How Genetic Testing Influences ADHD Medication Response

How ADHD Medications Manage Symptoms

Some of the most used medications in the treatment of ADHD help manage symptoms by increasing the release and/or usage of two key substances (or neurotransmitters) in the brain known as dopamine and norepinephrine. These medications exert many of their effects in a brain region called the prefrontal cortex. The prefrontal cortex helps to regulate thoughts and actions that rely on adequate levels of norepinephrine and dopamine. When levels are inadequate (like in those with ADHD), notable symptoms are experienced. These may include impulsivity, difficulty maintaining attention, hyperactivity and poor working memory  [1]. It should be noted, however, that although most medications work in the manner described, each specific medication can have unique effects and can impact additional areas of the brain.

Why ADHD Medications Affect People Differently

ADHD medications affect people differently due to several reasons, which can be in
combination with one another. These can help answer common Google searches like "ADHD medication not working" or "ADHD medication side effects".

Factors that impact many types of medications, including those for ADHD, include reduced kidney and/or liver functioning which could potentially contribute to increased side effect risk. Medical history also plays an important role, as ADHD medications can negatively
impact those with certain conditions, including anxiety disorders, sleep disorders and
cardiovascular conditions. Those taking specific interacting medications at the same time could be predisposed to various effects, including decreasing the effects of the ADHD medication such that it is ineffective or increasing them to a level that increases side effects, increasing susceptibility to a type of serious whole-body reaction (serotonin syndrome) or increasing seizure risk. 

Furthermore, the severity of ADHD also plays a role, as those with greater symptom burden may require higher doses compared to those with milder symptoms. Women approaching menopause may also experience a worsening in underlying ADHD, changing the relative effectiveness of a treatment. In general, age plays a notable role, as effectiveness and side effect risks differ between children/adolescents and adults [2]. The impact of side effects differs as well. For example, reduced appetite and resultant weight loss may have a more serious impact in children than in adults. Age of diagnosis and subsequent treatment can have an impact in key areas of life (e.g., academic achievements, career successes) and play a role in the prevention of negative life events (e.g., fatal accidents, illicit drug use).

The role of genetics can also play a role, as common variations in a key gene responsible for metabolizing some notable medications (CYP2D6) could increase risk of side effects, and in the case of one medication, reduce the chance of experiencing benefit. 

These might be some of the reasons brought up by a health care provider to someone
asking, "why do I get Adderall XR side effects?".

How Genetics Influence ADHD Medication Response

Variations in the CYP2D6 gene are quite common, and the enzyme it codes for can be
significantly impacted by common genetic variations, with functioning ranging from poor to ultrarapid. In fact, nearly 5% of the global population is estimated to be in the lowest function category (poor metabolizers) because of the presence of certain genetic variants [3].

Certain changes in this enzyme's functioning can have an impact on how someone responds to a specific medication. In fact, amphetamine mixed salts (commonly referred to as Adderall XR) are eliminated from the body at a reduced rate in those with specific types of variants [4] . This potentially puts affected individuals at increased risk of side effects, particularly in those whose kidney function is also decreased. In the case of another prominent medication called atomoxetine or Strattera (usually used when medications like Adderall XR don't work out for someone), those with reduced genetically influenced metabolism are more likely to experience side effects (e.g., decreased appetite, vomiting, constipation, insomnia, drowsiness etc.) which can influence how dose changes could be more optimally made. On the other hand, those with overactive genetically determined functioning of the enzyme are less likely to experience benefit and may benefit from an alternative treatment (e.g., Adderall XR if comparing Adderall vs Strattera) [5]. A somewhat similar medication called viloxazine (also considered nonstimulant ADHD medication like atomoxetine) or Qelbree appears to also be impacted by poorly functioning versions of this enzyme, which can increase blood levels of the medication compared to those with better functioning metabolism. Research has yet to link this effect to changes in how an individual might respond to it, which can be a consideration for prescribers comparing options (e.g., Qelbree vs Strattera or Adderall XR) [6].

When to Consider Genetic Testing for ADHD Treatment

Inagene's pharmacogenetic testing for ADHD may be especially helpful for those that have experienced side effects to some of the medications mentioned, reduced effectiveness with atomoxetine, or are simply apprehensive about getting started on their treatment journey and want to better inform treatment choices from the start to help reduce trial-and-error.

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