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 22 nd 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 22 nd 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 158 thamino 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 22 nd 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.
* 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.
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.
From here we should be able to spot three trends:
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.