Genes and Low Birth Weight Combine to Increase Risk of Conduct Problems Alongside ADHD

In the past, we have investigated the role of the COMT gene and its effects on the onset and severity of ADHD cases. Now it appears that this gene may play a role not only in the ADHD itself, but conduct or behavior disorders which often occur alongside (or are comorbid to) of ADHD.

Recall from earlier posts that COMT (which is short for Catechol O-Methyltransferase) refers to both a gene and an enzyme protein encoded by the gene, which is responsible for maintaining a balance of neurotransmitters such as dopamine in key regions of the brain. In essence, the COMT enzyme is responsible for breaking down levels of free dopamine in the prefrontal cortex region of the brain (the area highlighted in orange). Keep in mind that in another key brain region, called the striatum, another series of enzymes called the dopamine transporter (DAT) proteins play a greater regulatory role in maintaining dopamine levels. However, in the prefrontal cortex region of the brain (see area below), the COMT gene and COMT enzymes play a much greater role in regulating the balance of key neurotransmitters necessary for communication between brain cells.

The prefrontal cortex region of the brain is approximated by the area in orange in the figure above. Note that we are looking from the left side of the brain of an individual facing to his or her left. The numbering system refers to a subseries of brain regions from which this original figure was taken.

As a reference, the striatum region of the brain can be seen in the green areas of the figure below (original file source here):

Returning to our discussion on the COMT gene and the prefrontal cortex region of the brain, it is important to note that there are two main "flavors" of this gene and subsequent enzyme, the "Val" and the "Met" (I've mentioned previously in other posts what "Val" and "Met" stand for, but as a quick summary: "Val" is short for valine, and "Met" is short for methionine, both of which are common amino acids found in almost every protein in our bodies. However, these two amino acids exhibit slightly different biochemical properties, and a simple substitution of one for the other can actually result in significant changes as to how a protein functions. For the COMT enzyme, which is a special type of protein, the simple change from a "Val" to a "Met" or vice versa can actually dictate how efficient the whole enzyme becomes). COMT enzymes comprised of the "Val" form are actually 3-4 times more efficient at breaking down dopamine in key brain regions such as the prefrontal cortex, which results in overall lower levels of neurotransmitters such as dopamine.

Since individuals with ADHD are often deficient in free levels of dopamine in the prefontal cortex region of the brain, having the "Val" form of the COMT gene often poses a greater risk of exhibiting ADHD behavior. We have seen the effects of this Met/Val difference with regards to cognitive tasks and even the effects of these different gene forms on the onset of alcoholism-related ADHD symptoms. For example, on a post on gene variations and attentional control, we saw that individuals with the "Met" form of the gene (and enzyme) had improved attention-related control than those with the "Val" form.

With regards to conduct disorders comorbid to ADHD, it also appears that the lower dopamine levels associated with the "Val" forms of these enzymes is also a major determining factor in the childhood onset of anti-social behavior and conduct disorders. Furthermore, it appears that environmental factors and this "Val" form genetic factor can actually interact and combine, to increase the risk of an individual with ADHD in developing some sort of conduct problem to go alongside his or her ADHD symptoms.

Low birth weight, which has a number of implications for other disorders, was found to be a good indicator of childhood conduct problems appearing alongside of ADHD in its own right. It is believed that low birth weight is a good indicator of a poor prenatal environment, which is why so many disorders and developmental issues are often associated with low birth weights. Statistically, it was noted that children with low birth weights (less than 2.5 kilograms or 5.5 pounds) were at an increased risk of developing co-existing behavioral problems (conduct disorders) alongside of an ADHD diagnosis. As mentioned before, individuals who were unfortunate enough to have one or more copies of the "Val" version of the COMT gene plus a low birth weight, were statistically more likely to exhibit problems associated with conduct-related disorders.

As a quick reference to the severity of the effects of low birth weight and the "Val" version of the COMT gene, please consult the table below. This data was taken from an article by Thapar and coworkers on the effects of COMT genes and low birth weight on the onset of antisocial behavior in children with ADHD.

Notes on the table above: Relative Conduct Symptom Score refers to the severity of conduct problems which are given a numerical value (higher being more problems). I have assigned the first group a value of 1 as a reference. This refers to individuals who have at least one copy of the "Met" (which, in the cases of ADHD appears to be the "good") form of the COMT gene and enzyme, as well as a normal birth weight. As we can see from the table, having either a low birth weight or both copies of the "Val" (the "bad" form of the COMT gene with regards to ADHD) form resulted in a roughly 50% increase in symptoms of conduct or behavioral problems. However, for individuals who possessed both "Val" forms of the COMT gene and enzyme and had a low birth weight, we can see that conduct symptoms associated with ADHD shot up to over three times the original level. This at least suggests that while both genes and developmental environments can play a significant role in the onset of behavioral problems associated with ADHD, it is when these two factors are combined, that remarkable differences in symptoms begin to appear. In other words, strong gene-environment interactions are associated with antisocial behaviors in individuals with ADHD.

Keep in mind that these findings are somewhat inconclusive. Another research group performed a similar experiment, but was unable to replicate these findings which associated low birth weight and the "Val" form of the COMT genes to an increase in antisocial behavior in children with ADHD. Nevertheless, an additional study tied the presence of "Val" forms of the COMT gene to increased aggressiveness, conduct problems, and criminal behavior in individuals with ADHD. Although the information and conclusions from different studies on these topics remains controversial, the fact that the "Val" form of the COMT gene has been implicated in so many other deficits associated with ADHD, I believe that we should take notice of some of these recent findings.

The term conduct disorder itself has a relatively widespread range of meanings. With regards to ADHD and the content of this post, I consider conduct disorders to include behaviors such as oppositional behaviors towards parents, teachers and other authorities, negative peer interactions, pervasive negative attitudes and interactions towards peers and authorities, and, in more extreme cases, illegal substance abuse, cruelty to animals and other individuals, destruction of property, stealing, and other criminal behaviors (please not that the Thapar article highlighted more of the latter and more severe behaviors on the list when addressing the topic of conduct disorders). Of course, there is a fair degree of ambiguity and a wide range of severity in the behaviors from this list, but I think we can all begin to picture the difference between a child who is merely hyperactive, implulsive and inattentive versus one who has a pervasively antagonistic attitude and behavioral patterns to go along with the classic ADHD symptoms.

The unique thing about antisocial behaviors with regards to ADHD is that they appear to be more genetically heritable than generalized antisocial behaviors, and that ADHD-like hyperactivity can potentiate and worsen the severity of accompanying conduct problems. Furthermore, it appears that children may be much more susceptible to antisocial behaviors arising from damage to the prefrontal cortex than are adults. This article suggests that when two or more factors which each have notable effects on ADHD-related conduct problems or comorbid disorders, the combined effects of two or more of these factors can operate in a synergistic fashion. It is my opinion that many of these genetic and early developmental factors will take on an increasingly powerful role with regards to both the diagnosis and treatment of ADHD and accompanying comorbid disorders such as behavioral and conduct problems.

Cost Effectiveness of ADHD Treatments

In the previous post on the economic impact of ADHD, we examined some of the eye-opening numbers attached to the disorder of ADHD and its impact on society. We reviewed 4-5 publications on the subject, most of which attached an annual price tag of several thousand dollars to the direct and indirect costs of the disorder on individuals with ADHD and their families. These factors included loss of productivity at work (which can be up to almost a full month of the year less than non-ADHD counterparts), medical expenses from the disorder itself, as well as from the increase in risk-taking behaviors of ADHD patients, additional educational expenses, loss of work time for family members, and the increased cost of treatment for substance abuse (which is also much higher in ADHD individuals).

It is important to take these numbers and figures with a grain of salt, and see them more as projections as opposed to actual hard, concrete figures. However, they should begin to give us at least a ballpark estimate of the economic impact that ADHD has on our society. The natural question which should flow from this information is: what is the actual cost of treating ADHD? While the treatment options for ADHD vary immensely from individual to individual and treatment to treatment, a study by Jensen and coworkers has sought to investigate the approximate cost-effectiveness of different ADHD treatments. A summary of this study can be found here. I will highlight some of the key points from the article:

• Cost-effectiveness for ADHD treatment was studied in four different areas: medication treatment, behavioral management treatment, a combined medication/behavioral treatment, and community care-based treatment (this last one would include things like juvenile justice programs, community mental health services, etc) . These data were based off of an original 1999 study on children with ADHD called the MTA Cooperative Group.
• Treatment "effectiveness" was determined by the ability of a particular treatment to bring a child's behavior to a "normal" level. An outcome of "normal" was determined by using a cutoff score determined by a special psychological scale called the SNAP scale, which assigns numbers to behavioral improvements in multiple categories, and is determined by parents, teachers and clinicians. Although somewhat subjective in nature, this scale has been a good indicator of tracking improvements with regards to the disorder of ADHD.
• Different scenarios of ADHD with regards to comorbid (co-existing) disorders were also analyzed. These included both internalizing comorbid disorders (anxiety and depression), externalizing comorbid disorders (which include conduct disorders or oppositional behaviors), as well as a combination of both types of comorbid disorders.
• Costs were determined by average consulting fees of psychiatrists, psychologists and behavioral therapists from the American Medical Association Socioeconomic monitoring system surveys, the approximate costs of prescription drugs based on wholesale prices and common markup values (often around 40%), and wages of behavioral support staffs.
• Out of the different treatment methods available, medication alone provided the most bang for the buck, as far as the most cost-effective measures go. Behavioral therapy was found to be exceedingly costly in terms of its relative effectiveness, and in some cases, actually limited some of the improvements in the overall symptoms. Thus, from a strictly economic standpoint, medication treatment appears to win out as the most cost-effective treatment for ADHD.
• Interestingly, it appears that for children with more internalizing ADHD comorbid symptoms (anxiety and depression), the behavioral treatments were not only more costly, but reduced the overall effectiveness of the medication treatment option, when compared to the medication option alone. This was a bit surprising, and suggests, that behavioral therapy should be considered more for externalizing symptoms (such as oppositional behavior or conduct problems) than for internalizing ones.
• This report was not meant to knock the effectiveness of behavioral treatment for ADHD, it just sought to investigate the cost-effectiveness (or lack thereof) of this type of treatment. However, if cost is not a factor, a combined medication/behavioral treatment program led to much higher rates of "normalizing" childhood behaviors, especially in children who exhibited both internalizing and externalizing comorbid disorders. In other words, for children who have ADHD, anxiety or depression, as well as some type of oppositional behavior, combining medication with therapy can be much more effective than treatment via either medications or therapy alone. However, based on a cost-effectiveness model, for those on a tight budget or with limited resources, the medication treatment option still wins hands-down.
• It is also important to note that community-based care programs, while largely inexpensive, often, unfortunately, have little effectiveness in treating ADHD with or without these side disorders, even though medication managements and behavioral measures are often utilized. This suggests the importance of specialization of professionals outside of basic community resources for dealing with and treating these disorders, which, unfortunately, often carries a heftier price tag. However, the approximate increase in costs of medication management alone (including the cost of a qualified diagnosing professional outside of the typical "community" environment), was relatively small in comparison to the community care model. This again, supports the evidence of the cost-effectiveness of a predominantly medication-based treatment.
• The ineffectiveness of community-based care was explained in part by the relatively lower levels of dosing for medications as well as less follow up (community care physicians often followed up only twice per year in the study, while the individuals on the non-community care based medication treatment plan often got monthly visits).

I realize that some of these findings are confusing to interpret. There were sections of the paper which were difficult to follow at times, but I would just like to hammer home a few personal points with regards to my thoughts on the article:

• Given the pinch most of us are feeling with the economic situation, we want to seek out the best treatments possible for the dollar. Based on this study, it appears that treatment with medication is by far the most cost-effective option.
• If money (or insurance) is less of a problem, there are advantages to utilizing behavioral treatment methods for ADHD. However, based on the findings of the above study, it appears that behavioral treatment on its own is still largely cost-ineffective.
• The one exception to the above point is if a child exhibits both internalizing (anxiety, depression) symptoms and externalizing symptoms (oppositional behaviors or conduct issues) along with his or her ADHD symptoms. It appears that, based on the results of the study listed above, that a combined medication and therapy treatment may be advantageous, although the price still jumps once behavioral management treatments are introduced.
• I realize that the idea of "drugging" our children is inherently wrong in the minds of most individuals. While I personally have a natural bias against this treatment method, I have written extensively about the relative safety and lack of risk factors for most ADHD medications out there today. Given the fact that many of us are feeling the pinch economically, medication treatment is often the only cost-effective option to most people, and this study indicates how cost-effective this treatment method really is.
• By no means is this post meant to downplay the vital role of community-based programs and treatment options out there, for a number of individuals, these programs have been extremely beneficial. Additionally, I know that a number of children exhibit wonderful behvioral changes with regards to their ADHD and related disorders. Nevertheless, the purpose of this review was to simply investigate the cost-effectiveness of these treatment options, and, on the whole, these resources often provide less bang-for-the-buck than medication treatments.
• Finally, I acknowledge that this is just one major study, and that to attach an unquestionable certainty to these findings would be irresponsible. However, we should note that, from the previous post, that the cost of untreated ADHD poses as an enormous economic threat to our society. As a result, all of the measures addressed in the passage above offer at least some degree of advantage over leaving ADHD and its comorbid disorders untreated.

If I can find enough quality studies on the topic, I may post further discussions on the cost effectiveness of different specific medications for ADHD in the near future. In the meantime, we will be returning to more hard-science based articles for the next several posts.