Monday, June 1, 2009

ADHD gene ADRA1A: A good target for clonidine?

Does the gene ADRA1A affect ADHD comorbid disorders? Is it connected to clonidine's positive response in some ADHD patients?

This blog has spent a considerable amount of focus on genes connected with ADHD. Although genetic studies surrounding the disorder are often inconclusive (and often difficult to replicate or even contradictory), the high rate of prevalence of the disorder within families and the strong genetic component of ADHD (this blogger has seen some studies reporting it as high as 90%!), any new findings for genes associated with ADHD can be noteworthy.

Furthermore, the medication treatment options for ADHD can be cumbersome as well. Some medications, such as clonidine, while not intended to treat the disorder, can often work quite well when applied as an "off-label" treatment for ADHD. The question is why?

Gene-drug interactions are an increasingly popular and meaningful component of pharmaceutical research. As we are generally moving in the direction of individualized medication strategies, and away from one-size-fits-all pharmaceutical treatment for disorders as complex and diverse as ADHD, specific genes and the target proteins which they encode, are becoming increasingly relevant in the tailoring of individual treatments for ADHD and related disorders.

The ADRA1A gene and how it relates to ADHD and other comorbid disorders:

ADRA1A is located on the 8th human chromosome, which is believed to be one of the "hot" regions for finding genes affiliated with ADHD and related disorders. The "8p" sub-region of the 8th chromosome is believed to be connected to numerous other disorders as well, including psychiatric disorders such as schizophrenia and autism.

The gene is also believed to be associated with hypertension, a disorder which is frequently targeted by the anti-hypertensive clonidine. There is some evidence that the actual mechanism of hypertension as it relates to ADRA1A may actually be due to auto-immune related causes. If this is the case, then it may warrant further exploration into other auto-immune disorders, such as allergies (which can elicit ADHD-like symptoms, and are a relatively common comorbid disorder to those diagnosed with ADHD).

The ADRA1A gene "codes for" the production of a protein known as the alpha 1A-adranergic receptor, which a target of epinephrine (adrenaline) and norepinephrine (noradrenaline). Norepinephrine is an important neuro-signaling agent which is often imbalanced in key regions of the nervous system in many ADHD cases, and is a target of several ADHD medications, including atomoxetine (Strattera) and stimulant medications such as amphetamines. The alpha 1A-adranergic receptor has also been implicated in studies of traits common to ADHD. For example, stimulation of this specific receptor has been shown to decrease impulsivity, improve working memory, and increase vigilance (in the rat model). This particular receptor is also a target of clonidine.

Given the fact that drug treatment for comorbid disorders can often alleviate some of the co-existing ADHD symptoms as well (and given the fact that ADHD is believed to be connected to circulatory impairments including reduced bloodflow to specific brain regions associated with impulse control), it is possible that those individuals possessing the "wrong" forms of the ADRA1A gene and suffer from hypertensive disorders may be prime candidates for treatment with clonidine to alleviate ADHD symptoms. In other words, specific variations of the ADRA1A gene may make one more or less likely to have a successful response to clonidine as a treatment for not only hypertension, but also co-existing attention deficit and hyperactivity disorders. Additionally, clonidine can also be used to augment the effectiveness of stimulant medication treatments for ADHD and reduce negative side effects.

Indeed, variations within three subsections of the gene ADRA1A were associated with around a 50% higher likelihood of having ADHD, according to a recent study (although when taken as part of a multi-gene analysis, the effects were not as pronounced). The rate of occurrence of each of these three variations was roughly between 25 and 50% of the study population. In other words, these are not some rare or exotic mutations we're talking about, but relatively common forms of the gene seen in the population (those of European ancestry in particular).

While not directly related to other disorders sometimes seen alongside ADHD, the genetic proximity of ADRA1A to other genes in the human genome may be noteworthy. For example, ADRA1A is located in the same subsection of the 8th chromosome (8p21) as another gene whose mutations may lead to an increased risk of epilepsy. This may be important, because in general, the closer 2 genes are to each other on a chromosme, the more likely they will be transmitted together from parent to offspring. Thus, a parent who has both the "epilepsy" mutation and the ADHD-specific ADRA1A mutation(s) may stand a greater chance of passing these gene forms on together to their child. As far as treatment is concerned, there is general consensus that clonidine is safe for patients who are diagnosed with co-existing epilepsy, however a few case studies suggest that caution regarding clonidine and epilepsy may be needed. We have investigated complications in treating ADHD and comorbid epilepsy in earlier posts.

Interestingly, the 8p21 subregion of the 8th chromosome is also home to genetic regions believed to be affiliated with schizophrenia. There is some evidence that clonidine may be an effective augmentative treatment for schizophrenia when used in conjunction with another drug haloperidol. Thus, for individuals who exhibit symptoms resembling ADHD and schizophrenia, clonidine may be a potentially useful medication strategy to try under medical supervision.

It is important to note that many of these suggestions are largely hypothetical at the moment. Do not attempt to follow any of these suggestions without medical supervision. Nevertheless, given the complexity and variability of ADHD and the compounding effects of comorbid disorders, it is useful to investigate medication strategies which have shown to be historically useful in treating multiple disorders which can often occur alongside each other. This is particularly useful for ADHD, where constraints are often necessary for medication treatments due to the negative impacts that these ADHD drugs may have on other accompanying disorders. As a result, the potential of clonidine in treating a diverse range of disorders (which may, possibly by way of ADRA1A and other nearby genes share an underlying genetic predisposition), move this traditionally second or third-line medication closer to the forefront as a valid medication-based ADHD treatment option.

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