Why the Menstrual Cycle may affect ADHD Medication Dosing Levels

Do hormonal fluctuations result in variable ADHD medication dosage levels across the menstrual cycle?

We have investigated the impact of gender on ADHD in a number of earlier posts. We have covered topics such as:

• Gender Based Metabolic Differences in ADHD brains

• Gender Dependent ADHD Genes, including MAOA, SLC6A2, SLC6A4 and COMT

• ADHD subtypes and Comorbid Disorders

Clearly, there are a number of boy/girl differences in the root causes, diagnoses and treatment methods for the disorder.

However, we need to investigate whether intra-individual differences are also an important factor, especially where medication treatment and medication dosing levels are concerned. Based on a number of studies, it appears that women may actually require different medication dosing levels depending on where they are in their menstrual cycle. Additionally, post-menopausal drugs such as estradiol patches may also alter the drug effects of certain ADHD medications such as amphetamines. The main culprits are most likely fluctuating levels of estrogen and progesterone.

Here are brief summaries on some of the relevant studies and their findings. Wherever possible, I will include a link to the original studies:

• The link between Estradiol treatment and amphetamine medications: This study focused on whether pretreatment with estradiol played any role in the reaction to amphetamines. The drug used in this study was D-Amphetamine, which would correspond to the medication Dexedrine, however, this is also the predominantly active compound in medications such as Adderall or Vyvanse (once this "pro-drug" is metabolized). It is unclear at the moment whether chemical "cousins" to amphetamines, such as methylphenidate (Ritalin, Concerta, Daytrana, Metadate), also exhibit these fluctuations when combined with estradiol-releasing drugs.
  
  The study found that for females who took estradiol-supplementing treatments during the early follicular phase (pre-ovulation) of the menstrual cycle experienced an overall greater "stimulating" effect of the amphetamine medication (taken as 10 mg of amphetamine). This may suggest that a slightly lower dosage during this stage of the menstrual cycle might be warranted, and (as this blogger's personal hypothesis) may actually affect the addiction potential of ADHD stimulant drugs such as amphetamines.
  
  
• Another study by the same group found that estrogen may be responsible for some of the heightened euphoric effect felt from amphetamine-based drugs. However, the hormone progesterone may actually counteract some of this euphoria. During the luteal phase of the menstrual cycle (after ovulation), high levels of both estrogen and progesterone are seen (although levels of both of these taper off going into menstruation), so the effects of estrogen may be curbed. During the late follicular phase, where progesterone levels are low and estrogen levels begin to spike, the "high" may be at its peak, especially if stimulants are involved.
  
  
• A case study found that an increase in inattentive symptoms coincided cyclically with the menstrual cycle for a patient who was undergoing treatment for newly-diagnosed ADHD with a twice-daily dosing regimen of the stimulant medication Concerta.
  
  
• The findings from these two studies suggest the possibility that a slightly smaller dosing schedule with amphetamine-based ADHD medications (such as Adderall, Vyvanse or Dexedrine) may be warranted during the follicular phase. However, during the luteal phase, when progesterone levels are higher, the amphetamine-based effects are less pronounced. This may correlate to a slightly higher dosing regimen for amphetamine-based treatment for ADHD and related disorders.
  
  
• While there is a relatively good theoretical basis for this assertion above, practical consideration measures must also be considered. Based on the relative scarcity of studies (besides the 2 mentioned above) on the amphetamine-menstrual cycle interactions, it is unclear as to how pronounced the medication change should be.
  
  For instance, should someone taking 10 mg of Adderall during the follicular phase boost up to 15 mg for the luteal phase? 20 mg? 30 mg? Additionally, hormonal fluctuations vary during the phases themselves, such as the estrogen spike during the late follicular phase. Questions abound, especially when dealing with the brief ovulatory phase as well.
  
  

This blog post hopefully introduces what may be a new consideration to women who have ADHD and are currently taking stimulant-based medication treatments. Perhaps this posting simply confirms what you have already experienced.

Nevertheless, given the fact that administering variable levels of medication based on cyclical patterns such as time of day (like ramping up methylphenidate concentrations via controlled release formulations to offset "acute tolerance" based effects), and the fact that individuals with ADHD may experience seasonal variations in symptoms, at least suggests, that variable dosing of medications across the near-monthly period of the menstrual cycle may prove to be beneficial treatment strategy for females with ADHD.

ADHD, Methylphenidate and Blood Sugar Levels

ADHD medications may interfere with blood sugar levels and glucose metabolism:

When we think of common side effects of ADHD medications (especially of the stimulant variety), we often consider things such as cardiovascular risks (increased heart rates and blood pressure), appetite suppression (which may subsequently result in temporary growth impairment), interference with sleep, dampening of creativity and emotions (i.e. taking on a zombie-like state), irritability, moodiness, and the like.

However, it appears that another equally important, but often less-considered side effect of many ADHD medications is a change in blood sugar and glucose metabolism. The first part of this post will investigate some of the research out there on the effects of common ADHD medications on brain glucose metabolism. The second half will zero in on some of the general metabolic differences between the ADHD brain and the non-ADHD brain, and will also investigate possible effects of age, gender and co-existing disorders:

1. A drop in blood sugar following methylphenidate treatment: A case study involving a diabetic woman who underwent a surgical operation for a brain tumor. While we cannot make any logical conclusions about the population based on one individual of unique needs, the fact that a pronounced drop in blood glucose (over 25%) following methylphenidate treatment is at least worth noting. It is unclear as to whether the effects were due merely to the methylphenidate (common forms of this drug include Ritalin, Metadate and Concerta), or rather to a drug-drug interaction.
   
   
2. Methylphenidate reduces required brain glucose amounts to perform cognitive tasks: A study done at the National Institute of Drug abuse found that the administration of methylphenidate reduces the amount of glucose (the brain's desired energy source) needed to perform a thinking task. It is believed that this lower energy requirement is mainly due to less "wasted" energy from a constantly wandering and side-tracked mind, such as one seen in individuals with ADHD.
   
   Interestingly, this same study also found that during non-cognitive tasks, the differences in brain energy requirements did not change with or without the drug. This may at least call into question the merits of ADHD stimulant medication usage if higher order cognitive tasks are not required. Furthermore, if the brain is already focused, the utilization of methylphenidate may even be overkill. The authors concluded that this may be a primary reason why adverse effects in concentration and focus can be seen when methylphenidate is administered to "normal" functioning brains.
   
   
3. Methylphenidate's influence on brain metabolism may be regio-specific: Another study done by the same author as in study #2 found that the effects of methylphenidate on brain glucose metabolism may depend on individual subregions of the brain. For example, this study found that for the basal ganglia region of the brain (this brain region essentially governs how fast a particular individual's brain "idles"), the relative activity of this brain region was typically reduced following methylphenidate treatment, compared to activities in other brain areas. This may be a bit counter-intuitive, since basal ganglia activity is typically lower in individuals with ADHD and higher in individuals with obsessive compulsive or anxiety-ridden behaviors.
   
   However, other brain regions such as the frontal and temporal regions of the brain (which are responsible for filtering out unimportant external stimuli and inhibiting impulsive behaviors, and, perhaps not surprisingly, often show lower levels of activity in the ADHD brain), experienced a boost in metabolic activity following methylphenidate treatment. It is believed that these responses are modulated through categories of receptors for the brain chemical dopamine (called Dopamine D2 receptors, which help control levels of this important neuro-signaling agent, which is often deficient in key regions of the ADHD brain).
   
   In this blogger's opinion, this dual action of inhibiting impulsivity (which can potentially dampen creativity) and shutting down some of the basal ganglia activity may actually be a reason why "zombie-like" behaviors are sometimes seen in children medicated or overmedicated with stimulants for ADHD.
   
   
4. The "Energy Deficient" Hypothesis of ADHD: While still in the hypothetical stage, there is a fair amount of evidence suggesting that ADHD may be due, in a large part, to a lack of energy to specific neurons in key brain regions such as the prefrontal cortex (part of the "frontal" regions of the brain discussed in the past point). This ADHD as an energy-deficiency hypothesis carries that astrocytes (star-shaped cells that provide energy and nutrition for growth and repair of neuronal cells) may be starved of some of their important nutritional needs for glucose and related nutrients. As a result, they are unable to effectively "feed" the neurons in these key brain regions associated with governing attentional and impulsive behaviors in the brain. Should this hypothesis hold true, it would stand to reason that regulating and improving glucose levels either via either medication-manipulated, or alternative dietary methods may help offset some of the energy deficient imbalance in ADHD. Some natural supplemental options to boost glucose levels in the ADHD brain may include ginseng and carnitine.
   
   
5. Reduced brain metabolism in teenagers with ADHD: The results of this study on metabolic differences in teenage ADHD brains agree with many of the findings discussed in point #3 above. This study investigated the effects of an auditory-based attentional task on rates of brain glucose metabolism in adolescents with ADHD. It found that there was minimal differences between glucose metabolic patterns in the brains as a whole when comparing the ADHD and non-ADHD individuals.
   
   However, it is also worth mentioning that in other related studies on brain metabolism in teens with ADHD, it was found that metabolic deficits were seen at significantly lower levels throughout the brain as a whole. Interestingly, according to the second study mentioned, these differences in brain metabolism were only seen in the girls with ADHD and not the boys, which suggests possible gender-specific differences in the etiology of the disorder.
   
   However, upon investigating for the more hyperactive forms of the disorder in the first study (remember that ADHD behaves as a spectrum, in which some individuals have the predominantly inattentive symptoms, while others exhibit the hyperactive and impulsive symptoms more readily, these different predominant features are typically grouped together as unique subtypes of ADHD), it was found that the hyperactive component of ADHD corresponded to a significantly reduced level of glucose metabolism in the whole brain. This brings up the question as to whether these metabolic differences exhibit any sort of subtype-dependent effects with regards to ADHD.
   
   Also, as in point number 3 above, metabolic deficits were apparent in more specific brain regions such as the left frontal lobe regions of the brain. Even more remarkably, there appeared to be somewhat of a sliding scale with regards to the relationship between reduced glucose metabolism and increased symptom severity in this particular "hot spot" (the left frontal lobe) region of the ADHD brain.
   
   The following sidenote is a personal comment by the blogger regarding some of the methods of the previous study. As mentioned above, the test for this adolescent ADHD study involved an auditory based attention task. However, as discussed in earlier posts on this blog, we have seen that auditory processing disorders sometimes accompany ADHD.
   
   Furthermore, due to a high degree of symptom overlap, a comorbid auditory processing disorder can often be missed in an ADHD child or adolescent. Because of this, we should not rule out the possibility that comorbid auditory processing issues may interfere with the results of studies such as this one.
   
   We can see that auditory processing takes place in multiple regions throughout the brain, many of which do not have significant overlap with the "ADHD brain regions". One would expect the brain of an individual with an auditory processing disorder to work harder to achieve the same results as that of a non-auditory disordered individual. Thus, a confounding processing disorder could, in theory result in an increased demand for energy utilization to the portions of the brain responsible for stimulatory processing, which could leave less available energy for the frontal lobe regions of the brain responsible for modulating hyperactive and impulsive ADHD behavior. These assertions remain hypothetical at the moment, but this blogger feels that the presence of undetected comorbid disorders can easily skew the results of these metabolic studies on the ADHD brain.
   
   
6. Age-Dependent Decline in Brain Glucose Metabolism in Adults with ADHD: Apparently, metabolic differences in ADHD brains are not limited just to children, adolescents, and young adults with the disorder. Some of the findings of this following study may seem inherently counterintuitive at first. While ADHD symptoms often decline as an individual with the disorder ages, we would expect that an accompanying level of improvement in glucose metabolism in ADHD-specific brain regions would hold true. However, according to this study on brain glucose metabolism in older ADHD adults, it appears that the opposite is actually the case.
   
   The authors hold that the decrease in glucose metabolism may actually be markers of a more efficient process of brain metabolism (i.e. these older ADHD brains may somehow conform to an efficient energy-conservation state allowing them to function more optimally, thereby decreasing the prevalence of ADHD symptoms), although this finding is somewhat suspect in this blogger's personal opinion.
   
   As an interesting side note, the decrease in brain glucose metabolism in adults is apparently gender-specific, according to the study. This parallels the findings from some of the adolescent ADHD brain metabolic studies. The notable metabolic decreases were observed in women with the disorder to a much larger degree in men. The authors of the study suggested this may be due to hormonal influences, such as changes in post-menopausal women.
   
   Given the anecdotal evidence supporting the association between ADHD and higher onsets of neurodegenerative diseases later in life, this blogger finds the results of this study to be of particular interest. There may even be some claims that genetics may be partly to blame for the overlap between ADHD and neuro-degenerative diseases. For example, a gene referred to as DAT1 (short for dopamine transporter gene 1, located on the 5th human chromosome) may be connected to both ADHD and parkinsonism (a secondary or alternate form of Parkinson's disease). DAT1 also helps regulate dopamine function, (although via a different method than the dopamine receptors mentioned in point #3), by coding for an enzyme that helps transport or shuttle dopamine into and out of neuronal cells. We have discussed these dopamine transporter genes in earlier posts.

We have covered a number of works on the metabolic differences of glucose in the ADHD brain, and how they differ from the brains of non-ADHD individuals. There is the distinct possibility that stimulant medications used to treat ADHD, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana) can significantly alter brain glucose requirements. It appears that significant differences in brain glucose utilization patterns and efficiency may affect the entire brain, but certain ADHD "hot spot" regions of the brain may be particularly hard-hit. It is unclear whether this is due to preferential metabolic differences of the ADHD brain (compared to the "normal" brain), or whether it is due to an all-out brain energy shortage.

It is also worth noting that significant gender-specific factors may also affect this process, with ADHD girls in particular showing the greatest metabolic deficits. It also appears that these effects are also being observed across the lifespan of the ADHD individual. Finally, there is at least a hypothetical possibility that sensory processing difficulties or other comorbid disorders commonly seen alongside ADHD may also play a role in these metabolic differences of ADHD brains.

ADHD, Gender and the MAOA gene

The MAOA gene will be the last of the four-part series on genes believed to be connected to ADHD that exhibit a gender effect. The four genes, which were discussed in an article by Biederman and coworkers are listed below:

• SLC6A4 gene (also referred to as SERT or Serotonin Transporter Gene)
• COMT gene (also referred to as Catechol Methyltransferase Gene)
• SLC6A2 gene (also referred to as NET or Norepinephrine Transporter Gene)
• MAOA gene (short for Monamine Oxidase)
  

The first two genes on the list above are believed to exhibit a greater influence on males with ADHD than on females with the disorder. In other words, specific "ADHD" forms of these two genes often show up at significantly higher relative frequencies in males with the disorder than in females with ADHD.

In contrast, however, the SLC6A2 gene, which codes for the critically-important norepinephrine transporter protein, seems to have some type of genetic predisposition to ADHD females. We discussed this in the previous post on SLC6A2.

Location of the MAOA gene in the human genome:

Unlike the other three genes we've discussed, which appear on the first 22 chromosomes, the MAOA is unique in that it is located on the X chromosome (which is a sex-linked chromosome). Because of this, it is, perhaps without surprise, a possible gender-linked difference in ADHD connected to different forms of this gene.

The relevance of the MAOA gene to dosage levels of ADHD medications:

In a previous post, we covered extensively the different forms of the COMT gene and the implications on medication dosage levels. For MAOA, there is apparently an analogous gene-medication dosage connection as well.

Monoamine Oxidase inhibitors (MAOIs) are a class of drugs often used for treatment of depression and related disorders. This class of antidepressants have a mechanism of action that targets the enzyme Monoamine Oxidase, which is coded for by this ADHD gene MAOA. Given the fact that depressive disorders often occur more often and with greater severity makes the gender-based difference of the MAOA gene even more intriguing.

Blogger's personal note (feel free to skip this section, which reflects my personal opinions as to the direction that the ADHD medication battle may soon be heading in the near future):

I have mentioned in previous postings that I believe that analyzing specific genes believed to be associated with ADHD and screening individuals for which forms of the gene they have can be an immensely useful tool in the very near future. Given the fact that even slight variations in a specific gene can result in huge differences in the level of expression enzymes and other proteins encoded by these genes, having one of the "underactive" forms of a certain ADHD gene may play a huge role as to what level of medication dosage one must take.

Since many ADHD medications (as well as medications for many other types of disorders) are initially tailored by the individual's size and weight (in addition to the severity of the symptoms, of course), one's genetic makeup may be an equally important determining factor. For example, let's assume that an individual is exhibiting a number of depression-like symptoms, and is placed on a monoamine oxidase inhibitor drug (Which is actually unlikely, at least initially, since MAOI drugs are typically more dangerous than most other antidepressants, and are often used only as a last line of defense. Nevertheless, for the sake of example, let's consider it.).

Monoamine Oxidase Inhibitor (MAOI) drugs, as their name suggests, reduce the activity levels or expression of the monoamine oxidase enzyme (which is coded for by the MAOA enzyme). Now let's assume that an individual has a relatively rare genetic form of the MAOA gene, which produces an enzyme with only one percent of the activity of the more common MAOA gene forms. Because much less enzyme is produced or expressed compared to a normal case, this particular individual would likely need less of the MAOI drug to do the trick than would someone who expressed a much higher level of the enzyme. As a result, instead of giving a 30 mg dose of the drug (determined by the patient's size and symptom severity), the prescribing physician might want to initially start with a lower dosage. For a similar argument with regards genes and medication dosages dealing with the COMT gene ("COMT" is short for Catechol Methyltransferase) please see an earlier blog entry titled ADHD Genes Influence Medication Dosage.

Other diseases and disorders affiliated with the MAOA gene:

Anxiety: As previously mentioned, girls with ADHD are typically more prone to comorbid anxiety disorders than are boys with ADHD. There is some evidence, based on the mouse model (which is often a surprisingly good approximation of human behaviors with regards to psychological disorders, a topic which will be reserved for later posts) that mutations in the MAOA gene that reduce its function may be related to higher anxiety levels.

Aggressive, antisocial and criminal behaviors and MAOA:

Deficiencies of the enzyme Monoamine Oxidase, which is coded for by the MAOA gene, have been linked to impulsive aggression and related behaviors in mildly retarded individuals. Keep in mind, however, that this was obtained from a small study and that the disorder, known as Brunner Syndrome, is relatively uncommon.

A more focused study found that the MAOA gene may actually play a role in the "nature/nurture" debate as to why some individuals exhibit violent and aggressive behavior and why others do not. This study focused on children who had been mistreated and analyzed which of the mistreated children were prone to aggressive, violent or criminal behavior. According to the study, children who had "high levels of MAOA expression" (that is, children who had genetic variations of the MAOA gene which produced higher levels of the enzyme monoamine oxidase) were less prone to violent behavior, while those who had lower activity forms of the MAOA gene were more prone to criminal behavior.

As a result, screening individuals who have unfortunately endured a history of abuse for specific genetic variations, may actually help predict (and get a leg up on early treatment options for) the likelihood of that particular individual of developing violent, criminal or abusive behaviors themself. While we must guard against the tendency to put too much emphasis into one particular gene (or even group of genes) for predicted a complex and multi-faceted behavior pattern, I personally believe that we should try to take advantage of every little point of potentially valuable information at our disposal.

MAOA and Bipolar disorders:

One note of potential interest, however, is the fact that Brunner Syndrome (mentioned earlier) carries with it relatively high degree of overlap with bipolar disorders. Bipolar disorders may both occur alongside ADHD or exhibit such a similarity of symptoms (especially in younger children) that misdiagnoses between the two can occur. A study by Lim and coworkers found an association between the MAOA gene and bipolar disorders. However, while some other studies have supported this connection between bipolar disorders and the MAOA gene, other studies have brought in to question or refuted the findings. Also, please note that the study was done in males, which, according to the Biederman study are less susceptible to genetic difference-based ADHD than are females with the disorder.

Restless Legs Syndrome:

We have previously discussed some of the connections between ADHD and Restless Legs Syndrome. We have hinted at an underlying iron deficiency, which may affect levels of the important signaling chemical dopamine. A study was done on the MAOA gene and restless legs sydrome and concluded that for individuals with a "high activity" form of the MAOA gene were significantly more prone to developing restless legs syndrome. A note of further interest is that the same study saw an assocation in the MAOA gene variant and restless legs syndrome in females but not in males, lending credence to the possibility that girls may be more susceptible to MAOA gene differences in disorders besides ADHD.

The MAOA gene and disorders associated with specific brain regions:

Attention span: The MAOA gene (like most genes) does not express itself uniformly throughout the body. Instead, certain regions appear to be more targeted more than others. The cingulate is a region of the brain which we've discussed on more than one occasion in previous posts, and essentially acts as the brain's gear shifter. If this brain region is overactive, the individual can become overly focused on one particular topic or action (obsessive compulsive disorders or OCD-like behaviors can ensue), while underactivity in the cingulate region of the brain can result in someone's attention being scattered all over the place, like in most ADHD cases.

A study by Fan and coworkers found that different alleles (different versions of the same gene, which vary from individual to individual) of the MAOA gene corresponded to different levels of activity in the cingulate portion of the brain. These genetic variations and different levels of cingulate activity corresponded to differences in reaction timing to certain attention-based tests. The actual test used in the study was an "arrow test", which is described in more detail in an earlier blog post titled Gene Variations Which Affect Attention Control.

MAOA Gene, Brain Size and Tendency Towards Impulsive Behavior and Violence:

The different forms of the ADHD gene MAOA may affect more than just activity level in the cingulate region of the brain. A 2006 publication by Meyer-Lindenberg and coworkers titled Neural mechanisms of genetic risk for impulsivity and violence in humans found that individuals who had "lower activity" forms of the MAOA gene (and protein which it encodes) actually had smaller volumes in specific brain regions, including the cingulate (as well as larger volumes in other brain regions, some of which are believed to be affiliated with specific forms of ADHD).

There was at least somewhat of a gender-based difference with regards to this MAOA gene/brain size association, which was higher in males, according to this particular study. Thus it appears that while the MAOA gene may play a greater role in ADHD, anxiety and a handful of other disorders in females, it may have more of male-based effect in other disorders (some of which frequently occur alongside of ADHD themselves).

MAOA and Autism:

The gender based differences of the effects felt by different forms of the gene MAOA can also be seen in autism (which is a predominantly "male" disorder), at least based on the findings of some studies. Cohen and colleagues found that male children who had a lower-activity version of the MAOA gene displayed more severe autistic behaviors than those with higher-activity forms of the gene MAOA.

I realize that this has been a long and extensive post on the MAOA gene. To quickly summarize:

• The MAOA gene is located on the X chromosome, which makes it more susceptible to sex-linked differences (since females have two copies of this chromosome and males only have one).
• For ADHD and some other disorders which can often occur alongside of ADHD, such as anxiety, the MAOA gene has shown a tendency to have more pronounced effects in females.
• For other disorders, such Bipolar Disorders, Autism, and Violent/Aggressive behaviors, the MAOA connection appears to be stronger in males. Environmental factors (such as a previous history of abuse) may have a greater interaction with genes such as MAOA than we previously thought.
• The specific allele or form of the MAOA gene that a particular indivual has may play a role in governing the type of and optimal dosage levels of that individual's medication needs.

This concludes our four-part series on ADHD genes thought to exhibit gender-specific effects. However, we will continue to re-visit some of these topics in future posts on this blog.

ADHD, Gender, and the SLC6A2 gene

We are currently plowing through the four candidate ADHD genes listed below which have been investigated for gender dependence based on an article by Biederman and coworkers. The four genes are:

• SLC6A4 Gene
  
• COMT Gene
• SLC6A2 Gene
• MAOA Gene

We have seen in previous posts that both the COMT gene, and to a lesser extent, the SLC6A4 gene have exhibited a gender dependent behavior with regards to the disorder of ADHD. In other words, certain forms of these genes tend to turn up at a higher frequency in males with ADHD than in females with ADHD. While both SLC6A4 (which is often referred to as a Serotonin Transporter Gene or SERT), and the COMT (short Catechol Methyltransferase, an important enzyme of relevance to ADHD and related disorders) gene effects on ADHD are suggestively greater in boys, the SLC6A2 and MAOA genes are believed to have a greater impact on ADHD in girls. We will be investigating the SLC6A2 gene here:

Location of the SLC6A2 gene:
SLC6A2 is a gene located on the 16th human chromosome. It is responsible for coding the important protein Norepinephrine Transporter Protein 1, and hence, the gene (as well as the protein that it codes for) frequently go by the abbreviation NET.

Clinical relevance of this SLC6A2 gene:
Norepinephrine is an important signaling agent in the nervous system, and deficiencies of this important chemical are often seen in various brain regions of individuals with ADHD. The protein is analogous to other proteins we've previously discussed, such as the Serotonin Transporter Protein, which is often abbreviated as SERT (which is coded by the SLC6A4 gene which was previously mentioned), and the the Dopamine Transporter Protein (DAT), which we've discussed in other previous posts. The NET, SERT, and DAT proteins are responsible for clearing Norepinephrine, Serotonin and Dopamine from the areas in between nerve cells and into the surrounding cells themselves, which aims at establishing an optimal balance of these three signaling chemicals in and out of the cells.

This is especially important and clinically relevant to ADHD, where the signaling chemicals (especially Norepinephrine and Dopamine) are often out of balance, often exhibiting a sub-optimal concentration of these signaling agents on the outside of the cells. Many stimulants and other ADHD medications work by correcting this imbalance by targeting these protein transporters which shuttle the signaling chemicals in and out of the cells and surrounding areas.

However, different gene forms can actually affect the activity of these shuttling transporters as well, which can disrupt the balance of these important neuro-signaling chemicals Norepinephrine, Dopamine, and Serotonin. As a result, different forms of the genes that code for these transporter proteins may actually play a role of how great the imbalance of these signaling chemicals is, which can affect how much of a particular medication is actually needed to correct these imbalances. In other words, the amount of stimulant medication one may need for ADHD may ride, at least in part, on which form of COMT, NET and DAT genes that particular person has. For a more visual and detailed look at this gene-medication relationship, please see this earlier blog post on titled ADHD genes influence medication dosage.

Other disorders associated with the SLC6A2 gene:
Anorexia:
There is widespread discussion as to the overall prevalence of eating disorders in individuals with ADHD compared to the general population. However, several studies have linked ADHD to significantly higher rates of eating disorders. If this holds true for the population, another study of potential interest may involve the SLC6A2 gene. A particular form of this gene (referred to by the alternate term norepinephrine transporter gene in the paper) was associated with doubling the risk of developing anorexia nervosa.

Orthostatic Intolerance:
Orthostatic intolerance is a disorder in which noticeable physiological differences (heart rate, lightheadedness, fainting, etc.) occur as a result of postural changes (i.e. going from laying down or sitting to standing). Of course, some of these signs occasionally affect everyone, but for some individuals, the differences are much more pronounced and much more severe.

According to a study done by Shannon and coworkers, it is believed that the SLC6A2 gene (again, called norepinephrine transporter in this paper) may play a role in the effects of orthostatic intolerance. A mutant form of this norepinephrine transporter gene resulted in around a 50-fold reduction in functional ability of the norepinephrine transporter protein coded for by this mutant form of the SLC6A2 gene and was susceptible to major changes in norephinephrine levels and pronounced physiological changes upon changing postural positions (to the standing position). As a result, a fully functional SLC6A2 gene is apparently critical in regulating stable physiological functions in individuals.


Male vs. Female Differences of SLC6A2 and ADHD:
Like the SLC6A4 gene (and unlike the COMT gene) mentioned previously, the SLC6A2 gene showed statistically significant gender-based differences in preliminary tests, but failed to reach statistical significance upon a more detailed analysis. However, the authors of the study were quick to point out that there were gender-based differences in a specific sub region of this gene. Nevertheless, we must keep in mind that this gene, should it actually influence gender-based differences in ADHD patients, would play a much more minor role in the process than would other genes such as the previously-discussed COMT gene and the soon-to-be discussed MAOA gene.

As a note of potential interest, animal studies have actually shown differences based on analogous forms of this gene. For example, a study on rats (which, in general, shows a surprisingly high degree of overlap with human psychological disorders), showed that there was a gender-different responses to stress, even after gender-based hormonal differences had been taken into account. In addition, another analogous rat-based anxiety study (note that we previously discussed how females with ADHD exhibit more comorbid anxiety disorders than do ADHD males) showed that female rats without the SLC6A2 gene were much more prone to exhibiting behaviors of fear and anxiety than were male rats without the gene.

This possibly suggests a greater gender dependence of this gene, that is a greater "need" for a fully functioning SLC6A2 gene in females than in males. This may have potential implications in ADHD individuals, (many of whom exhibit some sort of anxiety-related disorder alongside their ADHD) by demonstrating a gender-based genetic influence into the mix. In this blogger's opinion, it is possible that genetic and clinical screenings for the SLC6A2 gene may be potentially useful factors in predicting one's likelihood of developing ADHD with a co-occurring anxiety disorder in the near future.

In the next post, we will finish our discussion of the four gender-based ADHD genes by going over the last gene of the series, the MAOA gene.

ADHD, Gender and the COMT gene

We have previously introduced a list of four ADHD genes which are being investigated for gender-specific effects. A list of the four can be found below:

• SLC6A4 gene
• COMT gene
• SLC6A2 gene
• MAOA gene

In the previous post, we investigated the SLC6A4 gene, which is located on the 17th human chromosome, and has a possible (but, at the current time a statistically questionable) preference towards being expressed in ADHD males than in ADHD females.

The second gene on the list, the COMT gene, is also believed to have a male-favoring genetic effect with regards to ADHD individuals. The COMT gene is located on the 22nd human chromosome. "COMT" is actually an abbreviation for catechol methyltransferase, which is an important enzyme involved in a number of neurological functions which have numerous ADHD-like implications. This important enzyme is coded for by the COMT gene (many genes share a name with the proteins which they encode). Unlike the SLC6A4 gene, this COMT gene has more grounds for statistical significance, both in gender-dependent and overall studies of genes believed to be associated with ADHD.

We have discussed the COMT gene and its role in ADHD in previous posts. We have also explored the possibility that COMT gene variations may affect attention control. Additionally, the presence of a specific form of the COMT gene, combined with a low birth weight, may be correlated to a higher prevalence of conduct disorders (aggressive, violent, oppositional and even criminal behaviors), which are sometimes seen at higher-than-normal levels within a subset of the ADHD population. Finally, different variations of the COMT gene may influence medication dosage levels for stimulants and other ADHD drugs.

Gender specific effects of the COMT gene and ADHD:

It is important to note that there is a fair amount of diversity in individual genes among the human (as well as other species) populations. Many of these genetic variations do not exhibit direct effects or physiological differences. However, in some cases, variations caused by a single bit of DNA in a key region of a gene can have significant effects. Such is the apparent case with the COMT gene.

Individual pieces of DNA (or nucleotides), are numbered for reference purposes. For the COMT gene, the Val158Met variation (also known as a polymorphism, which is another word for a variable form of the same gene), has been studied relatively extensively. "Val158Met" essentially refers to a DNA sequence change at the 158th position in the COMT gene which results in either a Valine (Val) or Methionine (Met) amino acid at a specific location in the COMT enzyme. This single DNA change in the COMT gene (and subsequent single amino acid change in the COMT enzyme) can result in drastic changes in the COMT enzyme effectiveness. This slight change can have effects on executive brain functions, response to morphine and other pain medications (as well as other drugs, as mentioned in a previous blog post titled ADHD genes influence medication dosage), differences in the overall pain response (among many other factors) and may even play a role into one's predisposition towards cannabis use.

Out of the "Val" and "Met" forms of the COMT gene (and resulting enzyme), there are believed to be gender-related differences. According to a publication on gender-based gene effects in ADHD, Biederman and coworkers found that males with ADHD had a greater likelihood of carrying the "Met version" (or allele) of the COMT gene than did females with the disorder. Another study by Qian and coworkers saw similar results. In addition, the Qian study found that the "Val "form of the COMT gene showed up at higher frequencies in females with ADHD than in males with the disorder.

Taking this one step further, the Met allele of the COMT gene has been tied to impulsive behaviors and aggression, two behaviors more commonly associated with males. Interestingly, a recent study just came out, which found the Met form of COMT gene to be associated more with the inattentive subtype of ADHD, while the Val form of the COMT gene was more connected to oppositional defiant disorders (which are often connected to the hyperactive/impulsive or combined subtypes of ADHD). As a result, the specific allele one has of the COMT gene may be a potentially useful tool as far as predicting which subtype of ADHD a person would be predisposed to, should they actually be diagnosed with the disorder.

Given the numerous associations of COMT in areas related to (as well as unrelated to) ADHD, we should remain on the lookout for future studies regarding the gene. The Val158Met polymorphism of this gene continues to be a hot topic of discussion and study. Additionally, the fact that a number of these associations have gender-based implications, makes COMT potentially the strongest of the four ADHD genes previously mentioned which are believed to have gender-dependent effects and expressions.

In our next post, we will investigate the SLC6A2 gene and its role on the gender dependence of ADHD. Unlike the COMT and SLC6A4 genes we've just discussed, which both have a predilection towards males with the disorder, this SLC6A2 gene is believed to have more of an influence on females with ADHD.

ADHD gene SLC6A4 favors males over females

In our last post, which asked the question "Are ADHD genes Gender Dependent?" we introduced four genes believed to be associated with the disorder of ADHD:

• SLC6A4 gene
• COMT gene
• SLC6A2 gene
• MAOA gene
  

In the next four posts, we will investigate each of the 4 ADHD genes listed above.

SLC6A4 gene, gender effects, and ADHD:

Out of the four genes listed above, the SLC6A4 gene has the least gender-based effects. The authors of the original paper on gender effects of four genes actually concluded that the gender specific influence of SLCA4 gene was not statistically significant. Nevertheless, the authors briefly noted that there was a greater influence on males than females for this particular gene (in the summarizing abstract portion of the paper).

The particular region of investigation on the SLC6A4 gene, which is located on the 17th human chromosome, was at a specific marker rs2066713 (If you are not familiar with this terminology, this is not important, it is just a way of citing a specific region of DNA and can be used to pinpoint a more exact location on a gene for studies on genetic variations, mutations, etc.). According to the study, at this specific marker on the SLC6A4 gene there was a higher likelihood that ADHD boys would receive the DNA base thymine ("T" for short) at this particular location than did ADHD females. This suggests that this "T" form (or "allele", which is a particular form or variation of a gene) at this particular spot on the 17th human chromosome which contains the SLC6A4 gene is more likely to be passed on to males with ADHD than females with ADHD. In other words, this "T" form of the SLC6A4 gene may be more associated with ADHD in males than in females. Of course, we must reiterate, that although a gender difference was observed, it was not sharp enough to be considered statistically significant, according to the original study.

Some other thoughts about the SLC6A4 gene and potential relevance to ADHD symptoms and behaviors:

• The SLC6A4 gene is often referred to by other more common names: the serotonin transporter gene (also abbreviated as 5-HTT, Serotonin Transporter, and SERT) is believed to be associated with a number of depression-related mechanisms. Interestingly, the link between the serotonin transporter gene and depression may also be susceptible to stress and other environmental factors. This gene is responsible for coding for and ultimately producing a serotonin transporter protein, which is frequently implicated in depression-related illnesses and is the target of antidepressant medications, such as Paroxetine (Paxil), Imipramine (Tofranil) and Fluoxetine (Prozac). In addition, the products of the SLC6A4 gene are also affected by amphetamines, which among some of the most common types of ADHD stimulant medications. In other words, the different forms of this SLC6A4 gene may actually play a role as to how an individual acts to a particular antidepressant or amphetamine medication. Again, keep in mind that there is often a fair amount of overlap of depression with ADHD (some experts argue that a "Depressive" form of ADHD should actually warrant its own ADHD subtype), so it is possible that gender based differences in this gene may be related to this hypothetical subtype in particular.

• However, other evidence suggests that the SLC6A4 gene may not be exclusively labeled as a "depressive gene". A study done on multiple genes believed to affect aggression and impulsivity (the latter being a common trademark of ADHD, while the former is occasionally seen extreme cases, although much more rarely, and typically only in the presence of additional comorbid disorders to ADHD), and found a nominal association between this SLC6A4 gene and cognitive impulsivity. Cognitive impulsivity, in essence, is associated with an individual making hasty decisions without carefully considering the consequences of one's actions, which frequently leads to negative or even dangerous outcomes. Not surprisingly, this is seen at much higher rates in ADHD individuals. Similar features are seen in ADHD individuals who have underactive functioning in the right frontal lobe region of the brain (a diagram of this region is given in an earlier blog post on differences in ADHD kids' brain regions), as well as those who have low tryptophan levels (which often correlates with depression and depression-like symptoms).

• There is also a possible connection of this particular SLC6A4 gene and autism, although numerous other studies have shown conflicting results. Nevertheless, given the fact that there appears to be a notable (but incomplete) overlap of ADHD and autistic symptoms, and the fact that autistic disorders are much more prevalent in boys, it is possible that there may be a tie-in between this "male-dominated" SLC6A4 gene form and a possible ADHD-autism connection.

• Finally, studies have linked variations in this serotonin transporter gene to bipolar disorders. This is also of interest because ADHD and bipolar disorders can occur together frequently and can sometimes be difficult to differentiate, especially at the pediatric level.

In the next few posts, we will be investigating three other ADHD genes believed to have gender-specific effects, which each have a potentially greater sex-related differences than this SLC6A4 gene.

Are ADHD Genes Gender Dependent?

In the past, we have investigated a large number of ADHD genes (that is, specific genes who have one or more forms or alleles which correlate to the disorder ADHD at higher-than-normal frequencies). We have also previously looked at some of the roles of gender effects on ADHD. However, we have not dedicated much time to exploring the possibility that these two factors may, in fact, be related.

A 2008 paper by Biederman and colleagues on sexually dimorphic effects of ADHD genes may shed some light on this potential association. They highlighted a total of four different genes which may be of influence with regards to the onset of ADHD. Two of these four genes appear to exhibit more of an influence on males, and the other two may exhibit more of an effect on females.

These four gender-related ADHD genes are listed below:

• COMT gene
• SLC6A2 gene
• MAOA gene
• SLC6A4 gene

We will be exploring each of these four ADHD genes affected by gender in subsequent postings.

Gender, Age and Subtype Effects on ADHD Comorbid Disorders

We have spoken extensively on some of the related or comorbid disorders associated with ADHD ("Comorbid" here refers to an accompanying disorder that frequently occurs alongside ADHD. These may include disorders such as depression, Tourette's Syndrome, allergies, substance abuse problems and the like). The topic of this post is to investigate whether there is a pronounced gender effect on these comorbid disorders; in other words, whether boys and girls are more prone to a particular disorder comorbid to ADHD based on their gender. As we will see later, age and ADHD subtype effects are also important factors with regards to comorbid disorders.

Much of this info was taken from an article titled Gender Differences in ADHD Subtype Comorbidity by Levy and coworkers. Here is a summary of some of the main points in the study:

• Approximately half to over three quarters of ADHD children carry some type of comorbid behavior disorder. These include oppositional defiant and conduct disorders, learning disabilities and communication disorders (including speech and reading difficulties). Additionally, many exhibit anxiety disorders such as generalized anxiety disorders or separation anxiety disorders.

• Additionally, ADHD has traditionally been separated into three different forms or subtypes: inattentive, hyperactive/impulsive, or combined (a combination of the other two subtypes). All three subtypes are heavily skewed towards the boys, which outnumber girls from anywhere around 2:1 to 5:1 (some studies skew this gender difference even higher, up around 10:1). Based on the study by Levy and coworkers, here is an approximate distribution (numbers indicate overall percentages among the study population, which includes non-ADHD individuals) among the prevalence of the three subtypes for both genders:
  

As we can see, all three subtypes are skewed heavily in favor of the boys.

• Of the three subtypes listed above, it appears that the subtype (again, perhaps not surprisingly) most associated with comorbid disorders (listed in the first point) is the combined subtype.
  

• There appears to be a discrepancy between the genders as far as internal/external symptoms of ADHD and related disorders. Some studies have suggested a general trend in which many of the symptoms or problems of girls with ADHD and related disorders are more internalized (i.e., they do not outwardly manifest themselves as readily as boys), which may contribute to the skewed gender differences mentioned above. On the contrary, the same study suggests that external or outward symptoms are more apparent in boys, which may compound this effect.

• Reading disabilities are, perhaps not surprisingly, more common in children with ADHD. It appears that reading disabilities correlate more to "internal" symptoms in girls and "external" symptoms in boys with ADHD, however, reading disorders appear to have very little overlap with conduct or oppositional behaviors such as aggression or delinquent behavior. Furthermore, reading difficulties appear to be more related to the inattentive side of the disorder of ADHD than the hyperactive/impulsive side of the disorder. In other words, the inattentive and combined ADHD subtypes are significantly more likely to have problems with reading than the exclusive hyperactive/impulsive subtype for both genders. It appears that reading difficulties and inattentive behavior may have an even stronger correlation in girls.

• Furthermore, with regards to reading and speech disabilities, there is a strong gender difference for non-ADHD individuals. However, once the disorder of ADHD is introduced, the gender difference becomes less of a factor (this holds for all three ADHD subtypes). This may at least suggest, that ADHD symptoms may override or overpower what appears to be more subtle gender differences with regards to speech and reading disorders.

• There is a significant association between generalized anxiety disorders and ADHD for both genders. Gender differences for the combined ADHD subtype were especially pronounced, with rates among females with the combined ADHD subtype being significantly higher than the combined subtype males. In addition, the combined subtype was more associated with generalized anxiety for both genders (when compared to the inattentive subtype), which suggests that hyperactivity/impulsivity may play some sort of role in generalized anxiety for both genders.
  

• With regards to separation anxiety disorders (such as from parents or loved ones), it also appears that there is a higher correlation to girls with ADHD, especially with regards to the inattentive ADHD subtype. For boys, the separation anxiety disorders were highest for the combined ADHD subtype. The study suggested that separation anxiety disorders may be a sign of immaturity for both genders, and may be indicative of later "internalizing" problems in girls. Furthermore, this assertion is in agreement with several studies which associate ADHD with a delay in maturity.
  

• Based on the two findings above, in which girls with the inattentive ADHD subtype had higher rates of separation anxiety disorders and girls with the combined subtype having increased rates of generalized anxiety disorders (both of which are considered more "internal" symptoms) than their male peers, it may be suggest that screening for ADHD in girls who exhibit anxiety disorders may be beneficial, in that it may reveal underlying comorbid ADHD and offset some of the skew among gender differences and ADHD.

• Finally, age has been shown to be an important factor with regards to symptoms and severity of ADHD comorbid disorders. In this study, comparisons were done between the younger (ages and and under) and older (ages 11 and older) children in the study population. For males, the prevalence of most of the comorbid disorders (speech and reading difficulties, oppositional defiance, generalized and separation anxieties) decreased with age, with the notable exception being conduct disorders, which increased with age. For females, age was less of a factor for all of the comorbid disorders listed above with the exception of Separation Anxiety Disorders, which decreased with age (supporting the earlier assertion that this disorder is tied to maturity levels and would naturally decrease as a child gets older). In addition, inattentive symptoms associated with ADHD actually increased with age for the female population of the study. This was the exception to the overall trend of decreasing ADHD symptoms with age, which was seen in the other two subtypes for females and all three subtypes for males.
  

I would like to conclude with a final note of personal opinion. I firmly believe that when screening, diagnosing and attempting to treat ADHD and comorbid disorders, we employ far too little emphasis on the gender differences surrounding these disorders. This can lead to several potential problems such as stereotyping or pigeon-holing certain behaviors (i.e. attributing hyperactivity/impulsivity as being a "male" characteristic and either intentionally or unintentionally overlooking these symptoms or behaviors in girls).

In addition, it appears that girls may have a higher prevalence of the more "internal" comorbid disorders such as anxiety, which are often more difficult to detect than the more outward comorbid disorders of oppositional defiance and conduct disorders. This may play a major part in the gender discrepancy of ADHD diagnosis, which may leave a number of girls with ADHD undiagnosed and untreated.

Additionally, the more "internalized" nature of female cases may also lead to a lack of diagnosis and treatment for comorbid disorders associated with ADHD as well. The Levy study pointed this out, citing the discrepancy between referrals for ADHD-related reading disabilities. Reading disorders for boys were more likely to be associated with some of these outward characteristics, while girls with reading disorders exhibited more of the aforementioned "inward" traits. As a result, the rates of referral for boys with reading disabilities (based on their overall representation in the population) was almost twice that of girls.

Furthermore, this study by Levy, as well as several others, indicate that there are several (sometimes unusual or counter intuitive) associations between gender, and ADHD subtype and the expression of symptoms of specific comorbid disorders. For example, attributing an increase in Separation Anxiety disorders to younger females with the Inattentive ADHD subtype or Conduct Disorders to the Combined ADHD subtype in males may give us some possible insight as to which subpopulations of ADHD children are most "at risk" for developing some of the aforementioned comorbid disorders.

Since several of these comorbid disorders carry their own lines of medication and other treatments, the subclassification of ADHD children based on age, gender and subtype may be especially beneficial with regards to developing successful individualized treatment plans. I firmly believe that by separating out and subcategorizing ADHD and its comorbid disorders based on factors such as age, gender and subtype whenever possible could lead to a new a wealth of information for diagnosing and treating ADHD and its associated comorbid disorders.