Drugs, Genes and ADHD

The Effects Specific "ADHD Genes" Have on Dosing ADHD Medications:

Below is a list of five of the most common medications for ADHD. In order to break down or metabolize these drugs, however, a series of steps must take place for effective absorption, delivery and clearance of these drugs. This process, however, requires a series of enzymatic steps. Generally, when a physician prescribes these drugs, he or she considers factors such as the patient's age, gender, symptom severity and past medication history. However, lost in the shuffle is a lesser-known, but often equally critical factor: the particular genes of the individual. It is these genes which play a large role as to how well these enzymes function (alongside other factors such as the person's nutritional status, as most vitamins and minerals act as chemical "helpers" to these enzymes, and deficiencies can lead to lower enzyme function and sub-optimal metabolic efficiency).

Unfortunately for prescribing physicians, the landscape of enzyme capabilities among the general population is far from uniform. Some individuals naturally possess enzymes or enzyme systems (which are coded for and dependent on the genetic makeup of the particular individual)which are more efficient than others (often by multi fold differences). If these enzymes are essential to drug metabolism (including ADHD medications), then a potentially crucial piece of information may be missing from the physician's repertoire of assessment tools for medicating at the proper dosage.

Much to the dismay of many a frustrated parent of an ADHD child, this often begins the laborious process of adjusting medication dosages through a glorified "guess and check" process. However, due to the need for a relatively small window of effective dosing (especially for psychotropic drugs such as those prescribed for ADHD and related disorders) and unforgiving margins of error in the optimization process, bits of information, such as a child's genetically-dictated levels of drug-metabolizing enzymes could be extremely useful. With the increasing efficiency, lowering costs of and wider availability of genetic screening methods, we may soon be able to predict a child's enzyme levels by their genetic makeup and facilitate the dosing of (and eliminating much of the guess-work from) their medications for ADHD or other disorders, saving both time and money while on the medication circuit.

Given the powerful role of enzymes and enzyme systems (and the specific genes which encode for them) for the delivery, metabolism and clearance of these medications, we should take a look at some of the genetic variations of these enzymes and the implications they may having in assisting the diagnosing physician in the near future for more effectively dosing ADHD medications.

Here are 5 common ADHD drugs (including one which is not prescribed but often used as a "self-medication" tool among the ADHD population), and the genetically-dictated enzymes which can play a role in their metabolism and dosing patterns and levels.

ADHD Drug #1: Strattera (Atomoxetine)

Key enzymes involved and gene of interest: SLC6A2, CYP2D6

We have already investigated another gene believed to have an impact on dosing with Strattera, the SLC6A2 gene. However, in that earlier post, we alluded to another gene responsible for the metabolism of the non-stimulant ADHD drug Atomoxetine. This gene is called CYP2D6. The CYP2D6 gene codes for an important enzyme of the same name (which is an important enzyme produced in the liver). The gene is located on the 22nd human chromosome (the 22q13.1 genetic region to be more specific if you are familiar with genetic markers).

Approximately a dozen different genetic forms (or alleles) of this CYP2D6 gene are seen in individuals of European ancestry. These forms are often designated by a star followed by a number, such as *1 or *4. While these numbers are used for naming purposes, it is worth noting that most individuals of European descent appear to carry either the *1 (the most common), the *2 or the *4 form of this gene. Additionally, *3, *6, and *10 forms are each found in about 1-2 percent of the population.

Interestingly, the *10 form of this gene is found in higher levels in individuals of East-Asian descent. A Chinese study found that a higher frequency of this *10 form in the population (the *10 form shows up in over half of the Chinese population, about 10 times more frequently than in whites), resulted in slower rate of drug metabolism of the ADHD medication Strattera (Atomoxetine) by the CYP2D6 enzyme.

Relevance of the CYP2D6 gene to medicating ADHD with Strattera: The *10 form of the CYP2D6 produces less enzymatic activity than the most common *1 form. This can result in about a 50% increase in Atomoxetine concentration in the blood and duration before clearance, which was seen in the Chinese study. As a result, for individuals with the exclusive *10 form (such as seen in much of the East Asian population), slightly lower or less frequent dosing levels of atomoxetine might be needed to get the same therapeutic effects. This is in agreement with another study suggesting a 50 to 75% dosage reduction of Atomoxetine for those with hepatic impairment (liver dysfunction), as the CYP2D6 enzyme is produced in the liver.

Additionally, this population may be at a slightly greater risk of side effects with the drug due to a slower clearance and greater buildup of the drug. Of course other genes and additional factors in the Atomoxetine pathway certainly play a role, but these genetic variations can still play a significant role in medication dosing strategies.

ADHD drug #2: Adderall (Mixed amphetamine salts)

Genes of interest: Catechol O-Methyltransferase (COMT) gene, Dopamine Transporter Gene (DAT)

In previous posts, we have spoken extensively about a gene called COMT, short for Catechol O-Methyltransferase and its role on dosing for amphetamine-related ADHD medications such as Adderall and Vyvanse. This previous discsussion on COMT and ADHD medication dosing can be found here.

However, there are a few other genes worth noting here for their potential roles in dosing with amphetamine-based ADHD medications such as Adderall. One of these is the Dopamine Transporter gene (DAT), which is located on the 5th human chromosome. This gene also goes by other names such as DAT1 or SLC6A3. The DAT gene codes for an important protein called the Dopamine Transporter protein, which is responsible for shuttling the important brain chemical dopamine in and out of neuronal cells.

A number of stimulant drugs used to treat ADHD and related disorders work, at least in part, by interacting with this dopamine transporter (DAT) to correct a dopamine imbalance (in general, individuals with ADHD often have too little dopamine in the regions between brain cells or neurons in key regions of the brain. Many stimulant ADHD drugs remedy this by blocking the shuttling of dopamine back into the cells, keeping adequate amounts in these "gaps").

Interestingly, on a side note, the DAT gene has been implicated (in conjunction with another dopamine-related gene called DRD4) in IQ levels an behavior problems.

Like the genes mentioned above, DAT exists in a wide number of different forms across the human gene pool. Some forms appear to increase ones predisposition to ADHD and various neurophysiological or behavioral disorders and have earned the moniker "high risk alleles" (remember, an "allele" is simply a specific form of a gene which varies within the population).

A study on families of ADHD children found that a specific form of the DAT gene which included a 480 base pair repeat (simply a repeating section of DNA which is 480 DNA "letters" long) allele was associated with greater severity of ADHD symptoms, especially in the combined ADHD subtype (which includes high levels of both inattentive and hyperactive/impulsive symptoms as opposed to a predominance of one).

Potentially, individuals with ADHD who carry this "high-risk allele" of the DAT gene (which is a substantial portion of the general population) may require slightly higher levels of medication dosage with amphetamine-based stimulants than their "lower-risk" counterparts. These differences may be even more pronounced if the individual carries the "Val" form of the COMT gene, mentioned in a previous post (given the current body of research on the subject, the contributions of the COMT gene dwarf those of the DAT gene with regards to governing amphetamine dosage levels).

ADHD drug #3 Vyvanse (lisdexamfetamine dimesylate)

Gene of Interest: Trypsinogen

Due to its chemical proximity to amphetamines (Vyvanse is essentially an "inactivated" form of the drug Dexedrine, which is an isolation of one of the potent components of Adderall). A special chemical "tag" is linked to the active part of the drug, which must be chemically cleaved to release the active form of Vyvanse (think of it as essentially breaking a seal to free up the drug) into its functional amphetamine-based product. Naturally, the genes listed above (and the enzymes which they encode) which metabolize amphetamines are of substantial interest for potentially influencing the effectiveness of ADHD treatment with Vyvanse as well.

However, the actual cleaving process of releasing the active component of Vyvanse is equally as important. If the drug is not freed, then it cannot be effectively metabolized.

Several enzymes which are called upon to metabolize the other ADHD drugs in this post do NOT appear to have a significant effect on Vyvanse. These include CYP2A6, CYP2B6 (both for nicotine), and CYP2D6 (for Strattera). This is good news for those who are already taking medications, as Vyvanse's relative independence of these drug-metabolizing enzymes means fewer adverse drug-drug interactions.

As far as genetics go, the genes coding for the breakage of de-activating chemical tag placed on Vyvanse may be of most importance, especially since this breakage (or "hydrolysis") is believed to be the slowest (or rate-determining) step in metabolizing Vyvanse for ADHD. The de-activating "tag" attached to Vyvanse is none other than the amino acid lysine. While the exact mechanism of cleaving this link is not fully known, one enzyme in particular may be extremely relevant to this process.

Trypsin is an extremely common digestive enzyme produced predominantly in the pancreas. It is responsible for breaking up chemical linkages much like that of the one used to de-activate Vyvanse. Thus, a genetically-governed deficiency of the trypsin enzyme could lead to a severely hampered absorption (and subsequent metabolism and clearance of the ADHD drug Vyvanse).

Trypsin is actually coded for by a series of enzymes, often referred to as Trypsinogen, which located on the 7th human chromosome (in the "q35" region of the chromosome to be more exact). Individuals with pancreatic deficiencies, including pancreatitis have been tied down to having mutations in this trypsinogen gene.

Therefore, while this genetic region on the 7th chromosome hasn't been sufficiently studied with regards to Vyvanse (at least to the best of this blogger's current knowledge), this blogger personally believes that aberrations in the region of the Trypsinogen gene on this 7th human chromosome may be a worthwhile place to look for genetic response-based differences to the ADHD medication Vyvanse.

ADHD drug #4: Concerta/Ritalin/Daytrana/Biphentin (methylphenidate)

Genes of Interest: Carboxylesterase 1 (also referred to as "CES1"), DAT (refer to ADHD drug #2: Adderall section for DAT's genetic location)

Carboxylesterase 1: Although the affected form of this enzyme, which is coded for by a gene on the 16th chromosome, is relatively rare, some key studies have indicated that deficiencies in the CES1 enzyme can be coded from specific forms of this gene. These rare, low-functioning gene-mutation forms of Carboxylesterase 1 result in extremely poor methylphenidate metabolism, resulting in a buildup of abnormally high levels of the drug in individuals with this enzymatically-deficient form.

In addition to their effects on amphetamines such as Adderall or Dexedrine, variations (often referred to in the literature as "polymorphisms") in the DAT gene also play a role in the response to methylphenidate. A Korean study found that a specific allele (the 10-repeat allele, which is the same form as the "high-risk" 480 base-pair allele mentioned earlier in the amphetamines section) predicted a poor response to methylphenidate.

Interestingly, however, several Irish studies suggest the exact opposite: the "high-risk" 10-repeat 480 base pair form of the DAT gene may produce larger amounts of the DAT protein (which shuttles essential dopamine out of the gaps between the cells, the opposite effect of what one wants if they suffer from ADHD), so the higher levels of expression of this transporter may make it a better candidate for methylphenidate.

Another Irish study may help resolve some of this discrepancy. It found that individuals with the so-called "high-risk" form of the DAT gene mentioned above exhibit a more positive response to treatment with methylphenidate with regards to treating their attentional symptoms based on the left side of the brain. Left sided inattention can be a reflection of brain damage or brain asymmetry, the latter being a common trait in the ADHD population. It should be worth noting that methylphenidate has been an effective treatment method for improving cognitive processes for those suffering from traumatic brain injuries.

Given the fact that in the amphetamine section we mentioned that the DAT gene was more connected to the Combined ADHD subtype (the original article specifically stated that the association did not hold for the strictly inattentive ADHD subtype). If this holds true, then we may have discovered a potentially significant gene/medication/ADHD subtype association.

It is this blogger's current hypothesis that the "high-risk"/480 base pair/10-repeat allele form of the DAT gene might predispose one to a MORE FAVORABLE response to methylphenidate treatment if inattention is the most persistent ADHD symptom (as in the predominantly inattentive ADHD subtype). Conversely, if the hyperactive/impulsive behavior either predominates or is largely present in an individual (such as in the hyperactive/impulsive or combined ADHD subtypes, respectively), then the "high-risk" label holds for this particular gene type, and the methylphenidate response potential goes down.

In other words, if large amounts of hyperactivity are present (which is the case in most ADHD children, as the combined subtype is by far the most common form), then this "high-risk" form of the DAT gene hampers methylphenidate's effectiveness, whereas if hyperactivity is largely absent, then the response to methylphenidate is actually more favorable. If this hypothesis were to hold true, then we could screen youngsters for this form of the gene and keep them far away from methylphenidate if they were bouncing off the walls, whereas if the exhibited more of an inattentive "space cadet" type of behavior then methylphenidate might be a good first choice of pharmaceutical treatment. Of course this theory could be completely off-base, but given this blogger's current knowledge and exposure to the current literature, this may be a plausible explanation.

Another possible explanation for this discrepancy between Irish and Korean studies: We have already seen that specific forms of certain genes can be found at considerably higher levels such as the *10 form of the CYP2D6 gene mentioned above with regards to the East Asian population. Keep in mind that this gene form was associated with the metabolism of Strattera (which exhibits a significantly different mode of operation than do stimulants such as methylphenidate or mixed amphetamine salts). However, there are a number of so-called ADHD genes which have been implicated with the disorder. The current thought here is that some genes exhibit a more powerful influence on physical or behavioral traits than do others. In other words, some genes simply act more "powerfully" than others. This is known as epistasis ("Epistasis" roughly means "standing upon").

***As a side note, please don't confuse "epistasis" with the whole dominant/recessive "big A/little a" (Aa) gene thing you probably learned about in middle school biology. Dominant/recessive refers to different forms of the SAME gene, whereas epistasis refers to DIFFERENT genes. For example, let's say, hypothetically that there was a rare gene for green hair located on the 20th human chromosome. However, a more "powerful" gene, say on the 14th chromosome codes for brown hair. This brown hair gene in this case would be epistatic, meaning that it would overpower the effects of the green hair gene altogether. This phenomena is quite common in genetics.

Getting back to our discussion, this blogger hypothesizes that there may be one or more other unidentified genes in either the Korean or Irish population which are epistatic to the DAT gene with regards to the methylphenidate response. If this was true, then it's quite possible that the effects of these hypothetical yet-to-be-identified genes might "mask" or override the effects of the DAT gene, and that the association with the "high-risk allele" may be largely coincidental rather than causative. Given the state of the current research on current "heavyweight" genes such as the COMT gene mentioned earlier, it is entirely possible that the overall level of contribution among specific "high-risk" DAT alleles might be less significant than many of these studies seem to indicate.

Of course the discrepancy could just as easily be attributed to small sampling sizes, slight differences in experimental methods or uncontrolled variables in the experiment (or a complete lack of true association between methylphenidate and the DAT gene at all, although given the current body of literature, this last assertion seems highly unlikely).

ADHD drug #5: Nicotine:

Genes of interest: CYP2A6, CYP2B6

I have included this drug due to the high rates of smoking among those with ADHD. As with alcohol, nicotine is often widely used as a form of self-medication for those with ADHD. Some research even suggests that individuals with ADHD exhibit a different response to nicotine and that nicotine withdrawal may produce different patterns in certain critical brain regions between ADHD'ers and the general population. Interestingly, there are some genetic regions which may tie into this behavior.

With regards to nicotine metabolism, 2 genes appear to stand out in particular: CYP2A6 and CYP2B6 (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism CYP2D6. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the CYP2A6 (hereafter abbreviated as "2A6") enzyme is responsible for the lion's share of nicotine metabolism. It is coded for by by a gene of the same name, located in the "q13.2" region on the 19th human chromosome.

Like the 2D6 gene for Strattera, the 2A6 gene can exist in multiple different forms. Some 2A6 gene forms produce higher levels of the 2A6 enzyme than others. Other forms of 2A6 are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. As a result individuals with these less efficient forms (called "slow metabolizers") of the 2A6 genes are less likely to develop nicotine addictions.

The relevance of these 2A6 genes on ADHD: The stimulating effects of nicotine are believed to be a major contributing factor to the higher prevalence of smoking among the ADHD population. If this is true, then slow metabolizers of nicotine may not derive the full effect of nicotine self-medication for attentional deficits, at least not as immediately as the fast metabolizers. On the flipside, they have lower cravings (like with virtually all stimulant drugs, the speed and rate of uptake and clearance of nicotine is a major factor in its addiction potential) and are exposed to less tobacco and often find it easier to quit smoking.

At least two alleles or forms of the 2A6 gene (using the "star/number" nomencalture us used in 2D6 for Strattera earlier in this blog), have been shown to coincide with slower rates of nicotine metabolism. They are 2A6*2 and 2A6*4 (these two forms are actually referred to as "null alleles" meaning that the 2A6 enzyme they code for has no activity).

Additionally, there are noticeable differences in the frequencies of these forms across different ethnicities among the global population. For example, these "slow metabolizing" gene/enzyme forms of are found in higher percentages in individuals of Asian ancestry (around 20%) compared to those of European descent (around 8%).

With regards to ADHD behavior, it is likely that people possessing these *2 or *4 forms of the CYP2A6 gene, may be less likely to use nicotine as a self-medication tool for their ADHD, or at least use the drug in lower doses, due to its lesser effects. On the flipside, however, there is another allele of the 2A6 gene, referred to as CYP2A6*1B. This version of the 2A6 nicotine metabolism gene actually promotes greater activity of the nicotine metabolizing enzyme, and speeds up the processing and clearance of the drug. As a result, individuals who possess this relatively rare CYP2A6 form may be more prone to more frequent use and abuse of nicotine, and individuals with ADHD who attempt to self-medicate with this drug may cycle through their nicotine more rapidly if they carry this *1B form of the gene.

Interestingly, another drug, bupropion (Wellbutrin), which is an anti-depressant often used off-label to treat more "depressive" forms of ADHD is a relatively common anti-smoking drug. Given the fact that a number of ADHD'ers who typically do not respond well to stimulants, but do respond to Wellbutrin may fall in this smoking category, it is possible that the fast metabolizers (i.e. the *1B individuals), may be good candidates for Wellbutrin, not only to stop smoking, but possibly also to treat unwanted ADHD symptoms.

Alleles of the CYP2B6 gene and enzyme with regards to nicotine and ADHD:

Shifting gears for a minute, we see that the CYP2B6 gene (as well as the enzyme which it encodes) also may also play a unique role in ADHD. The CYP2B6 gene is located on the 19th human chromosome (in the 13.2 region of the 19th, to be more specific). For individuals who lack CYP2A6 enzyme activity because of the reduced-activity or even "null" alleles, the enzyme CYP2B6 can metabolize nicotine in its place (it turns out that CYP2D6, the enzyme responsible for Strattera metabolism can also do the trick). For those who need to metabolize nicotine, but lack an effective CYP2A6 enzyme system, this is good news (however, this "B6" enzyme only functions at about 10% of the level of the "A6" enzyme, so B6 is not a very efficient "backup" for A6).

Beyond its role as a "backup" for the CYP2A6 enzyme, CYP2B6 may also be of clinical significance with regards to ADHD and similar disorders. In contrast to "A6", whose enzymes are predominantly generated in the liver, the CYP2B6 generated enzymes are expressed in brain tissue. With regards to the differences in neurochemistry and neurological functioning of the ADHD brain, the role of CYP2B6 is therefore potentially noteworthy.

Additionally, as we have discussed in earlier posts regarding ADHD and alcoholism, the 2B6 enzyme apparently also plays a role in alcoholism, and individuals who express higher levels of this genetically-encoded CYP2B6 enzyme in their brains may be more sensitive to alcohol, nicotine and other centrally acting drugs. The study even suggests that individuals with high levels of this gene-coded enzyme may be more prone to damages induced from these common chemical agents, including possible higher susceptibility to cancer.

For reference (using the "star" notation again), genetic forms of CYP2B6 which typically yield higher levels of this enzyme in the brain include the CYP2B6*4 (which shows up in about a third of the European popluation) form and the CYP2B6*9 (which is present in about a quarter of those of European descent) form. Again, don't worry too much about the specifics of these "starred" variants, just know that if you were to get a genetic screen and had one of these two enzymatic forms, you may be more sensitive to nicotine as a self-treatment ADHD "medication".

What this means is that ADHD individuals who harbor the higher-expressing "*4" and "*9" forms of the CYP2B6 enzyme in their brains may be more sensitive to chemical agents such as nicotine, and these same individuals may be more likely to suffer the toxic effects of this popular form of ADHD "self-medication".

In conclusion, we should note that some of these genes (such as DAT) have been well-studied and have repeatedly shown to be associated factor in proper dosing of ADHD medications. Others, however, such as the trypsinogen gene for Vyvanse are more at the theoretical level at the moment. However, this blogger believes that in the next couple of decades, (due in part to our expanding knowledge of the human genetic code and functional genomics), genetic screens will become foutinely more commonplace as a necessary tool for both prescribing and dosing medications. With regards to this general trend, psychotropic medications for disorders such as ADHD should be no exception.

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.

The Effectiveness of Adderall as an ADHD Medication

Adderall as an ADHD stimulant medication

Adderall is one of the most popular (and currently one of the most "trendy") types of ADHD medication. As a stimulant drug, Adderall is chemically and functionally similar to other ADHD stimulants including Ritalin, Dexedrine, Concerta or Focalin. However, while most of these medications contain either one or two compounds, Adderall technically contains eight. It is a combination of four different types of amphetamines (in the salt form) and their chemical "mirror images".

A bit of a side note on "mirror images" and drug chemistry: For reference sake, consider your left and right hands. They are identical in structure, but mirror images of each other. This mirror image effect plays an important role in pharmacology, and separation of the two mirror images can be extremely important. For example, one mirror image of the pregancy drug Thalidomide was used to treat morning sickness, while the other mirror image was linked to birth defects. Fortunately this grave difference between mirror images is not seen with ADHD stimulant medications. Some ADHD drugs, such as Dexedrine or Focalin only have the "right hand" form, which have different (and often more potent) properties than the "left hand" form. Nevertheless, both mirror images of each of the 4 different amphetamines are seen in Adderall, making it a combination of 8 distinct compounds.

Returning to the main topic, this post will be focusing on the overall effectiveness of the ADHD stimulant Adderall. This information comes from a large review done in 2002 in the Journal of Attention Disorders by Faraone and Biederman. A short synopsis of the orignal article on the medication Adderall and ADHD can be seen here. Please note that these studies focused primarily on the effectiveness of Adderall vs. a placebo and not Adderall vs. other ADHD medications. There actually are studies out there comparing stimulant medications for ADHD, which will be covered soon in later posts.

Also, the form of Adderall used for this review was the standard release version. No slower/extended release (Adderall XR) analyses were covered. Given the time of this publication, Adderall XR data was still scarce. Since 2002, this has changed, and additional insight will be covered in future posts. For now, I will be highlighting some of the main findings of the article below:

• Adderall outperformed the placebo in a statistically significant manner for both academic and behavioral improvements. These improvements were seen by all three monitoring groups: parents, teachers and clinicians, and were consistent, even among the several different ADHD rating systems used by the three groups.
• Additionally, consistency was seen with regards to the effectiveness of Adderall regardless of whether the stimulant medication was administered via fixed-dose (a set dosage for test subjects) or via "best-dose" (the dosing was tailored to the individual by considering the size and gender of the individual, history of other medications taken and the responsiveness to these medications). This suggests the possibility that Adderall may have a more flexible range of effective dosing than most other ADHD drugs.
• The study identified that there is often an inherent clinical bias in reporting the effectiveness of medications because "success" stories in which ADHD medications are effective are naturally published more often than for "failed" studies. A correctional factor (described in the article) was used to counteract this implicit effectiveness bias. Just keep in mind that published results are often not a full representation of data from the full spectrum of studies.
• Adderall treatment (at various doses) appears to be almost as effective in treating aggressive behaviors as in treating ADHD. This spells good news for individuals with ADHD who also exhibit potentially violent or overly-aggressive behavior.
• Although parents, teacher and clinicians all saw improvements with regards to ADHD across the board, the highest levels of measured improvement was typically seen by those in the medical profession. Parent and teacher evaluations showed similar levels of improvements with respect to each other, but their results were often not as pronounced as those done by clinicians.
• In addition to clinician reports giving higher ratings, the mode of measurement for ADHD symptom improvement was also a factor. Symptom ratings scales, refer to a reduction in negative symptoms associated with the disorder. They do not take into effect things such as improvements in school or improvements in social skills, as these are more difficult to monitor as measurable "symptoms".
• By contrast, global ratings also incorporate factors in addition to the symptom ratings. In addition to measuring levels of "sickness" like symptom ratings, global ratings measure more degrees of "wellness", such as the social or academic improvements mentioned above. As a result, global ratings typically offer a wider spectrum and offer a more complete and detailed portrait of improvements following modes of treatment for ADHD. Not surprisingly, due additional improvement categories which can be measured, global ratings typically result in higher rating scores of medication effectiveness than do ADHD symptom studies.
• Based on the layout and distribution of the data, and the overall high level of agreement in the results of multiple unrelated studies, the authors of the article concluded that additional studies on the topic of Adderall medication vs. placebo are unlikely to refute these results.

These results support the idea that ADHD treatments with Adderall are statistically superior to controls (i.e., it is highly unlikely that improvements along the spectrum of undesirable behaviors and effects of ADHD are due to the "placebo effect"). As a result, it is apparent that Adderall has solidified its place as a valid and viable treatment option for ADHD.

Nevertheless, we must now begin to focus on the overall safety of this ADHD drug, and how Adderall stacks up against other ADHD stimulant medications such as Ritalin, Focalin, Concerta, or Dexedrine. Please check for more posts addressing these two key areas in the near future.