How Genes Influence Clozapine Allergy?

What Is Clozapine?

Clozapine is an atypical antipsychotic drug used for treatment-resistant schizophrenia and reduces the risk of suicide.

It is preferred when other drugs are ineffective in treating schizophrenia.

Clozapine is a benzisoxazole derivative and can be taken with or without food.

It is available as a tablet, oral suspension, and orally disintegrating tablet.

Clozapine is metabolized in the liver, and over 50% of the administered dose is eliminated via the urine.

Is Clozapine a Controlled Substance?

Since clozapine is a controlled substance, it is available at a pharmacy only with a doctor’s prescription.

What Is Clozapine Used For?

Clozapine is the drug of choice for treating schizophrenia that has not responded to other medications.

Schizophrenia is a mental illness characterized by unusual or disturbed thinking, strong emotions, and a strong tendency to suicide.

How Does Clozapine Work?

Clozapine is a second-generation antipsychotic that helps reduce hallucinations and delusions common in schizophrenia.

The primary mechanism of action of clozapine is to change the activity of neurotransmitters (chemicals in the brain).

Clozapine acts as an antagonist (opposes the action) of dopamine and serotonin (neurotransmitters).

Clozapine has a greater affinity to dopamine D4 than the D2 receptor.

When it binds to the receptor, it results in the antipsychotic effects of the drug.

Is Clozapine Good For Anxiety?

A study published in the Nordic Journal of Psychiatry stated that clozapine helps manage symptoms like intense anxiety and aggressive behavior in some patients with schizophrenia.

Side Effects Of Clozapine

Despite clozapine’s safety profile, it may cause side effects in some individuals.

Some side effects of clozapine are:

Dizziness
Feeling unsteady or having trouble keeping balance
Drowsiness
Dry mouth
Restlessness
Headache
Increased salivation

Contact your doctor if any of the symptoms mentioned above become severe or do not go away in a few days.

Some severe side effects of clozapine that need immediate medical attention include

Uncontrollable shaking of hands
Confusion
Tendency to fall
Severe muscle stiffness
Vision changes
Behavioral changes
Stomach upset, nausea, constipation, pain
Unusual bleeding and bruising
Lack of energy
Appetite loss
Jaundice (yellowing of eyes, skin)

Some people may be allergic to clozapine. Signs of an allergy to the drug include:

Hives
Difficulty in breathing
Swelling of the face and throat
Burning eyes
Blistering and peeling of the skin

Does Clozapine Cause Constipation?

Around 30% to 60% of people on clozapine experience constipation as a side effect.

Clozapine is a known anticholinergic drug that reduces the motility of the gut.

Decreased gut (especially colonic) motility results in clozapine-induced constipation in some people.

In people who experience constipation by taking clozapine, doctors prescribe laxatives.

How Does Clozapine Affect Lifespan?

The rate of mortality is high in people who have schizophrenia.

Antipsychotics like clozapine have been linked to life-threatening conditions like agranulocytosis (deficiency of a type of immune cells in the blood).

However, studies have shown that patients taking clozapine showed lower mortality rates than those taking other antipsychotics and no psychotics.

Does Clozapine Cause Memory Loss?

A study conducted in rats stated that clozapine might cause cognitive impairment and memory loss in subjects without hippocampal lesions, but no memory impairment was observed in rats with hippocampal malfunction (as seen in schizophrenia).

Clozapine’s effect on memory and cognition is sex-related, and the effects were found to be different in male and female rats.

Clozapine: Interactions With Other Drugs

Drug interactions may cause adverse reactions and reduce the efficacy of one or both drugs.

It is, therefore, important to give a detailed medication history to your doctor before taking clozapine.

Some drugs that have major or significant interaction with clozapine are

Clonazepam (Klonopin)

Clonazepam is an anticonvulsant used to treat seizures, panic disorder, anxiety, and akathisia (a movement disorder).

Taking clozapine with clonazepam may increase side effects like dizziness, confusion, and drowsiness.

Elderly individuals may experience increased impaired thinking, judgment, or motor coordination on taking these two drugs together.

Alprazolam (Xanax)

Xanax or alprazolam is used to treat panic disorders and anxiety.

Taking Xanax with clozapine may increase the side effects of both drugs.

Depending upon the administration routes of both the drugs, some people may experience symptoms like extreme drowsiness, shallow breathing, weak pulse, confusion, and poor muscle coordination.

Lorazepam (Ativan)

Lorazepam is a benzodiazepine drug used to treat anxiety.

Taking lorazepam with clozapine may increase the side effects of both drugs.

Can You Be Allergic To Clozapine?

Some people may be allergic to clozapine.

If you are allergic to clozapine, avoid taking the medication.

If you experience any of the following signs and symptoms of clozapine allergy, report to your doctor immediately:

Breathing difficulty
Hives
Facial or throat swelling
Severe skin disorder characterized by fever, sore throat, bruising or blistering of the skin, red or purple skin rash, and skin pain.

Genetics Of Clozapine Allergy

ABCB1 Gene and Clozapine Allergy

rs1045642 is a single nucleotide polymorphism or SNP located on the ABCB1 gene.

People with the AA genotype may have greater plasma concentrations of clozapine and a greater risk of developing clozapine-induced agranulocytosis than those with the AG and GG genotypes.

Another study stated that the ABCB1 3435TT genotype was more frequent in people having clozapine-induced agranulocytosis than the 3435CC genotype.

HLA-DQB1 Gene and Clozapine Allergy

rs113332494 is an SNP in the HLA-DQB1 gene.

People with the G allele may have a greater risk of developing agranulocytosis and neutropenia than those with the C allele.

SLCO1B3-SLCO1B7 and Clozapine Allergy

rs149104283 is an SNP in the SLCO1B3-SLCO1B7 gene.

Individuals with schizophrenia having the TT genotype may have a greater risk of clozapine-induced neutropenia than those with the CT or CC genotypes.

Gene	SNP	Risk Allele	Effect
ABCB1	rs1045642	A	Increased risk for clozapine allergy
HLA-DQB1	rs113332494	G	Increased risk for clozapine allergy
SLCO1B3-SLCO1B7	rs149104283	T	Increased risk for clozapine allergy

Analyze Your Genetic Response to Clozapine

Recommendations To Use Clozapine

Diet

Limit your caffeine intake while taking clozapine, as it can reduce the drug's metabolism.

You can take clozapine with or without food as its absorption is unaffected by food.

Avoid alcohol consumption while taking clozapine.

St. John's Wort is a herb that induces CYP3A4 and CYP1A2 enzymes, reducing clozapine levels.

Pregnancy and Lactation

Inform your doctor if you are pregnant, planning to get pregnant, or lactating.

Clozapine is contraindicated in pregnant women as it may cause developmental defects in the fetus.

Clozapine enters breast milk and increases the risk for agranulocytosis in the infant.

Current Medications

Clozapine may interact with several drugs, herbs, and supplements.

Therefore, it is crucial to inform your doctor about your current medications and drugs.

Medical History

Inform your doctor about any medication conditions you may have.

Clozapine is contraindicated in conditions like agranulocytosis, myocarditis, metabolic syndrome, seizures, dementia, and orthostatic hypotension.

Summary

Clozapine is a second-generation antipsychotic drug used to treat resistant schizophrenia.
Since clozapine is a controlled substance, it is available only with a doctor’s prescription.
Clozapine works on various receptors in the brain to alter the production of neurotransmitters.
Clozapine opposes the effects of dopamine and serotonin, resulting in the effects of the drug.
Clozapine may cause side effects like dizziness, drowsiness, headache, and restlessness in some individuals.
In some studies conducted on rats, clozapine was found to cause cognitive impairment and memory loss.
Inform your doctor about all medications and supplements you are taking to avoid adverse drug interactions.
Some genes like ABCB1, HLA-DQB1, and SLCO13-SLCO1B7 are associated with clozapine allergy.
Inform your doctor if you are pregnant, plan to conceive, or breastfeed before taking clozapine.
Eat a healthy diet, and avoid caffeine and alcohol while taking clozapine.

References

A Sneak Peek Into The Gene Allergy Report

Get Insights On Common Allergies From Your 23andMe, AncestryDNA Raw Data!