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.

Reboxetine for ADHD Treatment

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

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

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

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

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

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

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

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

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

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

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

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

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

Other interesting points of note regarding Reboxetine:

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

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

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

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

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

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

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

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

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

ADHD medications protect against drug abuse

There is often a heated debate amongst professionals, families and individuals surrounding the safety of ADHD stimulant medications and their potential for abuse. One camp claims that exposing the brain to amphetamines or amphetamine-like substances (drug categories in which almost every ADHD stimulant medication falls) fosters a long-term dependance and subsequent drug addiction later in life. The other side claims that these medications are safe and that by not taking them, most individuals with ADHD will attempt to "self-medicate" with illegal drugs, nicotine or alcohol. So which side is correct?



While arguments and information support both sides of the issue, it appears that, as of now, the overall safety and efficacy of stimulant medications for ADHD is relatively high. In an earlier post, we discussed the overall safety and addiction potential of Ritalin for treating ADHD. It appears that amidst the hype, the overall potential for addiction with this drug is relatively low. This is not to say that there is no risk at all, the discussion suggested that individuals with ADHD are able to handle the stimulant drug with less of a risk for abuse than those without the disorder.



Nevertheless, this was but one study on ADHD drugs and abuse potential, so I have decided to review additional articles on the topic. Based on an evaluation done by Joseph Biederman, and published in the Journal of Clinical Psychiatry, on the topic of ADHD medications and substance abuse, it appears that taking proper medications for ADHD at the correct dose results in a reduced risk of having a drug addiction later in life.

Some key findings of this study include:

• A high percentage of previous studies on ADHD and drug abuse fail to take into account the factor of conduct disorders, which often occur alongside (but are not directly connected to) ADHD. Individuals with conduct disorders are more prone to abuse of stimulants and other drugs. Because of this, a number of these studies incorrectly label ADHD individuals on medication for having higher rates of substance abuse, when in fact, it is often the co-occuring conduct disorder.

• Along the same lines, instead of viewing ADHD as one disorder, it is more accurate to see it as a mosaic, occuring in multiple different forms and with multiple different side effects and overlapping related disorders. For example, issues such as depression, bipolar disorders, behavioral issues and learning disabilities, one or more of which often occur alongside ADHD all become influencing factors in areas such as substance abuse. Failure to allocate a "correction factor" for these co-existing and overlapping disorders unfairly puts the blame on ADHD and results in an inaccurately high level of negative effects being placed on the disorder.

• For studies which did factor out these co-existing conditions, it was determined that childhood ADHD by itself does increase both the potential for and earlier onset of substance abuse, by two-fold. The duration of abuse was also longer, and typically followed individuals into adulthood. Therefore, both ADHD, as well as symptoms which commonly occur alongside it can each, independently as well as in conjunction, increase the risk of future persistent substance abuse.

• The article referred to a large study done previously (by the same author, which included a 4-year follow-up for test subjects), which observed that siblings of ADHD children were much more likely to have substance abuse issues than the ADHD children themselves (around 4 times greater). Adults with ADHD were higher than either the ADHD children or their siblings.

• While unmedicated children with ADHD made up only 25% of the test subjects in the 4-year study listed above, they made up 75% of the substance abuse disorder cases. This was true not just for amphetamines (which are chemically similar to most ADHD stimulant medications), but also other drugs such as marijuana, cocaine, hallucinogens and alcohol.

• The article concluded that proper medication for ADHD in individuals (with a focus on males in their mid to late teens and early 20's) resulted in a significant reduction in later substance-abuse risk.

Based on these findings, we should strongly challenge the assumption that ADHD medications promote stimulant (or other types of chemical) abuse in individuals. Nevertheless, we should still be aware of some potential safety risks for ADHD medications.