Medication Concerns Surrounding ADHD and Epilepsy

Medication strategies for ADHD Comorbid Disorders

Medicating ADHD and Comorbid Epilepsy

In a previous post, we briefly discussed the challenge of medicating ADHD with a common coexisting disorder, namely Tourette's Syndrome. We saw that conventional medications that are often used in the first line of treatment for ADHD are often counterproductive if they make the accompanying disorders worse. Additionally, certain ADHD medications can pose increase risks or dangers to some of these co-occurring disorders. Several articles have been published on stimulant medications and their overall effectiveness and safety for epileptic patients. In this post, we will examine some of the strategies and concerns associated with treating Epilepsy occurring alongside of ADHD. We will tackle some of these medication questions in the second half of the post. However, in order to do this, however, we must first begin by discussing some relevant information surrounding the range, severity and diversity of the symptoms and underlying causes of these two disorders.

Like Tourette's, the disorder of Epilepsy also finds itself to be overlapping (or "comorbid") with ADHD. According to a study reported in the journal Archives of Disease in Childhood in 2005 done by Tan and Appleton, over 20% of individuals diagnosed with epilepsy have multiple symptoms of ADHD. Epilepsy, which is characterized by the presence of recurring seizures that are not provoked by external chemical or environmental triggers, is potentially the most dangerous comorbid disorder associated with ADHD. Further complicating this combination of disorders is the fact that a number of independent studies have linked stimulant drugs (which are often the primary mode of treatment for ADHD) to lowering threshold levels for seizures. As a precaution, stimulants such as methylphenidate are often avoided whenever possible in seizure-prone individuals.

However, relatively new evidence has shown that this may not necessarily be the case with regards to ADHD and comorbid epilepsy. It is important to note that a large number of studies linking stimulant ADHD medications to increased rates of seizures involved more "anecdotal" evidence of symptoms based on relatively small, non-random samples of individuals. While this information should not discredit the validity of these studies, it is important to realize that these studies do not carry the same amount of scientific "weight" as those of larger, randomized, population-based clinical trials.

Further complicating the issue is the fact that there are multiple subtypes, classifications and severity levels of epilepsy. For example, one of the milder forms of pediatric epilepsy is called CAE. CAE, which is short for Childhood Onset Absence Epilepsy, is characterized by short periods (typically less than 10 seconds) of lapses in consciousness, and is often accompanied by rapid or twitching eye movements. Unlike more severe cases of epilepsy, CAE is followed by an immediate full recovery in the individual. These short lapses, when not noticed or carefully observed are sometimes erroneously misread as ADHD since they do temporarily shut down memory, focus and attention, mimicking common ADHD traits.

Since the two disorders typically involve a completely different set of chemical signals, CAE individuals erroneously medicated for ADHD will naturally see little improvement with regards to either disorder. Of course, most competent trained professionals should easily be able to differentiate between the two (CAE episodes can typically be triggered and observed by inducing hyperventilation in a clinical setting, so a non-CAE individual with ADHD can quickly be separated out by this common procedure). Nevertheless, I feel that this possible misdiagnosis can be overlooked and is still worth mentioning. Also of interest in observing these two disorders is the fact that there is a gender bias for each one, although the biases are skewed in opposite directions. ADHD is seen much more often in boys than in girls (some medical professionals claim this ratio to be as high 4 to 1), while CAE is seen more frequently in girls.

Another common (and typically benign) form of epilepsy is called Centrotemporal or Rolandic Spikes. This form is often associated more with lack of facial control (partial facial paralysis and drooling), and physical speech impairments. It is believed that brain activity in many of these individuals, especially between episodes, is connected to a reduced attention span, similar to that of an ADHD individual.

Muddying this issue even further is the fact that these spikes are frequently seen in individuals who fall within the spectrum of autism. While diagnostic methods prohibit an individual from being concurrently labeled as both "ADHD" and "Autistic" (i.e., diagnostic criteria can only allow an individual to be labeled as one or the other but not both), it is important to note the large overlap of symptoms between the two. In other words, we have seen three disorders that all share a number of common overlapping symptoms.

These three disorders may even share a common genetic background. A genetic region on the 3rd chromosome identified as NHE9, has been suggested as having a possible association with ADHD. Another nearby region on the same chromosome has been tied to both autism and epilepsy, suggesting a strong possibility that all three disorders are at least in part tied down to a common genetic region. Since all three disorders are unique and often involve completely different sets of medications, it is easy to see that a misdiagnosis followed by a "mis-medication" can have profoundly negative consequences. With regards to this post, this means that individuals who do have ADHD and (appropriately) take stimulant medications may still see a relatively high frequency of epileptic symptoms, but these are often due to a common (and potentially genetic) underlying condition, and are often not due to the actual stimulant medications being administered for ADHD.

While there is the possibility of genetic overlap between ADHD and epilepsy, the two disorders typically follow completely different chemical pathways. ADHD is closely tied to two neuro-chemical signaling agents called dopamine and norepinephrine (also called noradrenaline), while epilepsy is typically tied to the neurochemicals Gamma Aminobutyric Acid (GABA), as well as Glutamic Acid and Aspartic Acid (both of which are dietary amino acids, and are chemically similar to the questionable food flavoring MSG). Nevertheless, it is true that stimulant medications that are used to treat ADHD (such as Concerta or Ritalin), have been shown to counteract the effectiveness of some traditional anti-seizure medications, namely phenobarbitone (also referred to as BAN, Luminal or phenobarbital). However, these earlier-version anti-seizure medications are often replaced by newer Anti-Epileptic Drugs (AED's), most of which don't have these negative drug interactions.

Additionally, several studies have actually pointed towards ADHD stimulant medications helping with seizure-potentiating conditions. For example, in a 1992 article in the Journal of Clinical Psychiatry, Wroblewski and coworkers observed that seizure-prone individuals with brain injuries actually saw a reduction in the number of episodes following the administration of the common ADHD stimulant methylphenidate. However, other related studies have failed to support these results.

Finally, it is also important to at least mention the possibility that stimulant medications used to treat ADHD may trigger seizures due to their well-known effects on the sleep cycle. While the exact causes of epileptic seizures are still unknown, it is worth mentioning that around half of these episodes occur either during or around periods of sleep. Additionally, sleep deprivation has been shown to increase the likelihood of seizures. It is my personal belief that we should never downplay these important facts and observations.

What I have really hoped to accomplish in this post is to provide you with a bit more background info surrounding ADHD stimulant medications and how some of the data connecting these drugs to increased seizures and epileptic episodes were acquired. Nevertheless, this was not meant to refute all claims that there is an increase risk of epilepsy that is involved by taking these medications, especially for those prone to seizures. Caution and careful monitoring by your physician are still paramount. It is my hope, and my main objective to simply arm you with a bit more information about these drugs, how they work, and how these common ADHD prescription medications can interfere with comorbid disorders such as epilepsy. Look for future posts for more "special cases" involving ADHD and other accompanying disorders.

ADHD medications

Medication with Atomoxetine for ADHD and Tourette's

ADHD medication

ADHD and Tourette's? Try Strattera (Atomoxetine)

One of the most difficult things about ADD and ADHD is that these disorders are often accompanied by other disorders (called comorbids). One of these disorders is Tourette's Syndrome. Tourette's is actually has a spectrum in and of itself, and can include behaviors such as twitches, tics, vocal "spurts", erratic movements, and in some cases, impulsive foul language. What makes Tourette's so interesting is that it tends to bridge the gap between disorders that are often found on opposite sides of the spectrum with regards to brain chemistry.


Over half of Tourette's individuals are also co-diagnosed with either ADD/ADHD or OCD (obsessive compulsive disorder). For individuals seeking treatment, the number of individuals with Tourette's that also have ADD or ADHD may be as high as 80%, according to some studies. ADHD is typically associated with low levels of the brain chemical dopamine in the front part of the brain, and high levels of serotonin. The latter, OCD, is typically affiliated with low serotonin and higher dopamine levels. Tourette's fits somewhere in between these two, from both a chemical and symptom-based standpoint.

Although there are a number of treatment options out there for ADHD, finding one that is effective in also treating the comorbid symptoms and disorders is also crucial. One of the reasons is that stimulants (such as Ritalin, Dexedrine, Adderall, or Concerta) often make several of the Tourette's symptoms, such as motor or vocal tics, worse. However, non-stimulant ADHD medications show some potential for treating these comorbid disorders. A likely reason is a different underlying chemical mechanism than that of stimulants. Several studies have indicated that the non-stimulant ADHD medication Strattera (Atomoxetine) has also been an effective treatment for Tourette's.

Although other drugs, such as Clonidine, have been tried and displayed positive results for a number of studies. However, Clonidine has also shown side effects such as sedation (drowsiness) in several different cases. While stimulants still serve as the primary mode of treatment for ADHD, we must be careful when the disorder is accompanied by other comorbid disorders, such as Tourette's. If this is the case, then non-stimulant medications such as Atomoxetine must be considered as viable alternatives in the ADHD medication world.

ADHD medications

ADHD Gene #7 SNAP 25 Gene

ADHD Genes

ADHD Gene #7: SNAP 25 Gene, T1065G allele, Human location: Chromosome #20 (20p11.2)

This will be our final installment in a series of 7 ADHD genes. Much of the information here is summarized in a publication by Faraone and Khan in a 2006 article in the Journal of Clinical Psychiatry. There will be further discussions on the topic of genes related to ADHD, so please stay tuned for future posts.

Nevertheless, the final ADHD gene, referred to in this post as SNAP 25, is of importance for discussion. SNAP 25 is short for the term "Synaptosomal-Associated Protein 25 Gene", which is located in the "p11.2" region on human chromosome #20. For more details on genes and gene locations and how they are relevant to our discussion on ADHD, please click here.

Of particular interest is the fact this SNAP25 gene is found to have a 100% match (meaning the DNA sequences are identical) in both chickens and mice. Because of this close match-up among the different species, genetic studies of this "ADHD gene" in mice (of which there are many) may provide information which is much more relevant to humans than other "ADHD genes" that have been covered. In other words, although the relative number of human studies involving this gene and ADHD is limited, a number of studies of the "mouse form" of this gene should be taken seriously.

In mice, a deletion (removal of part of a gene) for this gene results in spontaneous hyperactive behavior. Furthermore, motor abilities are noticeably compromised and physical changes to a part of the brain called the hippocampus (a part of the brain responsible for learning, memory development, emotional responses and various personality traits) were also seen. Therefore, some of the deficient "side effects" that are often seen in ADHD, such as poor memory, inappropriate emotional responses to certain situations and social maladjustments, may be affected, in part, by having the "ADHD form" of this gene. While the information surrounding this in humans should be viewed as only speculative at the present time, the direct behavioral correlations with the gene in mice are tough to ignore.

Unlike other ADHD genes, such as one in a previous post, where most of the "ADHD" behavior is tied to one single block of DNA, the correlation between the SNAP 25 gene and ADHD is more likely affected by multiple blocks of DNA on the gene. Nevertheless, the most statistically dominant form of the gene (also called allele, for more information on this, please click here) is thought to be what is called the T1065G allele. This "T1065G" notation means that the presence of a Thymine DNA base (Thymine is referred to as "T") instead of a Guanine ("G") at the DNA base 1065 (this a number is reference to where on the gene this replacement is located) results in a statistically-increased likelihood of developing ADHD.

If you are unfamiliar with the concept of DNA bases, please click here for a more detailed explanation.

While not of the statistical significance as the T1065G form, there is another nearby section of the gene that also may affect ADHD. In fact these two regions may "work together" to increase the likelihood of developing ADHD. This second form, which is backed by less statistical evidence than T1065G, is called the T1069C allele. This refers to a substitution of a Thymine (T) for a Cytosine (C) located on the 1069th base position in the gene. Keep in mind that these two regions are very close, separated by only 4 individual DNA bases. For more on what DNA bases are, please click here.

Among the key findings that we should draw from this research (as well as from other related studies) is this:
Individuals who have the "T" form at position 1065 in the gene instead of the "G" form are more likely to develop ADHD. Additionally, but to a lesser statistical degree, individuals who have the "T" form instead of the "C" at position 1069 are more likely to have ADHD as well. When combined (i.e. "T's" at both spots), the statistical likelihood of having ADHD goes up even further. Therefore, the SNAP 25 gene, located on the 20th chromosome in humans, is a good candidate gene to study and investigate for insight into an individuals genetic susceptibility to ADHD.

Again, if this explanation is difficult to visualize, please click here for another post with a relevant explanation.

Of course, SNAP25 is just one of many potential ADHD genes. However, if one is to have several of the "right forms" or alleles of multiple ADHD genes, the statistical likelihood of developing ADHD will continue to climb. Look for another post in the near future where I will summarize the results of the 7 "ADHD genes" that have been discussed in this section.

ADHD Genes

ADHD gene #6. Serotonin receptor 1B gene (HTR1B)

ADHD Genes

ADHD Gene #6: Serotonin Receptor 1B (HTR1B), human chromosome #6 (section q13)

This is our sixth gene of topic in our discussion of ADHD genes. The Serotonin Receptor 1B gene (HTR1B). Like the 5 ADHD genes previously discussed, the gene HTR1B is thought to have at least some influence on the development of ADHD. (If you would like some more background information on what genes, chromosomes, DNA and alleles are, and how they relate to ADHD, please check out this link to another section of the blog here. I have outlined some of the specifics in this area). As its name suggests, this gene is responsible for creating a specific binding site (or think of a "docking site"), for the important neurochemical serotonin. Essentially, there are multiple forms of this gene, which is located on the 6th chromosome in humans (the "q13" refers to a more specific location of the gene on the chromosome, if you would like further explanation on how this looks, please click here).

As mentioned in another post, sometimes the smallest changes in DNA can produce noticeable results in the resulting biology, and ultimately, behaviors, of an individual. This gene appears to be no exception. At one specific point of this serotonin receptor gene (HTR1B), some individuals have a DNA base of "G" (short for "Guanine"), while others have the DNA base of "C" (short for "Cytosine", for more info on what this means, please click here). It appears that the simple change of one small piece of DNA from a "C" to a "G" on this particular "ADHD gene" can have a significant effect with regards to ADHD. Individuals with the "G" form of this particular gene are statistically more likely to have ADHD than those with the "C" form.

Furthermore, the connection with ADHD seems to be strongest to a particular subtype of ADHD. Individuals with the "G" form, or allele, tend to exhibit behavior that is more concentrated on what is referred to as the inattentive subtype of ADHD. The inattentive subtype, as its name suggests, is a form of ADHD in which the inability to maintain attention for a necessary period of time is the dominant negative attribute of the disorder (in contrast to other subtypes of ADHD, which have a more concentrated impulsive component, and/or hyperactive components, which are highlighted by highly impulsive or hyperactive behavior, respectively). While other genes may be tied to these other types of ADHD, the "G" form of the HTR1B serotonin receptor gene appears to be significantly correlated primarily with the inattentive ADHD subtype.

Please remember that the "G" form of this gene is not some weird mutation or genetic malfunction. It is a perfectly common form of the gene that is found in a number of regular individuals. Furthermore, there have been several studies done on this form or allele of the HTR1B gene, including one done on fraternal twins that did not show a significant correlation between the "G" form of the gene and the frequency of ADHD. Nevertheless, the data from several other studies, when pooled together, have strongly suggested a significant statistical correlation between the "G" form and the likelihood of exhibiting inattentive ADHD behavior. In other words, we should be cautiously optimistic about this association. Keep in mind, however, that the presence of this form of the gene, or any of the previously discussed "ADHD genes" does not, single-handedly, "doom" an individual to ADHD, it simply means that individuals with this form of the gene are statistically more likely to develop ADHD. We will be wrapping up this section of posts on ADHD genes with the seventh and final ADHD gene, the SNAP 25 gene, in tomorrow's blog.

ADHD genes

Genetic terms and background information

ADHD Genes

Genes, Chromosomes, DNA and alleles: What are they and how do they relate to ADHD?

Author's Note: I realize that a lot of readers may not have any sort of background in genetics, which is why I constructed this page. If you are unfamiliar with how genes, DNA, Chromosomes, and alleles all tie together, this should serve as a great resource page. I tried to make it as straightforward as possible and use an analogy that makes the concept of genetics easy to follow. A number of other posts deal with the fact that a lot of causes of ADHD are inherited from parents to children. I am posting a number of sections on specific genes and alleles that are tied to the disorder of ADHD. Please check out the resources below:


Genes are comprised of long strings of DNA (typically numbering in the thousands or ten-thousands) and serve as a blueprint instructing the body as to:

1.) Which products (enzymes, hormones, etc.) to manufacture

2.) Where to manufacture the desired products

3.) How much of the products to manufacture

4.) When to stop, inhibit, or shut down manufactured products



Scientists generally agree that there are somewhere between 30,000 and 50,000 different genes in the human system.

DNA
DNA is short for the term Deoxyribo Nucleic Acid. It comes in four flavors or bases.

1.) Adenine (abbreviated as "A")
2.) Guanine (G)
3.) Thymine (T)
4.) Cytosine (C)

With all of the genetic diversity and variation among humans out there, it might seem strange that it all comes from four primary bases or options. However, we can see that, with four different options at every spot, we can build up a huge number of different possible sequences. Given the fact that the total length of DNA in humans is around 3 billion bases long, this means that there are an ENORMOUS number of possible combinations at our disposal.

For example, a segment of DNA may be in the following sequence: "CCGATA". This means that a Cytosine is strung to another Cytosine, which is connected to a Guanine, which is connected to an Adenine, which is connected to a Thymine, which is connected to another Adenine.

DNA's structure is typically in the helical form (think of a winding staircase). It can exist either in the single-stranded form or double-stranded form. The double-stranded form contains two strands bound together, winding up in staircase form called a double helix. The double-stranded form is relatively stable, because of a phemonomena called base pairing.

Base pairing:

The four DNA bases (A, T, C and G) tend to pair up with each other in what it called complementary base pairing. "A" tends to pair with "T" and "G" tends to pair with "C". In other words "A" and "T" are complementary, and "G" and "C" are complementary.

For example, consider our earlier sequence of "CCGATA": If this sequence is part of one DNA strand, the other one will typically match up with a complementary strand of "GGCTAT".

Do you see how that works?
CCGATA <---- strand 1 GGCTAT <---- strand 2
The C's on strand 1 match up with the G's on strand 2, the A's on strand 1, match up with the T's on strand 2 and vice versa. This pairing up and bonding between the two strands of DNA makes the DNA double helix quite stable. Since we know how the strands match up with each other, if we can find out the sequence of one strand, we can figure out what the other one would look like. For example, if we have one strand that has the following sequence:

AAATTGCCG

we can predict that the other one will "match up" with

TTTAACGGC.

Again, the A's from one strand match up with the T's from the other and the G's from one strand match up with C's from the other and vice versa.


Genes and DNA: The "highway and towns" analogy

Genes actually make up a relatively small percentage of the body's total DNA (thought to be less than 10 or 15%). One of the best ways to think of this is to envision a large highway that connects a number of towns together, but also passes along through long stretches of open country. The "highway" is the DNA, while the towns, (where the functional stuff "happens") are analogous to the specific genes. The stretches of highway in between the towns serve a limited function; their main purpose is to serve as a buffer space between the important towns. Similarly, the vast majority (over 85%) of DNA is not in the genetic region and is of limited function.

Since there are so many genes (towns), in humans, it would make more sense to create multiple highways to incorporate all of them instead of having just one long one. Essentially this is what nature does. It subdivides the DNA into different “bundles” or "groups" called chromosomes. The number of different “highways” varies from species to species; in fruit flies, the number of highways is 4, in humans, the number is 23. Additionally, human beings actually have two “pairs” of highways, one coming from each parent. Going back to our road analogy, think of our highway as a divided one, with one way going eastward and the other going westward. The two highways are “paired up”, that is, they go through the same towns and cover the same stretches of land in between, but there are now two highways instead of one. Therefore, with humans, we (typically) have 23 pairs of chromosomes (highways), for 46 total.

For humans, one of those pairs of highways is sex-determinant. If both highways are marked “X”, then you are female, if one of your highways is “X”, but the other is “Y”, then you are a male (you cannot have both highways or chromosomes as “Y” because your mother can only pass on an “X” chromosome, while your father can pass on either an “X” or a “Y”). While sex determination is a critical function of the sex chromosomes, it is important to realize that these “X” and “Y” highways also contain a number of genes themselves. These genes are referred to as “sex-linked”. If certain traits or inherited disorders show up exclusively or highly disproportionately in males or in females, chances are, at least one “sex-linked” gene is responsible.

Doing a bit of math we can see that with around 30,000-50,000 different genes (towns) and 23 pairs of chromosomes (highways), we would expect a typical highway to contain somewhere from 1000 to 2000 genes (towns). While the number of genes are not evenly distributed (some chromosomes or highways are larger than others), 1000-2000 genes per chromosome is a good estimate. Keep in mind, too, that the genes or towns vary in size as well; some may be cover a much longer stretch of highway than others. The distribution of genes among chromosomes normally does not vary from individual to individual, so you, your sister, your best friend and your next door neighbor will all typically have the exact same number of genes in the exact same order on a particular chromosome.

Taking this analogy a bit further, where we can identify a certain town as a "gene", we can further subdivide that town into smaller sections (think of individual blocks within a town). For example, one of the “ADHD genes” called the Dopamine Beta Hydroxylase Gene (DBH), has a location of “9q34”. What that means is that this gene is located on Chromosome #9 (“Highway 9” to follow the analogy), section “q34”. “q34” actually does not refer to one particular town, it still covers a slightly larger space than that (think along the lines of a county), but it does help narrow the location down quite a bit. Further numbers or letters beyond the “34” (which typically follow a “.”, such as “34.1”), can help narrow the location down even further to the city, and eventually block or even specific building level.

Alleles:
As mentioned, almost all humans carry the same number of genes in the same order, on the same chromosome. In other words, town #487 on chromosome 12 will be the same “gene” for you, as it is for Bob. Additionally, most of the blocks in your 487th town will look exactly the same as they would in Bob’s 487th town. However, there are some specific blocks that will show some variation between your town and Bob’s town. These slightly different forms of the same town are what are referred to as alleles (slightly different forms of the same gene).

Some genes have different alleles that differ in only one spot. For example, the first 8 blocks of your town and Bob’s town may contain the exact same buildings in the same order, but the 9th block in Bob’s town may contain a McDonald’s while yours contains a Burger King. Also, some alleles may differ by having a slightly longer or shorter segment for a particular block. For example, Bob’s town (allele) may have an extra gas station between blocks 15 and 16, while yours may have additional park space between blocks 19 and 20. A genetic analogy to this would be having a few extra pieces of DNA than Bob in a particular section of a gene.

Either way, it is important to remember that your genes and Bob’s genes are over 99% identical, there are just some minor differences such as those mentioned above. However, even these minor differences can have a number of prolific effects. For example, if your town and Bob’s town have the same number of residents, but Bob’s has 3 more gas stations than does yours, who do you think will be better adapted to supply enough gasoline for the town in the event of a fuel delivery truck failing to show up on a particular day? If your town has one additional power station than Bob’s, and a recent heat wave pushes up the power demand for a week, whose town will be better suited?

Similarly, a few small differences in individual variations of the same genes can play notable roles when dealing with disorders such as ADHD. A few key changes can significantly enhance or inhibit levels key proteins or neural chemicals. For example, the compound dopamine is an important signaling agent in the nervous system in which adequate levels are needed for proper brain function in areas such as maintaining an attention span. Not surprisingly, a number of ADHD individuals have lower than normal levels of dopamine in the frontal regions of the brain. Certain genes are responsible for producing key enzymes that aid in the manufacture and delivery of this important brain-friendly compound. Unfortunately, some forms or alleles of these genes are less effective in manufacturing these key enzymes. As a result, individuals with these alleles are more prone to dopamine imbalances in key regions of the brain. As a result, they are more prone to having ADHD. In the context of attention deficit disorders (ADD) and attention deficit hyperactivity disorders (ADHD), we will examine which forms or alleles of specific genes are tied to ADHD.

ADHD Genes