablets. And it should be taken orally as prescribed by the physician.

• The drug must be taken after a doctor’s recommendation, and the dosage should be followed as directed.

• Clozapine should be taken at the same time every day, and the drug should not be taken more or less than prescribed.

• The FDA recommends a daily dose of 900 mg (milligram) of Clozapine as the maximum recommended dosage. The typical dose is 400 mg daily for men and 300 mg per day for women.

• Clozapine intake should not be suddenly stopped without a doctor’s consultation. Doctors usually reduce the dosage gradually before completely stopping the medication.

What Are the Precautions That Should Be Taken Before Taking Clozapine?

The following precautions must be considered before taking Clozapine:

• The healthcare provider must be informed about allergies to Clozapine or any ingredient present in the medicine. Any other pre-existing drug allergies should also be notified to the healthcare provider.

• Any prescription and non-prescription drugs, vitamins, nutritional supplements, and herbal products taken must be reported to the doctor and pharmacist. For example, suppose the patient takes any of the following medicines; it should be reported to the doctor so that appropriate measures can be taken to adjust the dosage of the drugs to prevent any toxicity or side effects:

Diphenhydramine (antihistamine), Ciprofloxacin (antibiotic), Erythromycin, Benztropine, Cimetidine, Bupropion, Cyclobenzaprine, antihypertensive drugs, anti-anxiety drugs, drugs for other mental conditions, oral contraceptives, drugs for seizures, etc.

• If any of the close relatives or family members had suffered from prolonged QT interval (a rare cardiac condition that could result in irregular heartbeat, dizziness, or untimely death) or is suffering from diabetes, it must be immediately informed to the doctor. In addition, other health problems like urinary system problems, prostate problems, nausea, constipation, abdominal distension, high blood pressure, low blood pressure, liver diseases, kidney diseases, lung diseases, glaucoma (a set of eye disorders that affects vision), etc., should also be notified to the doctor.

• If a patient is pregnant, breastfeeding, or planning to become pregnant, they should inform their doctor immediately, especially if they are in the last few months of their pregnancy. If Clozapine is taken in the last months of pregnancy, it may have adverse effects on babies after birth.

• Drinking alcohol and smoking should be avoided while taking Clozapine because alcohol can add to the drowsiness caused by the drug, and smoking or tobacco consumption can reduce drug efficiency.

• Hyperglycemia may be experienced while taking Clozapine, even in nondiabetic patients. Therefore, if symptoms like increased thirst, frequent urination, increased appetite, weakness, lethargy, blurred vision, etc., are experienced, then the doctor must be immediately informed.

• It is crucial to inform the doctor as soon as certain symptoms are experienced because increased blood sugar levels can result in a severe condition known as ketoacidosis. If ketoacidosis is not treated right away, it could become life-threatening. Dry mouth, nausea, vomiting, shortness of breath, fruity-smelling breath, and diminished consciousness are all signs of ketoacidosis.

What Are the Side Effects Caused by Clozapine?

Clozapine can cause the following side effects:

• Drowsiness or sleepiness.

• Impaired balance and feeling dizzy.

• Headaches.

• Restlessness.

• Increased salivation.

• Dryness of mouth.

• Nausea and vomiting.

• Constipation.

• Stomach distension and swelling.

• Loss of bladder control.

• Fainting.

• Confusion.

• Muscle stiffness.

• Profuse sweating.

• Altered behavior.

• Unusual bleeding and bruising.

• Decreased appetite.

• Lack of energy.

Other adverse effects include:

• Agranulocytosis: Agranulocytosis can be defined as the reduced number of agranulocytes (neutrophils, basophils, and eosinophils) in the blood that increases the susceptibility to infections. Patients who take Clozapine have a one percent risk of developing agranulocytosis. Most cases require close monitoring of blood absolute neutrophil counts since they typically arise early in the course of treatment, between six weeks and six months.

• Myocarditis: Myocarditis can be defined as the inflammation or swelling of the heart muscles that can cause a reduction in the pumping of blood, shortness of breath, chest pain, irregular heartbeat, etc. Less than three percent of patients will experience Clozapine-induced myocarditis. However, the first four weeks of treatment are when patients experience this fatal, dose-independent side effect more frequently. Myocarditis symptoms in these patients can range from a flu-like illness to respiratory and cardiovascular problems.

• Metabolic Syndrome: A metabolic syndrome is a group of ailments that coexist and raise the risk of developing heart disease, stroke, and diabetes. Due to increased insulin resistance, Clozapine is linked to considerable weight gain, type 2 diabetes, diabetic ketoacidosis, and elevated lipid levels. However, it is crucial to note that metabolic syndrome development may also be influenced by other variables, such as a poor diet and a sedentary lifestyle.

• Seizures: The seizure threshold may be lowered by Clozapine in both epilepsy patients and normal subjects. The danger may be more common in younger individuals and is often dose-dependent, ranging from one to six percent.

• Pulmonary Embolism: Pulmonary embolism is the blockage of one of the pulmonary arteries due to a blood clot. Clozapine increases platelet adhesion and aggregation in a recent study that included several other antipsychotics. Pregnant women and older patients who are taking high doses appear to be at greater risk.

What Is Clozapine Toxicity?

• The degree of harm that the drug can do to an organism is referred to as Clozapine toxicity. Clozapine toxicity is dose-dependent, and it might affect the whole system.

• Clozapine is only accessible through a unique restricted distribution method due to the risks associated with using this medicine. Therefore, the Clozapine Risk Evaluation and Mitigation Strategies (REMS) Program was established by the Clozapine producers to ensure that users do not take the medication without the required monitoring.

• Clozapine can cause serious blood problems. Before starting treatment, throughout treatment, and for at least four weeks after treatment, the doctor will order specific lab tests. Once per week at the start, the doctor will order the lab tests; as the treatment progresses, the frequency of tests may decrease.

• The doctor should be immediately informed if the following symptoms are experienced- extreme fatigue, drowsiness, weakness, fever, chills, or other flu- or infection-related symptoms; abnormal vaginal discharge or vaginal itching; mouth and throat sores; delayed healing of wounds; burning or painful sensation while urinating; sores or discomfort in or around the rectum; stomach pain.

• Several dose-dependent side effects, like myocarditis, pulmonary embolism, metabolic syndrome, agranulocytosis, seizures, constipation, etc., may occur due to Clozapine toxicity or Clozapine overdose.

What Should Be Done in Case of Clozapine Toxicity?

Symptoms of Clozapine toxicity include; extreme drowsiness, fainting, slowed breathing, unconsciousness, altered breathing, etc. If these symptoms are experienced by an individual, then the emergency helpline should be immediately contacted. The patient must be immediately taken to the ER (emergency room), and medical aid should be given. If not treated on time, Clozapine toxicity can be fatal.

Conclusion:

Due to its numerous fatal side effects, many practitioners are reluctant to prescribe Clozapine for patient safety reasons. Agranulocytosis, a side effect of clozapine that necessitates stopping treatment and seeing a hematologist, is one of the biggest worries. However, there are several other effects of toxicity that require immediate treatment and management. In addition, Clozapine toxicity can be fatal if the symptoms are ignored and medical aid is not given promptly.