For anyone who has suffered multiple epileptic seizures, medications are usually the first line of treatment. There are many different drugs used to control epilepsy symptoms and prevent further episodes. The type of medication prescribed depends on many factors, such as the type of epilepsy and type of seizure, risk of side effects, as well as what other medical conditions and medications you may be taking. The risk of side effects varies from drug to drug and from person to person. Finding epilepsy treatment that leads to seizure remission without adverse effects can be challenging. Up to 30% of patients do not respond well to the anticonvulsants they try. Here we provide an overview of how your DNA can impact the metabolism of different antiepileptic drugs, AEDs for short, and the role of genetic testing in guiding personalized treatment to reduce medication side effects.

The role of liver enzymes in epilepsy treatment

Various liver enzymes, called cytochromes P450, play a key role in determining how quickly your body clears an antiepileptic drug. An incorrect AED dose can lead to excessive sleepiness, reduced concentration, “brain fog,” and gastrointestinal upset. By assessing genetic variations in specific liver enzymes using pharmacogenetic testing, you and your doctor can learn which of the AEDs are cleared too slowly, at a regular rate, or too fast. This information helps guide medication selection and dosage so that you get the right amount of the right drug to be effective for your body. This article examines the science behind how the primary genes involved in metabolizing AEDs, HLA, CYP2C9, CYP3A4, CYP2C19, UGT2B15, and UGT1A1, affect the way you respond to medications.

What medications are used to treat epilepsy?

It is critical to use the appropriate type of medication to match your condition and seizure type. Some medicines are prescribed to reduce the risk of seizures, while others are only given for acute status epilepticus (prolonged seizures). The table and information below describe how a pharmacogenetic test would guide AED prescribing decisions for a medical professional based on a person’s unique genetic makeup.

How your drug metabolism can guide epilepsy medication decisions

Dosage of phenytoin (Dilantin), divalproex (Depakote) and valproic acid should be adjusted according to variations in the CYP2C9 gene. People who are poor CYP2C9 metabolizers (slow enzyme activity) should not take divalproex, phenytoin or valproic acid due to the high risk of drug intolerance. Individuals with reduced activity of the CYP2C9 enzyme need a significant dose reduction to improve the tolerability of these medications.

Brivaracetam (Briviact) or lacosamide (Vimpat) are metabolized by the CYP2C19. Up to 10% are people in North America are poor CYP2C19 metabolizers and may need alternative treatment. In comparison, 18% of North Americans are rapid or ultrarapid CYP2C19 metabolizers and may not benefit from these drugs at standard doses.

Clonazepam (Klonopin) and lorazepam (Ativan) are recommended for treating acute status epilepticus but should not be prescribed for prolonged use. These drugs are administered intravenously in an intensive care setting with continuous EEG (electroencephalogram) monitoring. The CYP3A4 liver enzyme metabolizes clonazepam, and it can interact with many other medications. About 10% of people have inherently reduced the activity of this enzyme. The CYP3A4 enzyme also metabolizes topiramate and ethosuximide.

Lorazepam and lamotrigine (Lamictal) are metabolized by the UGT enzymes UGT2B15, UGT1A1 and UGT1A4, in which variations are very common. People with reduced UGT2B15 activity when taking standard lorazepam dose may experience excessive sleepiness and other side effects. Valproic acid is also known to increase lamotrigine blood levels as a side effect.  Therefore, dose adjustment might be needed taking into consideration both genetic variations and concurrently used medications.

Levetiracetam (Keppra) is one of few AEDs that is not dependent on liver metabolism and can be used in combination with other medications for epilepsy treatment without any problem.

Mismatched medications can be fatal

Negative side effects are the most common reason for stopping or skipping epilepsy medications. Severe adverse effects may occur if the drug is not compatible with your genetics. Insufficient epilepsy treatment and poor compliance can leave you, or your family members unprotected against seizures and at high risk of potential death or seizure-induced accidents. Pharmacogenetic tests like Pillcheck can help avoid adverse side effects and give individuals peace of mind on the right medications.

A recent report shows that people on a more aggressive treatment regimen, with three or more antiepileptic medications, have a three times lower risk of sudden death than people treated with one AED alone. Combinations including lamotrigine, valproic acid and levetiracetam were associated with a considerable reduction of this risk. Concurrent treatment with statins also reduced the risk of death, while antidepressants had no effect. While no one specific antiepileptic drug was associated with a higher risk than the others, poor adherence to treatment significantly raises the chance of seizure-related death. In general, the chance of side effects increases the more medications a person takes. Pharmacogenetic testing can be instrumental in guiding medication selection and tailoring medication dosage to reduce these risks and improve peace of mind with overall treatment.

Other genetic variations can affect risk of toxicity

Specific genetic variations in the HLA-A and HLA-B genes can affect the risk of skin toxicity, known as Stevens-Johnson syndrome (SJS). People with epilepsy, particularly of Asian descent, should be tested for the presence of variants in the HLA genes before starting antiepileptic medications to assess the risk of SJS. In Canada, provincial health systems cover specialized HLA testing when prescribed by your doctor.

Considerations for long-term epilepsy treatment

Topiramate and vigabatrin can lead to visual impairment, such as glaucoma and permanent bilateral visual field constriction (difficulty seeing from the side). People with a family history of glaucoma, cataracts and age-related macular degeneration (AMD) should avoid these medications. Specialized clinical diagnostic genetic tests (separate from pharmacogenetic testing) can assess your inherited risk of eye disease.

Cannabidiol as a new therapy

The FDA recently approved cannabidiol (CBD) to manage specific forms of epilepsy, Lennox-Gastaut and Dravet syndromes, under the EPIDIOLEX® brand name. Unlike consumer-grade CBD oils or gummy pills that you can buy without a prescription, EPIDIOLEX is a formulated version with exact dosing.

Although CBD has a wide dosage range, you should not add CBD for epilepsy treatment without consulting your doctor and pharmacist. CBD is metabolized by CYP3A4 and CYP2C19 and can interfere with the metabolism of brivaracetam, lacosamide, phenytoin, valproic acid, and other AEDs. The FDA drug label for EPIDIOLEX warns that the use of cannabidiol increases blood concentrations of some epileptic drugs. So, the use of CBD is not without consequence on a patient’s antiepileptic treatment.

The risk of potential drug-drug interactions should not be ignored. Studies show that cannabis users often need higher dosages of anesthesia to become sedated and stay unconscious. A recent study showed that cannabis users required more than a triple dose of propofol. CBD can impact response to most AEDs, significantly increasing the risk of severe side effects in people with epilepsy. It is best to consult an expert pharmacist if you are considering medical cannabis while taking other medications. Pillcheck can assist in assessing whether you can use cannabinoids safely.

Pharmacogenetic testing informs epilepsy treatment

Pharmacogenetic tests can assess the metabolism of multiple medications used for epilepsy treatment. Pillcheck is a leading pharmacogenetic medication optimization service that includes a precision pharmacogenetic test and a medication review by a clinical pharmacist. Pillcheck pharmacists will provide written recommendations for your doctor on safe AED drug selection and dosage ranges to help manage your epilepsy. The objective of Pillcheck is to help improve the management of your disease.

Summary

• Epilepsy medication should be matched to epilepsy type and your genetic profile
• Mismatched treatment can lead to undesired side effects and reduced compliance with treatment, which could be fatal
• HLA genes determine the risk of SJS, severe AED-induced skin toxicity. Ask your doctor if you are in a high-risk category
• Pharmacogenetic testing coupled with a pharmacist review of medications can provide insights into your metabolism of many drugs used for epilepsy treatment
• Knowing your inherited drug metabolic profile can help your doctor select appropriate drug doses and reduce side effects.

Selected references

Simona Balestrinia, and Sanjay M. Sisodiyaa, Pharmacogenomics in epilepsy Neurosci Lett. 2018 Feb 22; 667: 27–39.

Sveinsson O, et al., Pharmacologic treatment and SUDEP risk. A nationwide, population-based, case-control study Neurology; September 23, 2020.

EPIDIOLEX FDA drug label https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf

Muhammad A. Alsherbiny and Chun Guang Lii Medicinal Cannabis—Potential Drug Interactions Medicines (Basel). 2019 Mar; 6(1): 3.

Ortega-Vázquez A et al., Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy The Pharmacogenomics Journal volume 20, pages845–856(2020).