ADHD Genes Influence Medication Dosage

This blog originally began by exploring seven different genes that were thought to be tied to ADHD. However, there is another gene of interest, that was not on that list, which is also believed to be a key factor in how much of a stimulant medication is needed for treating a person with ADHD. The gene in question is referred to as COMT, which is short for Catechol O-Methyltransferase. COMT "codes" for an important enzyme by the same name in humans, the Catechol O-Methyltransferase protein.

The COMT gene is located on the 22nd human chromosome in the q11 region (don't worry too much about the exact location, "q11" simply refers to a more detailed location on the 22nd chromosome. Keep in mind that the COMT is just one of the 30,000 to 50,000 plus genes, which are spread out over 23 pairs of chromosomes in humans. The point here is simply that one slight change to one gene can have profound effects on the way the body handles stimulant drugs such as amphetamines).

It is interesting to note that this genetic region has also been tied to other disorders which either occur alongside of ADHD (that is they are comorbid to ADHD) or have some symptom overlap with the disorder. These include schizophrenia, bipolar disorders, and even panic disorders. Additionally, there have been studies which tied in this genetic region to eating disorders including anorexia.

Like many proteins (enzymes are a specific class of proteins), the COMT enzyme can exist in several different forms in the human population. In one segment of the enzyme (the 158th amino acid from the end), an individual can either have the amino acid valine (often abbreviated as "Val" or simply "V") present or the amino acid methionine (also abbreviated "Met" or "M")present. In humans of European background, only about 15-20% carry the Met form of the COMT gene in both copies of their 22nd chromosome.

However, the minority of individuals who do carry this rarer "Met" form in both chromosomes generally require smaller doses of stimulants such as amphetamines for regulating ADHD symptoms. A brief explanation follows below:

Blogger's note: the majority of this information comes from a 2003 publication in the journal PNAS (Procedings of the National Academy of Sciences) in the USA by Mattay and Coworkers. A copy of this article may be found here. Please keep in mind that the description below is a simplified version of what is in the original article. If you have a scientific or medical background, I encourage you to follow the link above and check out the original article. Otherwise, the descriptions below give a fairly good overview of the content of the article.

• Individuals with ADHD often have lower free levels* of the important brain signaling agent dopamine (see region #1 in the figure below) in a region near the front of their brains called the prefronal cortex (PFC). However, evidence has also shown that if dopamine levels are too high (region #3 in the figure), then problems can occur also. It is hypothesized that free dopamine levels in the prefrontal cortex follow a sort of upside-down "U"-shaped curve. For maximum effectiveness via medications or other treatment options, you want to be at the highest point on the curve (region #2 in the figure). Please refer to the illustration below:
  

* Please note: "free levels" here refers to levels of the brain chemical dopamine that are not taken up by neuron cells. Dopamine can be shuttled in and out of the cells from the area outside the cells. For individuals with ADHD, the amount of dopamine outside of the cells in this "free" space is often lower than in other individuals. Many ADHD stimulant medications (such as amphetamines) counteract this effect by reducing the transport of dopamine into the surrounding cells, or even reversing the process. This artificially boosts dopamine concentrations outside the cells and offsets some of the negative chemical effects of ADHD or related disorders.

• Based on the hypothetical upside-down "U" curve above, most individuals with ADHD would naturally fall somewhere around region 1, that is, the amounts of free dopamine (see *'ed section above for explanation on this) are below the optimal level. In other cases, free dopamine levels can be too high (region 3 above), and can lead to anxiety, depression, or even schizophrenia-related symptoms.


• The enzyme COMT mentioned above is responsible for breaking down free dopamine between neuron cells by converting it to another compound (called 3-methoxytyramine. The exact process of this is beyond the scope of this post, just remember that COMT enzyme functionally lowers the levels of free dopamine in between neuronal cells by converting it to the 3-methoxytyramine).

• Additionally, it appears that the "Val" form of the enzyme mentioned above, is approximately 3 times more active than the "Met" form of the enzyme. As a result, more dopamine is typically converted to the 3-methoxytyramine product mentioned above for individuals who have the "Val " form of the gene. Therefore, individuals who have the "Met" form of the enzyme COMT often have higher baseline levels of free dopamine in the front brain region than do those with the "Val" form of the COMT enzyme.
  

To help visualize this, in the case of the graph below, individuals with the "Met" form of the COMT enzyme would be closer to region 2 (optimal dopamine-based function in the PFC region of the brain) than do individuals with the "Val" form (who would be closer to region 1 in the graph below).

• This prefrontal cortex region of the brain is an important region of the brain to analyze for individuals with ADHD, because it is responsible for areas of cognitive function such as working memory (i.e. not simply "memorizing" facts, but being able to retrieve and utilize them). This is a function of higher level thinking, and is typically much more taxing in individuals with ADHD and related disorders.


• A well-known task used as a diagnostic tool for disorders involving the prefrontal cortex region is called the Wisconsin Card Sorting Test, which measures the learning process of matching specific cards based on common features (for more information on the Wisconsin Card Sorting Test, please click here). Studies have shown that different forms of COMT genes (the "Met" and "Val" forms described above) can affect performance on this test.
  
• Based on results from Mattay and coworkers, it appears that individuals who had copies of the Met form of the COMT gene in both pairs of their 22nd chromosomes did significantly better on the Wisconsin Card Sorting Test (which suggests a better, more efficient functioning in the PFC brain region with regards to working memory) than did individuals who possessed the Val form of the COMT gene for both chromosomes. However, after treatment with amphetamines, individuals with the Val forms of the gene significantly improved on the test, while individuals with the Met forms of the gene did noticeably worse. Therefore, we see that treatment with amphetamine stimulant medications can boost cognitive function for one type of the COMT gene, while the same (relatively low amount) can significantly reduce cognitive performance efficiency with another form of the same gene.

• Interestingly, based on animal model studies, it appears that tasks which require the use of the working memory listed above is connected to a boost free dopamine levels in the prefrontal cortex region of the brain to a certain degree. It is unclear as to whether this holds across the board, but it at least suggests the possibility that an organized "brain workout" program which regularly challenges the brain by utilizing the working memory may be a potential powerful supplement to treatment with stimulant medications for treating ADHD. This appears to be a wide-open topic of future study. Regardless of whether this previous hypothesis holds true, the working memory vs. dopamine connection will be a key factor which we will see later in this post.
  
• As mentioned above, stimulant medications such as amphetamines Adderall, Dexedrine, and Vyvanse (once metabolized), can cause a boost in signaling via increased free dopamine levels between neuron cells. Returning to our hypothetical upside-down "U" curve for a moment, we can see that proper amphetamine dosage may push an individual to the optimal (read "most efficient") dopamine-based signaling in the PFC region of the brain for an ADHD patient:

As we can see above, treatment with amphetamines (AMP) can shift the dopamine-based signaling process in this prefrontal cortex region of the brain. Note that if the drug dosing is too high ("Met high AMP" arrow), we can "over-correct" the level of peak functioning of the Prefrontal Cortex (PFC) region in the brain, which is thought to worsen the severity of symptoms for ADHD and related disorders. In this particular case above, the low Amphetamine dose was close to perfect for individuals with the "Met" form of the COMT gene, whereas higher doses of amphetamine were preferable for those with the "Val" form of the COMT gene.

This can result in a paradox for treatment via stimulant medications, that is too much stimulant medication can often result in similar effects as those caused by too little. For a further explanation of this, please check out Dr. Charles Parker's blog entry on the therapeutic window of stimulant medications. Unfortunately, given the similarity of symptoms, prescribing physicians sometimes make the mistake of thinking that they are under-dosing when they are really overdosing. The results of this may lead the patient even further away from the "optimized" region of PFC function, and actually, and unknowingly worsen their ADHD symptoms.

• Before going any further, I need to clarify a bit with regards as to what constitutes "optimum" PFC function. As mentioned, the PFC or Prefrontal Cortex region of the brain is thought to be involved with the disorder ADHD. As I've mentioned earlier, individuals with ADHD often have lower-than-normal levels of dopamine, as well as norepinephrine (which is a chemical cousin to adrenaline) which are both key agents for signaling throughout the nervous system. Given the fact that this brain region has a relatively low number of dopamine transporter proteins, the COMT enzyme's level of activity becomes even more significant, since it has fewer proteins to "compete" with to regulate free dopamine levels. For other signaling agents such as norepinephrine, there are more of these transporter proteins available, so these become much less of a factor with regards to ADHD and related disorders. As a result, it appears that when we want to address and regulate signaling in the prefrontal cortex region of the brain, dopamine is the main agent of concern.
  
• If an individual is at a non-optimal PFC function level (either to the left or the right of the "peak" of the upside-down U curve, their performance on cognitive tasks such as working memory becomes much less efficient and much more difficult. As a result, tasks such as recalling and using the memory function for a higher level task can become extremely taxing to both an untreated individual with ADHD (who are often "left" of optimal) on the curve or depression or anxiety-related disorders (who sometimes fall to the "right" of optimal) on the upside-down U curve. Either way, their brains must work harder than an average person's to accomplish the desired task.

• However, various treatment options such as nutritional approaches or medications can lead either of these two individuals to closer to optimal PFC levels (that is closer to the top or "peak" of the upside-down U curve shown above). However, over-compensating via over-medication or other means can push an individual back down the "U"-curve away from optimal brain function.
  
• The level of exertion or difficulty in this region of the brain can actually be measured by advanced processes such as fMRI (which stands for Functional Magnetic Resonance Imaging). A form of fMRI called BOLD fMRI (BOLD stands for "Blood Oxygen Level Dependent") can detect via imaging processes changes in the amount of oxygen required of neurons in a certain brain region to perform a given task.
  
• If the PFC region in the brain is at sub-optimal function (less efficient), then a greater degree of exertion in that region in the brain is required to carry out a task, and a greater oxygen requirement is needed. This greater demand shows up on the BOLD fMRI. However, if the PFC region of the brain is pushed towards a more optimal level (closer to the top of the upside-down U curve), then this brain region is more efficient and requires less oxygen to perform the same task.

• As a result, BOLD fMRI can be used to determine how medications or other external stimuli can influence brain function and efficiency.
  
• Continuing on with the study on the COMT gene variations, we must also investigate the effects that cognitive tasks such as working memory, when combined with medication effects, have on the efficiency of the Prefrontal Cortex (PFC) region of the brain. Here's another example using our favorite upside-down-U-curve, for a hypothetical individual with ADHD. We will see some of the potential outcomes when three factors are all combined: Genetics (the "Met" or the "Val" form of the COMT gene), Amphetamine dosage levels (high AMP or low AMP) and Cognitive challenge via working memory (WM) tasks:

From here we should be able to spot three trends:

1. Due to the fact that their overall activity of the COMT enzyme is lower (which leads to less conversion of dopamine to the 3-methoxytyramine and higher free levels of dopamine in the region between neuronal cells in the PFC region of the brain) , individuals with the "Met" form of the COMT gene are closer to the optimal efficiency in the brain's PFC region. This often reduces the severity of ADHD symptoms when cognitive tasks are required.
2. The use of stimulant medications such as amphetamines can also boost the dopamine-based signaling to closer-to-optimal levels up to a point. For individuals with the Met form of the gene, low levels of amphetamine (low AMP), and a working memory task (+WM), the balance was at the top of the curve, and at optimal function for the PFC brain region. However, excessive medication can cause an individual to slide back down the other side of the "mountain", as seen in the figure above for the individual with the "Met" form of the gene and high levels of amphetamine (AMP) treatment for a cognitive task involving working memory (WM).
3. We see that utilizing cognitive tasks such as working memory can also push an individual to the right of the curve listed above. In fact, as tasks become more mentally challenging, the individual may continue to move further and further to the right on the curve. Therefore, if faced with a relatively easy working memory task, an individual may operate at near-peak PFC function (i.e. near the top of the curve), but for higher-level working memory challenges, this same individual will begin to fall down the right side of the curve, away from optimal function.

This should raise several issues, which prescribing physicians often face. Do we want to medicate more for behavioral related issues, or for improving cognitive performance? This becomes a serious problems, as incongruencies are often seen between parent and teacher evaluations for the same individual. Given the fact that cognitive tasks such as working memory are more utilized in certain subjects such as mathematics, logic and physical sciences, we can see the effects of too little or too much medication (as well as specific gene forms such as "Met" or "Val" for the COMT gene) can have on an individual.

By no means are these results or observations quantitative. In other words, you can't simply plug in an individual's gene form ("Met" or "Val" for the COMT gene), and level of difficulty of upcoming cognitive tasks into an equation to find out the perfect level of stimulant medication required to achieve optimum performance in the PFC region of the brain. However, the take-home message is this: clearly there is an intersection of genetics, medication dosage effects and degree of cognitive challenge which must be optimized for peak mental function. These must all be considered as relevant factors when attempting to treat an individual with ADHD.