Genetics and ASD: How DNA testing can guide autism treatmentRuslan Dorfman, PhD, MBA
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that arises due to various genetic variations. Recent genomic studies identified the role of structural DNA changes in hundreds of genes conferring ASD risk. Although there are no medications that can cure the core symptoms of autism, medication may help address some of the behavioural problems, such as irritability, anxiety, depression and ADHD. Here we describe how genetic analysis can help to optimize autism treatment.
The American Academy of Pediatrics, in a recent clinical report on autism, recommends starting early behavioural autism therapy. Many children with ASD also end up taking medications that are used for managing irritability, ADHD and epilepsy. A 2015 review highlights the efficacy of various medications for autism treatment, but side effects can be concerning. If a child is going to take antipsychotic, ADHD or antiepileptic medications, you need to understand how his/her body is going to metabolize each drug.
Autism and medication response
Most drugs are metabolized by a group of liver enzymes called “cytochromes P450” or “CYPs”. Genetic variations can affect the activity of these liver enzymes. The level of specific enzyme’s function determines both the efficacy and side effects of different medications for the individual. Slower drug clearance increases the risk of side effects due to drug build up in the bloodstream. Faster metabolism reduces the drug’s blood concentration and effectiveness.
Pharmacogenetic testing shows the activity level of these liver enzymes and predicts how each individual person will respond to various medications. This enables a person to avoid medications and dosages that are likely to cause adverse side effects, or that may simply be ineffective based on his/her genetics. The Pillcheck pharmacogenetic testing service combines DNA analysis with an expert pharmacist review of medications to help find optimal autism treatment for each individual.
Risperidone (Risperdal) and aripiprazole (Abilify) are two FDA approved drugs for treating autism irritability. These Antipsychotic medications may help with aggression, self-harm, and behavioural problems in both children and adults with autism. Risperidone may cause some undesirable side effects. It affects hormonal balance and may lead to breast enlargement in teenage boys (gynecomastia). The use of antipsychotics can also worsen involuntary movements.
The CYP2D6 liver enzyme metabolizes both risperidone and aripiprazole. Other antipsychotic medications, such as clozapine and olanzapine, are also metabolized by this liver enzyme. Up to 50% of people in North America have altered CYP2D6 metabolism (either faster or slower than what is considered “normal”). For people with altered CYP2D6 metabolism, quetiapine might be tried as an alternative. It is metabolized by a different liver enzyme called CYP3A5. Drug response genetic tests can provide useful insights on autism treatment.
Benzodiazepines are used to treat anxiety and sleep disorders. They are also taken to manage outbursts of aggressive behaviours and irritability. However, chronic use of benzothiazepines is associated with the risk of dependence and excessive sleepiness. Clonazepam (Klonopin), lorazepam (Ativan) might be used for autism treatment but should not be prescribed for prolonged use. Clonazepam is metabolized by the CYP3A4 liver enzyme, and it can interact with many other medications. About 10% of people have inherently reduced the activity of this enzyme.
Lorazepam is cleared by a different enzyme called UGT2B15, in which variations are very common. People with reduced UGT2B15 activity experience excessive sleepiness and other side effects. A DNA test can provide actionable insights on how your child may respond to benzodiazepines.
Stimulants and ADHD medications
Methylphenidate (Ritalin) and atomoxetine are drugs generally used to treat ADHD. They may also help with other symptoms that often go together with autism, including hyperactivity, impulsivity and inattention. Clinical studies suggest that about half of children with autism benefit from stimulants, though some experience negative side effects such as sleep disruption. Although amphetamines are stimulants, they should not be used for ASD treatment due to significant impact on sleep. Atomoxetine does not impact sleep and can be used for adolescents with ASD when sleep disturbance is an issue.
Low-dose venlafaxine, which is an antidepressant of the SNRI class, could improve self-injurious behaviour and ADHD-like symptoms when combined with antipsychotic medication. The CYP2D6 liver enzyme metabolizes atomoxetine and venlafaxine. A DNA test can determine whether your child is a normal, slow or fast metabolizer of this medication.
While many people with autism take antidepressants, clinical studies provide mixed evidence on the impact of SSRIs (selective serotonin reuptake inhibitor) on autism symptoms. Still, they may be useful for treating obsessive-compulsive disorder, depression, and anxiety in ASD children. Sertraline (Zoloft) was shown to improve separation anxiety. Citalopram (Celexa) and fluoxetine (Prozac) might be prescribed to manage phobias and anxiety. SSRIs are generally metabolized by the CYP2C19 or the CYP2D6 liver enzyme. The CYP2D6 metabolizes fluoxetine, so it should not be used along with antipsychotics due to the high risk of drug-drug interactions.
Genetic studies show that up to 77% of people in North America have altered metabolism in one or both enzymes. DNA tests can provide insights on which antidepressants could be used for managing anxiety, depression and phobias as part of autism treatment. However, SSRIs have no positive impact on repetitive behaviours, and antipsychotics SSRIs can exacerbate uncontrolled repetitive movements.
Beta-blockers can be helpful in managing movement disorders, but these drugs will suppress melatonin production and therefore impact sleep. Melatonin supplementation can reduce sleep disruption for people taking beta-blockers. Metoprolol, nebivolol, timolol and propranolol are beta-blockers that are metabolized by the CYP2D6 enzyme. They should be used with caution when taken along with antipsychotics and antidepressants metabolized by this enzyme. People who are ultrarapid or slow CYP2D6 metabolizers should avoid these beta-blockers due to a significant risk of side effects.
Epilepsy is common in ASD children; antiepileptic medications might be needed. Phenytoin (Dilantin), divalproex (Depakote) and valproic acid are commonly-prescribed antiepileptic medications. The dosage of these drugs should be adjusted according to variations in the CYP2C9 gene. ASD children who are poor CYP2C9 metabolizers should not take divalproex, phenytoin or valproic acid due to the high risk of drug intolerance. These individuals might be treated with brivaracetam (Briviact) or lacosamide (Vimpat), which are metabolized by the CYP2C19. However, over 18% of people in North America are rapid or ultrarapid CYP2C19 metabolizers and may not respond to these drugs. Additionally, 10% are poor metabolizers and may need alternative treatment.
Antiepileptic drugs gabapentin, pregabalin and oxcarbazepine are not metabolized by liver enzymes and are instead eliminated by the kidneys. All antiepileptics may cause acute toxic shock known as Stevens-Johnson syndrome (SJS), which manifested as a severe skin reaction. Autistic children of Asian descent should be tested for the presence of variants in the HLA genes that determine immune response associated with SJS – before starting antiepileptic medications. Clonazepam is a benzodiazepine that can also be used for treating epilepsy in children that carry high-risk HLA alleles. Of note, Pillcheck does not include the HLA genes because this test is only relevant for specific ethnic groups and such a test is covered by provincial health systems in Canada.
The role of genetics in autism treatment with medication
- In children with autism and agitation, movement disorders might be drug-induced
- The risk of drug-induced side effects is linked to the liver enzymes responsible for drug metabolism.
- DNA testing can help to find which medications may help and to understand which autism treatment options can be used safely.
- Pillcheck is a quick and easy pharmacogenetic test that reports on a variety of medications. It covers many medications used for autism treatment, including antipsychotics, ADHD drugs, antidepressants, antiepileptics, benzodiazepines and beta-blockers, and assists physicians in selecting optimal drug and dose for your child.
- LeClerc S and Easley D, Pharmacological Therapies for Autism Spectrum Disorder: A Review P T. 2015 Jun;40(6):389-97.Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespanPharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan
- Brigham and Women’s Hospital. (2012, September 28). Making headway on beta-blockers and sleep. ScienceDaily.
- Doyle, CA, Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan Dialogues Clin Neurosci. 2012 Sep; 14(3): 263–279.