Genes and ADHD Brainwave Patterns

There is mounting evidence surrounding the genetic basis for ADHD. Some studies place the blame on genes, as heritability of ADHD may be as high as 75 percent. Some of the specific ADHD genes under investigation can be seen here.

EEG has been a hot topic of discussion as of late for individuals suffering from attentional difficulties. Short for electroencephalography, EEG is an electrical measuring device used to monitor brainwave patterns and frequencies. In general, the higher the frequencies, the more "alert" the individual is:

Some common states and their EEG ranges can be found below. Note that the numbers are in hertz or cycles/second

Delta: 1-4, sleep
Theta: 5-7, daydreaming
Alpha: 8-12, relaxation (watching TV)
SMR (Sensorimotor Rhythm): 12-15, Focused relaxation, live sporting events, easy video games
Beta: 13-24- concentration
High Beta: over 25-30, anxiety and related symptoms

Individuals with ADD or ADHD often (not surprisingly) have more difficulty staying in the Beta range and are seen excessively in the Theta state. EEG programs are available in which the individual attempts to remain in a beta state for as long as possible. Essentially, they "train" the brain to hold a higher frequency, often through some type of interactive computer game which stops when beta frequencies are no longer maintained.

To be perfectly honest, I know relatively little about the intricacies of this procedure. However, based on what I've gathered so far on the subject, this practice seems to have had a moderate amount of success. Some consider it to be too costly or over-prescribed, while others swear by the results. Based on what I've read, typical treatment is often comprised of weekly interactive EEG treatments for a period of 1-2 years. At this point, I am not in a position to give advice on this alternative treatment measure for ADHD and related disorders, but I do find at least the theory behind it to be highly plausible.

Returning to the genetic basis surrounding EEG measurements for a moment, we see that the degree of heritability is thought to be highest somewhere around the high alpha and low beta states (right around the Sensorimotor Rhythm region mentioned above) and begins to decrease at both higher (high Beta) and lower (Delta and Theta) states. Given the difficulties of achieving a consistent Beta state for ADHD'ers, we can see that these difficulties may fall right in the eye of this storm of heritability and genetic predisposition.

A comparative study was done examining EEG patterns of un-medicated children with ADHD who had siblings or parents with the disorder. This study measured baseline brainwave frequencies and brainwave patterns when the subjects underwent a Continuous Performance Task.

In a nutshell, Continuous Performance Task tests measure both inattention and impulsivity, both of which are landmark ADHD characteristics.

How the Continuous Performance Task test typically works:
An individual may be asked to press a computer button only after seeing a specific letter or shape. If that letter or shape is shown only rarely, then the individual enters a "bored" state (which is often connected to Theta activity, which is typically higher in ADHD individuals to begin with). As a result, he or she may space out and miss when the letter or shape is finally presented on the screen. This "miss" is called an error of omission, and is reflective of inattention.

On the flip side, if the letter or shape is constantly being shown, the individual may attempt to "guess" when it is next displayed and push the response button prematurely. This is an error of commission, and is more connected to impulsivity.

Correlations in EEG patterns between siblings was much higher for measures taken in a state of cognitive activation (i.e. when undergoing the continuous performance task listed above) than EEG baseline patterns. This suggests that ADHD genetic differences are much more pronounced during cognitively challenging situations, than during rest. In other words, similarities in brainwave patterns of ADHD siblings are greater during cognitive tasks than while at rest.

• The only statistically significant EEG pattern seen between siblings at the resting or baseline state was that of the theta state in the frontal region of the brain. This is interesting to note, because this region, which includes a brain domain called the prefrontal cortex, which is thought to be one of the major "hot spots" for chemical imbalances in an ADHD brain.

• During these performance tasks, which involve periods of concentration, it was noted that correlations between sibling brain wave patterns were extremely high; higher than a cause which was purely genetic would indicate (since non-identical twin siblings only share half of the same genetic material). This suggests that among these siblings, both genetics and overlapping environmental factors are both at work.

• While all brain wave states during concentration tasks were thought to be genetically connected, it appears that changes in the alpha state (and somewhat with the theta state)were the most pronounced. This was believed to be due to an overall decrease in these overall frequency states during concentration tasks, which suggests that in order to maintain concentration for a cognitive tasks, the brains of these individuals were forced to work "harder" by operating at a higher frequency (Beta) state. To overstate the obvious, this supports the idea that ADHD brains must work harder to maintain an attention span by bumping up to a higher state.

• One note of particular interest: It appears that genetics (i.e. having at least one parent with the disorder) plays a much greater role in errors of omission (see description near the top of this post) than in errors of commission. Since errors of omission are more associated with inattentive behavior and errors of commission are more associated with impulsive behavior, it suggests that genes are more likely involved in individuals who are more of the predominantly inattentive ADHD subtype than they are for the hyperactive-impulsive ADHD subytpe.

• While genetics appeared to be connected to overlaps in brain wave states and how hard the brains of ADHD siblings had to work to maintain attention, there was little statistical evidence linking actual cognitive task performance to family-based genetic heritability. In other words, while the brains of these children with ADHD had to work harder to complete the cognitive task, the overall abilities to actually perform the task were not thought to be tied to familial inheritance (such as from the parents).

• This above point suggests two things: 1.) Individuals with ADHD are able to over-ride genetic predispositions and maintain an attention span, albeit at a higher cost, and 2.) EEG is a powerful diagnostic tool that is a more accurate predictor of genetic heritability of ADHD than are physically detectable symptoms (such as observed bouts of inattention, hyperactivity or distractibility).

While these findings are encouraging, it is important to note that EEG-based treatment of ADHD is still in a period of relative infancy. However, like the experience of watching a duck on the water (who appears to be calmly floating along while his legs are thrashing below the water's surface) EEG offers the unique ability to detect the "thrashing below the surface" of an ADHD brain. The studies above strongly suggest that there may be a much greater genetic component to this thrashing than we previously expected.

Reboxetine for ADHD Treatment

In previous blog posts, I have mentioned some unconventional and lesser-known medications used to treat ADHD. Many are either new to the market or have primary uses not designated as ADHD drugs, such as anti-depressants, mood-stabilizers, anti-convulsants, etc. Unfortunately, these results are often obscured or hidden from the general public. The medical community (somewhat understandably) often initially shies away from these studies because they are often done on a small scale, have less-rigorous built-in-controls, are not done by big-name researchers, are studied in foreign countries, and are published in less-prominent journals. What is often surprising is that the results of treatment with these less-publicized medication choices, is that, although small and somewhat isolated in nature, a number these studies have displayed eye-opening levels of success, and should warrant further investigation.

The beauty of being a blog-writer, as opposed to a highly-publicized journalist, is that one can take more of a "chance" by reporting some of these findings, without feeling pressured to stick to the more "mainstream" findings.

Without further ado, the drug of topic for today is Reboxetine.

Like many ADHD drugs, Reboxetine (also marketed under labels such as Solvex, Prolex, Vestra, Davedax, Edronax or Norebox). It's main line of treatment is for depressive and panic disorders, but has also shown solvency in the treatment of ADHD on a small-scale. Like many other ADHD medications, Reboxetine exists as a mixture of two compounds, which are mirror-images (also called enantiomers), of each other. It is used in a number of European countries, but is yet to be approved in the United States.

Functionally, and to a lesser-degree, chemically, Reboxetine resembles another common ADHD medication, Strattera (Atomoxetine). Unlike many types of anti-depressant medications, which often target the key neuro-signaling agent serotonin, Reboxetine's primary target is another major signaling compound known as norepinephrine. Norepinephrine, a chemical "cousin" to adrenaline, is often found to be at lower-than-normal levels in the surrounding environment outside neuronal cells in individuals with attentional and depressive (in addition to other related) disorders. Essentially, there is an imbalance in the amount norepinephrine inside and outside the cells on the nervous system. Reboxetine functions as a "blocker" of the process of taking norepinephrine up into neuron cells, which helps restore the balance of this neurotransmitting agent inside and outside cells in the nervous system.

This selective restoration of balance concerning levels of norepinephrine serves other benefits as well. For example, disorders such as fibromyalgia and chronic pain are associated with norepinephrine level imbalances. Based on multiple case studies, it appears that reboxetine can help alleviate at least some of these pain-related symptoms. Attentional deficits are often (perhaps, not surprisingly) a secondary symptom of pain-related disorders, so this is of some therapeutic value already. Additionally, migraine headache pain is also a common comorbid symptom of ADHD. However, there is more...

One of the most difficult issues surrounding drug design is specificity. We naturally want the drug to reach its desired target in the body. However, it is often difficult for a drug to reach only its specific target and avoid all other undesired ones. Unfortunately, this is not always possible, and one of the main consequences of a drug's lack of selectivity is unwanted side effects. In the case of Reboxetine, however, it appears that its overall degree of affinity for unwanted targets (often referred to as receptors in biological terms) is less than many other comparable medications. In other words, Reboxetine is less "promiscuous"; it has minimal interaction with target receptors for other neurotrasmitters such as acetylcholine (which can lead to digestive dysfunction, and is partly responsible for the dry-mouth and constipation symptoms found in many drugs) and serotonin (which can lead to drowsiness and other sedative effects).

Returning to the specific topic of ADHD, however, Reboxetine has shown to have some other advantages over other ADHD medications.

• Reboxetine is long-lasting. Reboxetine's plasma half-life is around 13 hours (that is, it takes around 13 hours for half of the drug to be cleared and eliminated in the body). In comparison, atomoxetine (Strattera) has a plasma half-life of around 4 hours.

• It serves as a good "back-up" treatment for ADHD as a medication. While stimulants remain the drug class of choice for ADHD, roughly 30% of children with ADHD show little response to stimulant medications. Based on findings from a recent study, children with previous adverse effects to methylphenidate were able to handle Reboxetine. In addition, based on a side-by-side comparison study of Reboxetine and methylphenidate, the Reboxetine performed equally well with its counterpart as far as reducing ADHD symptoms.

• While some medications have shown to be effective in treating the predominantly inattentive symptoms of ADHD or the hyperactive-impulsive symptoms of the disorder, Reboxetine appears to improve symptoms of both. Based on a study of boys ages 6-16 of the Combined subtype (that is, they show significant levels of inattentive as well as hyperactive and impulsive symptoms), treatment with Reboxetine showed significant improvements based on parent ratings in as little as 2 weeks.

• In addition, Reboxetine has shown some success in treating conduct disorders, which are often comorbid to (or occur alongside of) ADHD. In this case, the disorder was called hyperkinetic conduct disorder, which is very similar to ADHD, but with more severe behavioral issues and a greater probable genetic component.

• While specificity in choice of biological targets appears to be an advantage of Reboxetine, it also appears that Reboxetine can also boost free dopamine levels in the prefrontal cortex region of the brain (which is a region thought to be highly-connected to ADHD). Dopamine is another highly important agent used in signaling throughout the nervous system and its cells, and is intricately connected with ADHD in the prefrontal cortex region of the brain (which is located behind the forehead). Reduced levels of dopamine in between nerve cells in this important region of the brain (like the lower levels of norepinephrine described above), typically results in an increased onset of negative ADHD symptoms. These effects are thought to be more indirect, as norepinephrine carriers can also transport and clear dopamine from the areas in between neuron cells. However, if these carriers are tied down or "busy" handling the Reboxetine, then these carriers are less available to shuttle away the free levels of dopamine in this critical brain region. As a result, a gradual build-up to more "normal" levels of dopamine are seen, which often results in a reduction of ADHD symptoms.

Other interesting points of note regarding Reboxetine:

• As mentioned above, Reboxetine was rejected by the FDA in the United States, although it has been used widely in over 50 other countries. The reasons for its rejection by the FDA have not been disclosed in full to the general public.

• While the study mentioned above cited the effectiveness of Reboxetine treatment for some children who had experienced adverse side effects with methylphenidate, around half of the children in the study who showed negative side effects to methylphenidate also saw similar effects to Reboxetine (although many were more mild than for methylphenidate).

• While Reboxetine does not target serotonin receptors like many other antidepressant medications (which can cause sedative effects), drowsiness is still one of the more common side effects of the drug. Additionally, treatment with Reboxetine can also lead to appetite suppression, which is a common side effect of stimulant medications used to treat ADHD.
  

• While dopamine is the main agent of concern in the prefrontal cortex region of the brain with regards to the disorder ADHD, norepinephrine levels in this brain region are thought to be connected to oppositional behavior. While this study used atomoxetine for treating these symptoms (albeit in a rat model), it leaves the door open for investigation of treatment with atomoxetine or reboxetine for both ADHD along with comorbid conduct disorders such as Oppositional Defiant Disorder (ODD, which is actually quite common in ADHD individuals).
  

• Reboxetine is metabolized mainly in the liver, using an enzyme called CYP3A4. Several other drugs and food compounds also utilize this enzyme system. This is important because when two or more drugs or food-substances share a similar pathway, there is a much greater potential for these substances to interfere with each other. The result is often impairments or drug-drug interactions. For a comprehensive list of other types of drugs and compounds which also use this enzyme system, please click here. Although not emphasized in the previous link, I personally found it interesting that the compound quercetin was a strong inhibitor of this enzyme system. Quercetin is found in high concentrations in foods such as onions, teas, apples, and berries, many of which are touted for their numerous health benefits such as cardiovascular health and antioxidant properties. While no significant studies (at least to the best of this writer's knowledge), have been done on the effects of quercetin and the drug Reboxetine, there is a strong possibility that high levels of consumption of these healthy antioxidant-rich foods may actually interfere with the metabolism of Reboxetine and potentially alter its effectiveness in treating ADHD or related disorders.

In spite of a number of positive findings surrounding the drug, there is still a shroud of mystery (much of which is due to the FDA rejection of the drug in the U.S.) over the effectiveness of Reboxetine for treating ADHD on a large scale. Given the fact that its main function is that of an antidepressant, it would appear that functionally, Reboxetine would be useful for treating individuals with ADHD and comorbid depression (in a way somewhat analogous to drugs such as Wellbutrin).

Nevertheless, some of the promising results surrounding the drug suggest a potential for treatment of comorbid conduct disorders. This may serve as a potential all-in-one approach, as opposed to being prescribed multiple drugs for multiple co-existing symptoms. The versatility of this drug is intriguing, especially when we consider the relative specificity that Reboxetine has almost exclusively for the signaling agent norepinephrine.

Given the fact that this class of antidepressants appears to bypass the serotonin-dependent pathways, it is possible that this drug could be used in conjunction with other anti-depressant drugs as well, with a reduced potential for negative drug-drug interference.

Finally, due to its comparatively long half-life, and potential interference from foodstuffs such as quercetin, there is an increased risk of unwanted buildup and possible side effects associated with toxicity issues surrounding the drug. Nevertheless, there is room for further exploration, especially in the context of approaching ADHD treatment from a different angle than most stimulant medications. This is definitely a drug to keep on the radar for the near future.

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.

Evaluation of Vyvanse for ADHD Treatment

A new drug called Vyvanse (Lisdexamfetamine) has entered the world of ADHD stimulant medications relatively recently. Vyvanse was originally marketed as an ADHD treatment for children, but has recently been approved by the FDA for adult and adolescent use this past April. A cousin of the popular ADHD medications Dexedrine and Adderall, Vyvanse includes some key modifications from these other meds. Some reports (unverified) suggest that Shire Pharmaceuticals, the makers of Vyvanse, are pushing this new drug aggressively over Adderall XR. While Adderall is a chemical mixture of amphetamine salts including enantiomers, Vyvanse only contains the one enantiomer thought to be more "active".

A quick side note on enantiomers: Entantiomers are essentially "mirror images" of the same chemical compound, like a person's left and right hand. The body, like most objects in nature, react differently to and often heavily prefer one "mirror image" over the other. Certain ADHD medications such as Focalin, have already employed this technique. Focalin is an isolation of only one of the two mirror images that make up Ritalin, another popular ADHD medication. In addition, the ADHD medication Dexedrine also employs this mirror-image selectivity regarding its composition.

The second major difference between Vyvanse and other amphetamines such as Adderall, is that Vyvanse is listed as a "pro-drug". A pro-drug is essentially an inactive form of a drug, which, when broken down or metabolized by the body, releases the active drug form. Vyvanse contains an amphetamine which is chemically linked to an amino acid (a building block component of proteins) called lysine. In the body, this chemical linkage is severed by special enzymes which separate Vyvanse into the amphetamine drug and leftover lysine fragment (which is easily disposed of, since lysine is a naturally occurring amino acid in its own right).

***Blogger's note: I will be citing a number of studies previously conducted on the drug lisdexamfetamine. Keep in mind that this is a relatively new drug, so it does not have the history of a drug such as methylphenidate. Nevertheless, I have tried to keep a good balance of sample studies on the drug to report on. The list of studies mentioned and referred to here, are by no means exclusive! While not all of the studies used the Vyvanse brand of the drug, I will be using the terms "Vyvanse" and lisdexamfetamine interchangeably throughout the post.

***Additionally, please do not take this information as official medical advice. I am simply trying to highlight some of the pluses and minuses of the drug and arm you with information so you can better consult with your physician on the merits of this drug.

This chemically-modified form carries several apparent advantages for Vyvanse:

• Since the lysine link must be cleaved to release the active form of the amphetamine drug, Vyvanse naturally lasts longer in the system than do straight amphetamines. While most other stimulant medications rely on the capsules encasing the drugs to slowly dissolve and thereby slow down the release of the drug, Vyvanse already has what is essentially a controlled release built in to the drug itself. As a result, a single dose taken early in the day can last up until the evening hours, which allows individuals to avoid the hassle or stigma of needing to take the medication during the work or school day.

• Most of amphetamines problems stem from their addiction potentials. Generally, the faster the amphetamine gets into the blood stream and gets into (as well as out of), the brain, the greater the "high", and the more addiction-forming the drug. Again, by its built-in slow release mechanism, Vyvanse enters the blood (as well as the nervous system) at a slower, more controlled pace, thereby reducing its addiction potential. Even when snorted or injected, lisdexamfetamine exhibits notably reduced addiction potentials, when compared to other amphetamine-based stimulants. For example, when injected via IV, subjects who took Vyvanse needed 1-3 hours to feel the drug effects while isolated d-amphetamine (analogous to Dexedrine) felt the effects in only 15 minutes.

• Due largely in part to the fact that Vyvanse's drug effect needs to be "activated" biochemically, it is poses less risk for tampering and related abuses (i.e., crushing and snorting) as well.

Additionally, Vyvanse also carries some other distinctive advantages:

• While many drugs effectiveness are often dependent on the level of acidity in the stomach and intestinal tract, Vyvanse appears to be only mildly affected. It dissolves quickly in the gastro-intestinal tract, and its solubility is minimally affected by digestive pH.

• The presence of food only results in a slight delay in Vyvanse's absorption. When taken alongside a fatty meal (fatty foods generally impede the absorption process, as they themselves are slow to clear the gastro-intestinal tract) the delay in amphetamine release from Vyvanse was only about an hour. This was in contrast to around a 2.5 hour delay when Adderall was taken with fatty foods. As a result, Vyvanse appears to be less affected by the presence of food than other well-known amphetamines, suggesting an increased versatility as an ADHD stimulant medication treatment.


• This next statement is the blogger's opinion and is not supported by direct evidence. Nevertheless I believe this is a topic worthy of investigation: In a previous blog post, we discussed celiac disease and how it can ravage the digestive tract and result in ADHD-like symptoms. While these symptoms are likely the result of a different path than ADHD caused by genetic or environmental factors, it may be worth noting that Vyvanse may alleviate some of these inattentive symptoms better than other ADHD medications, due to the fact that it may absorb better in a digestive system damaged by celiac disease or the pH changes which often accompany it (poorly digested carbohydrates can alter the pH in the digestive system immensely). While this will not treat the underlying cause of celiac disease, it may mask the some of the ADHD-like symptoms better than other medications. This assertion is simply a personal hypothesis and is yet to be studied or verified.

• In addition to its resiliency regarding foods and digestive pH, it appears that Vyvanse may be less susceptible to negative drug-drug interactions than many other agents. Many medications target a key metabolic system referred to as Cytochrome P450. While to complex to discuss in detail in the limited scope of this post, the P450 system of proteins plays an integral role in drug metabolism, the body's antioxidant levels, and regulation of toxicities, it appears that the effects of the drug lisdexamfetamine on the P450 system are minimal. Since many drugs do operate via this system, Lisdexamfetamine should therefore pose less of a threat regarding negative drug-drug interactions.

• The drug apparently has a good track record as far as behavioral improvements and attention span are concerned. A study was done using a rating scale called SKAMP (which stands for the initials of its creators: Swanson, Kotkin, Agler, M-Flynn and Pelham), which is used to determine classroom behavior. According to the study using this particular rating scale, measurable improvements were seen in both attention span and classroom conduct for periods of up to 12 hours after taking their last dose of lisdexamfetamine. Prolonged behavioral changes are typically not seen to this degree, and the fact that the subjects were diagnosed and medicated previously suggest the potential effectiveness of Lisdexamfetamine even for "stubborn" ADHD cases.

• The same study also employed a mathematics-based test called PERMP (short for Permanent Product Measure of Performance). Notable improvements were seen in both both speed and accuracy on this test following a 5-week amphetamine treatment program. Lisdexamfetamine's positive effects on this cognitive task peaked around 4.5 hours after the last dose was administered and held relatively steady for the next 7-8 hours. The results of this study suggest that Lisdexamfetamine can improve the inattentive and behavioral symptoms of ADHD as well as enhance cognitive performance abilities for a prolonged period of time. This suggests great potential for use as a "school drug".

• A study on adult stimulant drug abusers by Jasinski and Krishnan presented at the 2006 US Psychiatric and Mental Health Congress found that the study's subjects found Lisdexamfetamine to be much less "likable" than other amphetamines, further suggesting a reduced addiction potential for an already-at-risk group.

• When taken around breakfast time (7:30-8:00 a.m.), Vyvanse showed remarkable "staying power" throughout the day, based on results from a behavioral rating scale taken in the mid-morning, afternoon and evening time (the last being around 6:00 p.m.). This is good news for teachers and parents, and suggests a more gradual tapering-off of effects, and a lesser "rebound effect", in which negative symptoms rapidly reappear, often within the hours of 4 and 6 p.m.

• Amphetamine levels delivered via the lisdexamfetamine system are thought to stabilize within about 5 days. This is good news, especially since many ADHD medications can take up to 3 weeks to normalize their effects.

• Lisdexamfetamine is apparently processed and broken down in an efficient manner, and is typically cleared from the body without system buildup.

• Lisdexamfetamine has also shown more consistency than many other drugs as far as less variation from patient to patient. While this is neither good or bad by itself, it does suggest a greater inherent stability in that it appears to be less susceptible to the effects of other bodily functions which are variable from person-to-person. As a result, I see this greater predictability will make it a preferable choice for many prescribing physicians. Of course, the flip side is that ADHD is an extremely complex and multi-faceted disorder, and clinicians may fall into the trap of seeing a "one-size-fits-all" solution and begin to treat Lisdexafetamine as a fall-back, default prescription.
  

This blog, of course, is not designed to sound like some sort of promotional "infomercial" touting all of the benefits of Vyvanse while leaving out potential risk factors. To keep things balanced, I have included some of the negative attributes of this particular stimulant medication as well:

• While the study by Jasinski and Krishnan on the reduced "likability" of Vyvanse was encouraging, it is not recommended for individuals with a history of drug abuse, as previous non-prescription drugs can interfere with its effectiveness.

• Additionally, Vyvanse reduces the presence of a key enzyme in the body which is targeted by anti-depressants called monoamine oxidase. A number of anti-depressants called monoamine oxidase inhibitors (MAOI's) also target this enzyme and reduce its presence. Due to the potentially harmful combination of amphetamines and MAOI's, these MAOI drugs should not be taken alongside Vyvanse. Please note that certain substances, such as cigarettes, and even turmeric or curry (in large doses) can also have potentially negative effects with Vyvanse.

• Slight elevations in heart rate and blood pressure (mainly the diastolic pressure, which is the smaller of the two numbers and represents the blood pressure at the "resting" phase of the heart) and slight changes in heart rhythms were seen with Vyvanse, especially in the upper dose (70 mg) levels. However, this is a relatively common occurrence within the family of stimulant medications. For further information, please see the earlier post Are ADHD Stimulant Drugs Bad for your Heart?

• Like most stimulant medications used to treat ADHD, appetite suppression was also a common side effect (this is due, in part, to increased levels of free dopamine, an important signaling agent in the nervous system, which, also plays a role in the feeling of "fullness" in an individual. By artificially boosting free levels of this neuro-chemical, a reduction of hunger symptoms are often seen), even at the lower 30 mg doses. However, actual weight loss did not become a huge symptom until the upper levels (around 70 mg doses) were approached.

• Insomnia can also be a problem with Vyvanse, even at lower doses. As a result, it is advised to give this medication as early in the day as possible.

• The "classic" side effects (that almost all medications now somehow seem to evoke!) such as headache, nausea, vomiting, etc. all remained relatively low until the 70 mg level was approached.

• Keep in mind that this drug still functions as a stimulant, and is therefore inherently better-suited for the more inattentive or impulsive forms of ADHD. Given the negative interactions with the MAOI class of antidepressants and the fact that stimulant drugs in general can worsen depressive symptoms, I recommend that extreme caution be used when prescribing this medication for individuals with comorbid ("comorbid" means "occurring alongside of") depressive symptoms alongside their attention deficit disorder.

Medication Doses Available:

30 mg, 50 mg and 70 mg were the original strengths available, but recently 20 mg, 40 mg and 60 mg doses have been added. The amount of amphetamine delivered in Vyvanse compared to Dexedrine approximately a 5:2 ratio. For example, 50 mg of Vyvanse corresponds roughly to 20 mg Dexedrine, 25 mg Vyvanse to 10 mg Dexedrine, etc. 30 mg is often a starting point for children, but doses can be carefully ramped up under the guidance of a physician. In general, it appears that many of the negative side effects can be kept at bay by staying under the 70 mg amount.

A quick side note: For another good source of information on medication dosages, I recommend the blog of Dr. Charles Parker. His blog can be found here. Additionally, he talks about a paradox called the therapeutic window. This is interesting to note, because sometimes ADHD medications which are prescribed at too high of a dosage actually result in ADHD symptoms to re-emerge and give the false impression of underdosage. You can check out this blog article here.

With regards to upper limits and safety measures, based on the studies mentioned above, negative side effects tend to increase around the 70 mg mark. Nevertheless, studies have been done at levels up to 130-150 mg. It is interesting to note that once this high range was reached, the amphetamine concentration in the blood began to taper off. This is good news with regards to the potential for overdose and buildup of toxic levels (note the relatively efficient rate of clearance of Vyvanse mentioned earlier in this post).

As a final word of caution: Remember that Vyvanse is essentially a new delivery method of amphetamines. I have highlighted some of the positives such as lower addiction potential and prolonged modes of action. However, keep in mind that there is often a strong "publication" bias, in that studies which find a drug to be ineffective or even counter-effective are often not reported or published. I therefore urge you to take some of these "glowing" reports on the drug with a grain of salt. Nevertheless, I remain at least cautiously optimistic with regards to the potential merits of lisdexamfetamine for treating ADHD and related disorders. We will be investigating other ADHD medication options shortly in future blog posts.

Celiac Disease causes ADHD Symptoms

One of the biggest challenges in diagnosing and treating ADHD is trying to separate it out from other disorders that often present similar-looking symptoms. One such disorder is known as celiac disease. When gluten (a type of plant protein found in corn and wheat) is ingested in individuals with celiac disease, an inflammatory response in the upper portion of the small intestine occurs. When repeatedly challenged by gluten exposure, damage can occur to this portion of the digestive system, which leads to painful symptoms and impaired digestive and absorptive function.

The latter is of particular interest, since we have seen in other posts that nutrient deficiencies can lead to or exacerbate the onset of certain ADHD symptoms. For example, iron has been shown to be a useful supplement in treating certain underlying factors in ADHD, as seen in previous posts. It is thought that a celiac disease-damaged system can contribute to iron deficiency, likely through impaired iron absorption, thus presenting a challenge to the ADHD patient.

Interestingly, celiac disease has also been linked to other neurological disorders such as depression and depressive-like symptoms. This may be due to poor absorption of the amino acid tryptophan (which is found in high concentrations in turkey, and is a big reason why turkey can make a person sleepy). Tryptophan is converted to another important agent in the body called serotonin, which is often found to be reduced in patients with depression and other related symptoms (sugar and milk can also give a temporary rise in serotonin levels, which is why ice cream and chocolate are often "comfort foods").

In addition to depressive behaviors, possible connections have been identified between celiac disease and other metabolic disorders such as diabetes and thyroid problems. We have explored the possible connection between ADHD and thyroid dysfunction in a previous post. Additionally, there is a possible connection between celiac disease and other symptoms or common ADHD comorbid disorders such as epilepsy, dyslexia (which is thought to be a possible result of impaired gluten breakdown), anxiety disorders and social phobias and impaired sensory functions.

The good news to all this is that a gluten-free diet (which, unfortunately, can be very difficult to administer due to the prevalence of wheat in the Western diet) has been shown to ameliorate most of these negative symptoms. A study done on celiac disease patients and ADHD symptoms found that after treating patients with a gluten-free diet for 6 months, a number of ADHD-like symptoms subsided. The study used a method called Hypescheme, which is a type of computerized checklist used to quantify and analyze data involving ADHD and related disorders in a statistically significant fashion.

Statistically-significant improvements were seen in the following areas: attention to detail, duration of attention span, ability to complete tasks, distractibility, fidgety behavior, leaving a seat (when expected to remain seated), noisy disruptions and answering questions prematurely.

However, statistically significant improvements were not seen in other categories characteristic of ADHD. These include: losing/forgetting materials as well as restless and interruptive behaviors.

In previous posts, we have seen that certain treatments may be favorable for either inattentive ADHD type behaviors, hyperactive-impulsive ADHD behavior, or a combination of the two, called the ADHD Combined Subtype. It is interesting to note that the gluten-free diet results in improvements in characteristics that may be considered either "inattentive" (task completion, attention to detail, distractibility) or "hyperactive-impulsive" (fidgeting, noisy behavior and blurting out answers prematurely). While many studies on the possible connection between food additives and ADHD (see last paragraph of this post for more on this) seem to highlight the hyperactive side of the disorder, this celiac disease study seems to indicate a more mixed improvement across the whole spectrum of the disorder when a gluten-free diet is introduced.

Given the fact that many individuals who have celiac disease lack many of the outward signs of digestive symptoms of the disorder, and the fact that there are so many potential overlapping factors between the symptoms of ADHD and celiac disease, it is quite possible that you or your child's ADHD may be a misdiagnosis of an underlying cause of celiac disease or a related disorder. I therefore strongly recommend individuals who are diagnosed with the disorder of ADHD (especially those who have had poor or adverse responses to previous treatments) to consider testing for celiac disease. This of course, is not meant to knock the competence of most physicians and other professionals, but rather a plea to eliminate a potentially common misdiagnosis through a relatively simple procedure. Several antibody-based tests can be used to detect celiac disease or related disorders with relative ease.

In general, there has been a lengthy debate over the connection between ADD and ADHD and food allergies. While previous studies had certainly performed, a landmark study was done in the mid 1970's by Dr. Benjamin Feingold which sought to link the relationship between food additives and food coloring and hyperactivity. Numerous studies have since followed on this topic, many of which have supported Feingold's hypothesis and many which have refuted it. As a result, a number of physicians began to recommend elimination diets in an attempt to control attention deficits and hyperactive behavior. We will be investigating the original Feingold article and summarize the effectiveness of these elimination diets in treating ADHD symptoms in the near future.