The Role of Genetics in Anticonvulsant and Antipsychotic Treatment

Understanding Anticonvulsant and Antipsychotic Medication Efficacy with PGx Testing

Anticonvulsants and antipsychotics are crucial medications used to manage conditions such as epilepsy, bipolar disorder, and schizophrenia, prescribed by Mental Health Professionals. However, like many medications, their effectiveness and side effect profiles can vary widely from person to person. Emerging research suggests that genetics plays a significant role in determining how well these medications work and how likely patients are to experience side effects. Understanding these genetic factors via PGx testing can help personalise treatment, making it more effective and safer for patients.

 

An Overview of Anticonvulsants and Antipsychotics

Anticonvulsants are primarily used to control seizures in epilepsy but are also prescribed for mood stabilisation in bipolar disorder. Common anticonvulsants include Carbamazepine, Valproate, Lamotrigine, and Phenytoin.

Antipsychotics are used to manage symptoms of psychosis, including delusions, hallucinations, and severe mood disturbances, commonly associated with conditions like schizophrenia and bipolar disorder. These drugs include Risperidone, Clozapine, Olanzapine, and Quetiapine.

 

How Genetics Influence Response to Anticonvulsants

Genetic variations can significantly impact how patients absorb, distribute and metabolise anticonvulsants and therefore how effective these drugs are in controlling seizures or stabilising mood. Here are some key genes that have been identified:

CYP2C9 and CYP2C19 Genes:

These genes encode enzymes that are critical in the metabolism of several anticonvulsants, including Phenytoin and Valproate. Variants in these genes can affect the speed at which these drugs are metabolised:

CYP2C9:
Variations in this gene can lead to slower metabolism of Phenytoin, increasing the risk of toxicity. Patients with certain CYP2C9 variants may require lower doses to avoid side effects such as dizziness, unsteadiness, and in severe cases, drug-induced toxicity.

CYP2C19:
This gene is involved in the metabolism of Phenytoin and Clobazam. Poor metabolisers with certain CYP2C19 variants may experience higher drug levels, leading to an increased risk of side effects, while ultrarapid metabolisers may require higher doses to achieve therapeutic effects.

HLA-B*1502 Gene:

This gene is particularly important in patients of Asian descent who are prescribed Carbamazepine. The presence of the HLA-B1502 allele is strongly associated with a significantly increased risk of developing Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), both of which are severe and potentially life-threatening skin reactions. As a result, genetic testing for HLA-B1502 is recommended before starting Carbamazepine in patients with Asian ancestry.

SCN1A Gene:

The SCN1A gene encodes a sodium channel that is crucial for neuronal function. Variants in this gene can affect the efficacy of sodium channel-blocking anticonvulsants such as Lamotrigine and Carbamazepine. Patients with certain SCN1A variants may not respond as well to these medications and may require alternative treatment options.

 

How Genetics Influence Response to Antipsychotics

Antipsychotics are also subject to genetic influences that can affect their efficacy and side effect profiles. Some of the key genes involved include:

CYP2D6 and CYP3A4 Genes:

These genes encode enzymes that metabolise many antipsychotic drugs, including Risperidone, Haloperidol, and Aripiprazole.

CYP2D6:
Variations in CYP2D6 can lead to differences in how quickly these drugs are metabolised. Poor metabolisers may have higher drug levels and are more prone to side effects such as weight gain, sedation, and movement disorders. Ultrarapid metabolisers may require higher doses to achieve the desired therapeutic effects.

CYP3A4:
This enzyme also plays a role in metabolising antipsychotics such as Quetiapine and Clozapine. Variations in CYP3A4 can lead to differences in drug levels, affecting both efficacy and the risk of side effects.

DRD2 Gene:

The DRD2 gene encodes the D2 dopamine receptor, which is the primary target of many antipsychotics. Variations in this gene can influence how well a patient responds to antipsychotics. For example, certain DRD2 variants have been associated with a better response to drugs like Risperidone and Olanzapine, while others may be linked to a higher risk of side effects such as weight gain or movement disorders.

HLA-DQB1 and HLA-B*1502 Genes:

HLA-DQB1:
This gene has been associated with an increased risk of Clozapine-induced agranulocytosis, a serious condition where the white blood cell count drops dangerously low, leading to a higher risk of infection.

HLA-B*1502:
Similar to its role in anticonvulsant therapy, this gene is also relevant in antipsychotic treatment. Although less common, there are cases where Carbamazepine, when used as a mood stabiliser in bipolar disorder, can cause severe skin reactions in individuals with the HLA-B*1502 variant.

 

The Impact of Genetic Testing in the UK

In the UK, the use of pharmacogenetic testing is gradually increasing, particularly for medications with known genetic risk factors. Testing for genes like CYP2C9, CYP2D6, and HLA-B*1502 is becoming more common, especially in cases where patients have experienced adverse reactions to medications or where there is a high risk of severe side effects.

 

What This Means for Doctors

Understanding how your patient’s genetics can influence their response to anticonvulsants and antipsychotics can help you prescribe the most appropriate medication and dosage.This personalised approach can reduce the likelihood of side effects and improve the effectiveness of your treatment, potentially leading to better overall outcomes.

If you’re considering genetic testing or want to learn more about how PGx testing can improve your patient’s outcomes, please fill in the quote form here and we'll be right in touch.