ADHD Subtype Differences and Stress

Why ADHD Subtypes Matter: Inattentive vs. Hyperactive-Impulsive ADHD and the Cortisol Response to Stress

There is growing evidence that the three traditional subtypes of ADHD (Inattentive ADHD, Hyperactive-Impulsive ADHD and the Combined ADHD subtype) may in fact, be more accurately classified as separate disorders altogether. Although the ADHD sub typing method is still likely to persist, new biochemical studies have begun to shine light on some of the physiological differences associated with the three distinct ADHD subtypes.

Significant outward expressional differences among the different subtypes can be seen, such as a more passive, less self-directed behaviors among the predominantly inattentive subtypes and more novelty seeking, stubborn and non-compliant behaviors once the hyperactivity component is added in. Perhaps this is not surprising, given the definition of impulsivity. Nevertheless, differences in accompanying disorders comorbid to ADHD also lend credence to the idea of separating the subtypes out into unique stand-alone disorders.

It has even been posited that the disorder be subdivided further based on accompanying comorbid conditions, but at the moment this sub-classification seems unlikely. Along with comorbid conditions, age and gender differences among the ADHD subtypes have also been postulated.

Although outward behavioral expressions and phenotypes suggest stronger distinctions among the ADHD subtypes, it is the physiological and biochemical differences among these subtypes which may offer some of the most convincing evidence that a further re-classification of the disorder is warranted.

It is possible, for instance, that symptoms such as hyperactivity may predominate more than inattentive behaviors from prior medical problems such as childhood ear infections (which might seem counterintuitive, given that we would expect ear infections to promote hearing loss and compromise the attention side of the disorder more than the hyperactive-impulsive components). However, evidence for the biological differences of ADHD subtypes often goes well beyond earlier exposures to diseases and external stressors.

Getting to the meat of this issue are some recent studies on what is known as the HPA axis of the nervous system and the effects of this. "HPA" stands for hypothalamic-pituitary-adrenal, which include three essential components of the nervous system, which plays an extensive role in the fight-or-flight response in humans. So how does this tie in to ADHD?

One of the key components of this HPA axis is hormonal fluctuation. The chemical cortisol (you may have heard of cortisol from all of those late night TV and radio ads blasting cortisol for its contribution to body fat) is actually a stress-related hormone, meaning that the body produces it in response to internal or external stressors.

The kicker here is that there is now at least some evidence that the production of this cortisol hormone may be variable among the different ADHD subtypes.

It appears that children with the predominantly inattentive component of the disorder are more likely to exhibit a high cortisol response to stress while those with the more hyperactive/impulsive subtypes (just to avoid confusion, the study actually looked at the combined ADHD subtype, which includes the hyperactive component, and not the much rarer hyperactive-impulsive subtype) may have a significantly lower boost in the stressor hormone.

This may not be all surprising, given the tendency and stereotype of the inattentive ADHD kids as being more lazy, overweight couch potatoes, while the hyperactive-impulsive kids are associated with being rail-thin fidgety and bouncing off the walls.

While this study seems to fit the bill and make sense, it is important that we try not to read too much into these results. After all, a number of other studies on the subject found little to no subtype difference with regards to HPA or the cortisol response. However, another recent study did advance this HPA notion a bit further.

This study, done by Maldonado and coworkers, found that ADHD children who exhibited more of the hyperactive-impulsive traits of the disorder had lower cortisol response levels to stressors than did the inattentive symptom dominated groups. It is important to note that the HPA/cortisol/impulsivity association has been studied extensively in the literature.

For example, an earlier study on ADHD children in Korea, the researchers concluded that "the blunted HPA axis response to stress is related to the impulsivity in patients with ADHD", as evidenced by higher error rates on attention-based tasks. To put it another way, a higher HPA axis response (including the secretion of the cortisol hormone) is thought to be advantageous as far as attention symptoms are concerned.

As an interesting side note, this blunted HPA activity subsequent "dulling" of the fight-or-flight response among the ADHD population may, in part, explain the high percentage of ADHD'ers in stressful occupations such as firefighters, EMT's, ER physicians, and combat personnel and the like. In other words, due to the reduced HPA response among most of the ADHD population, ADHD'ers are less likely to be overwhelmed in stressful situations, and may actually be at an advantage in occupations such as these. Remember, ADHD can have its advantages!

Further muddying the waters with respect to cortisol and the HPA axis and ADHD is the presence of comorbid disorders. Another recent publication addressed this issue and found that for boys with ADHD, the presence of a comorbid anxiety disorder was likely to raise the cortisol levels in response to stress for the child, but the presence of an oppositional or disruptive behavioral comorbid disorder showed a tendency to lower the cortisol response to stress in the ADHD child.

These findings show agreement with some of the earlier statements made above, given that comorbid anxiety disorders are often hallmark characteristics of either the inattentive or combined sub-components of ADHD, while oppositional or conduct disorders are seen at higher frequency with the hyperactive/impulsive or combined ADHD subtypes.

Blogger's personal note: The concept of oppositional behaviors in ADHD is somewhat interesting. It appears that there may be much more going on under the surface with regards to ADHD and oppositional/conduct disorders and dysfunction within the nervous system. These behaviors may be associated with seemingly unrelated functions among the ADHD population such as bedwetting. I don't mean to sound like a "conspiracy theorist", but for an interesting read on the subject, this blogger personally recommends an earlier post entitled Bedwetting ADHD Kids and Depressed Dads: Is there a Connection?

Returning to our topic of discussion here, it is important to remember that in the first study mentioned, it was the hyperactive-impulsive children who showed more of a blunted cortisol response to stressors, so these observations from research groups in three different countries all seem to be reaching similar conclusions.

In conclusion, we should take away from these studies that the different ADHD subtypes may exhibit distinct hormonal response differences, as well as neuro-chemical activity differences between the ADHD and the non-ADHD populations. In general the more hyperactivity and/or impulsivity we see, the lesser the HPA-derived cortisol response e would expect to see in reaction to stressful situations.

We can also see that comorbid disorders alongside the ADHD may either further dampen this HPA activity and cortisol response (as in the case of oppositional disorders), or counteract the ADHD response by boosting HPA activity and cortisol levels (as in the example of many anxiety disorders). The take-home message is this: ADHD subtype differences and the presence of comorbid disorders can play a pivotal role in the hormonal fluctuations among the ADHD population.

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 #5: Serotonin transporter gene (5-HTT)

ADHD Genes

ADHD Gene #5: Serotonin Transporter Gene (5-HTT, also referred to as "SLC6A4"): 5-HTTLPR long allele, location 17q11.1-12

This is the fifth gene that is being discussed on our list of ADHD genes. If you are not familiar with some of the terms in this post, here is a section on background information as it pertains to our study on ADHD genes. For a list of the other ADHD genes, please click here. The Serotonin Transporter Gene is found on human chromosome #17 (the q11.1-12 refers to a more specific region on the chromosome, and is not important for the time being). As mentioned in previous posts, genes come in different forms or alleles. One of the forms, or alleles of the Serotonin Transporter (5-HTT) gene has been associated with an increased risk of developing ADHD.

It is important to note that the terms Serotonin Transporter Gene, 5-HTT, and SLC6A4 all refer to the gene as a whole. The term "5-HTTLPR" refers to a specific section or part of the gene that can vary from individual to individual. For more background information on how genes are structured, please click here.

When the results of several family studies was pooled statistically, individuals with the "long" allele of the gene ("long" refers a form of the gene that has slightly longer DNA sequence than the shorter form of the gene), had an increased likelihood of developing ADHD than those with the "short" allele of the gene. Nevertheless, there is still some evidence that the "short" form may be tied to a higher incidence of ADHD as well (however, the trend in evidence typically favors the "long" allele).

Based on three different studies, there is some preliminary evidence suggesting that this "ADHD gene" (5-HTTLPR long allele), may be linked to autism as well, but a number of more recent studies have failed to support this claim. Nevertheless, it is known that individuals with certain forms of ADHD may possess higher levels of the neurochemical serotonin, which is also typically seen at higher levels in autistic individuals. Keep in mind that the gene of discussion in this post, 5-HTTLPR, is responsible for transporting serotonin into cells, with the "long form" (the "ADHD form"), transporting more serotonin than the "short" or "non-ADHD" form.

Based on how the most recent classifications, definitions, and diagnoses of mental disorders are done, individuals that fall anywhere on the autistic spectrum cannot be labeled as "ADHD" or vice versa (i.e., an individual may be diagnosed as being one or the other, but not both). However, a number of individuals with ADHD exhibit a number of symptoms that overlap with autism as well as vice versa. Of potential interest, our gene of topic, 5-HTTLPR, is responsible for shuttling serotonin into immune cells called lymphoblasts. Lymphoblasts are essentially an early, immature form of lymphocytes, which play a major role in an immune reaction such as an invading pathogen or an allergic response. The "long form" or "ADHD form" of this 5-HTTLPR gene shuttles more serotonin into the lymphoblast immune cells than does the short, "non-ADHD" form.

Higher levels of serotonin in these types of immune cells have been tied to an increase in migraine headaches, something that is also seen at higher levels in ADHD individuals. However, at the time, the cause is thought to be due more to an improper serotonin breakdown and disposal in these immune cells than transport mediated by the 5-HTTLPR gene. Nevertheless, it is an observation of potential interest.

Serotonin transporters, such as 5-HTTLPR, are also thought to play a role in seasonal affective disorders and depression. Higher activity levels of serotonin transporter proteins are seen during the fall and winter months (when depression is typically higher) than in the spring and summer. Although this 5-HTTLPR is likely not the primary culprit, the "ADHD form" of this gene does result in an environment similar to the "winter blues". This is due to the fact that the longer "ADHD form" of the gene transports more serotonin into cells and away from the space in between the cells. The net result is lower levels of free serotonin, which is typically seen in patients suffering from depression. Not surprisingly, depression is seen in much higher levels in several types of ADHD when compared to the general population.

One caveat here: some of the comparisons here are meant to simply report on a potential genetic overlap among ADHD and other disorders or diseases (migraines, autism, depression, etc.). At this point, there is not enough information to adequately confirm that the "ADHD version" of the Serotonin Transporter gene being discussed in this post is the primary cause of some of these other disorders. However, keep in mind that some of the underlying mechanisms of action are very similar and should suggest further investigation.

ADHD genes