Friday, February 27, 2009

CREM Gene, Melatonin and ADHD

In the past, we have investigated several different ADHD genes, or genes that are believed to play some type of role in the disorder of ADHD. A recent article, titled CREM mutations and ADHD symptoms suggests that another specific gene, called CREM (short for Cyclic Adenosine Monophosphate Responsive Element Modulator), may actually play an integral role in the onset of ADHD and its symptoms as well.

Before we go any further, we must bear in mind that the journal in which this article is located is titled Medical Hypotheses. As the name suggests, we should be careful not to confuse hypothesis with thoroughly-investigated scientific data. However, the arguments are typically well laid out, and many of these hypotheses are in fact well-grounded based on a number of well-researched facts which point in their directions. In other words, a number of scientific studies or findings are often preceded by publications of these hypotheses, so we could very well be at the cusp of a new scientific discovery.

A second point worth mentioning is that the CREM mutation article is actually based on the mouse model. This in itself is not unusual, as numerous other studies on ADHD have used analogous murine models, such as the spontaneously hypertensive rat (SHR) model. Numerous comparison studies have supported the validity of SHR as a relevant and accurate model of ADHD in humans (although a few studies have disagreed, these disagreement studies are relatively small in number, however). Furthermore, based on the high degree of similarity between the DNA sequences in the human and mouse CREM genes, there is also a potentially high degree of functional overlap between the two. As a result, it is highly possible that CREM gene findings in the mouse may carry over well into CREM gene studies in humans. Additionally, mice with mutations in the CREM gene have been shown to exhibit ADHD-like behaviors.

Location of the CREM gene:
If you are not familiar with human genetics, the human genome typically has 23 different chromosomes (which come in pairs, so 46 chromosomes total), which are numbered 1 through 23. Scattered out through these 23 different chromosomes are some 30,000 to 50, 000 total different genes (the number is constantly in debate, but this is typically a good estimate), which means that the average chromosome will typically carry between 1,000 to 2,000 different genes on it. Further numbering and lettering schemes denote more specific locations of these genes on the chromosomes. In humans the CREM gene is located on the 10th chromosome. For a more detailed look at the specific location of the CREM gene, please click here.

The association between CREM function and ADHD:
The CREM gene is believed to play a significant role in regulating the secretion of the hormone melatonin throughout the day. Melatonin, which is chemically similar to another key hormonal and neuro-signaling agent serotonin (serotonin actually converts to melatonin in the body), plays a number of roles, such as the regulation of sleep patterns. Melatonin is typically secreted by a specific gland called the pineal gland. For most individuals, lower levels of melatonin are produced during daylight, while higher levels are produced during darkness, which leads to the feeling of sleepiness. Furthermore, emotional states such as chronic stress can also effect melatonin production and secretion.

The CREM gene is believed to exhibit a controlling mechanism on the melatonin secretion patterns throughout the daily process. However, mutations or deletions (i.e. removal) of the CREM gene can result in a number of changes, such as different melatonin secretion patterns and excessive movement (locomotion) and activity at night. In other words, day/night differentiation is typically reduced if mutant or lower-functioning forms of the CREM gene are present.

The connection to ADHD:
Numerous findings suggest that individuals with ADHD are prone to differences in genes which regulate key chemicals in the neurosignaling process (as well as their receptors, or biological targets to which they bind). These include serotonin, dopamine and norepinephrine. Melatonin levels are also typically different in individuals with ADHD, and these ADHD individuals are more prone to daytime sleepiness due to oversecretion of melatonin. Furthermore, several studies indicate that individuals with ADHD are more prone to sleep disorders and abnormal sleep patterns in general, although a number of other studies have indicated conflicting results to this assertion. As a result, the melatonin regulating activities of CREM may be at work as underlying factors to these melatonin-related sleep disorders.

The role of ADHD medications on regulating melatonin levels:
Abnormal melatonin levels (caused by CREM mutations or other factors) may be able to be offset by common ADHD medications. For example, methylphenidate (Ritalin, Concerta, Daytrana), has been implicated as a potential agent in correcting sleep disorders in children with ADHD. This is somewhat interesting, because it contradicts numerous other findings in which stimulant medications have been shown to interfere with sleep.

**Blogger's note: While there are a number of studies regarding impaired sleep quality due to ADHD stimulant medication, we must remember that strategic timing and lower dosing of stimulant medications can significantly reduce the number of sleep-impairments. Most of the sleep problems, at least in my opinion based on personal experiences, are due to the administration of medication doses which are too high and given too late in the day. Although outnumbered with regards to the current number of publications for or against it, I personally side with the assessment that methylphenidate, when administered at the proper dose and the proper time for real ADHD cases, is actually beneficial for promoting and regulating sleep patterns. Again, I want to reiterate that this is simply my opinion based on personal observations and research.

The CREM mutations and ADHD symptoms authors referred to a small study they did on the effects of methylphenidate on lowering melatonin levels. Based on these (extremely limited) findings, it is possible that melatonin regulation via methylphenidate treatment may be a contributing factor to the drug's effect on sleep performance. However, we should be careful not to put too much stock into this finding, since melatonin levels are highly variable among individuals (i.e. comparison of absolute melatonin concentrations between individuals is often ineffective, and intra-individual fluctuation of melatonin levels occur throughout the day anyway).

While the hypothesis that the CREM gene (which, as mentioned, is located on the 10th chromosome in humans) may play a significant factor in regulating melatonin levels and affecting ADHD behavior is predominantly theoretical at this point, I personally believe that this possible connection is at least worth mentioning. Additionally, potential gene/medication interaction studies may emerge, such as studies involving different methylphenidate dosage requirements based on the different CREM gene mutations. We have discussed analogous gene/medication interaction studies in previous posts such as the one entitled ADHD Genes Influence Medication Dosage . We should remain on the lookout for future studies on the possible connections among these different areas.

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Anonymous said...

I find this rather interesting. In the days before I knew I had ADHD, a coworker who was always taking food/vitamin supplements of different kinds suggested that I try Melatonin for my sleeping problems. It didn't do a thing for me, and I ended up giving him the rest of the bottle of pills.

A few years after that, I discovered that I had sleep apnea -- both obstructive (~15%) and central (~85%). Another few years later, I discovered that I also had "ADD". Even with the meds, I'm still sleepy during the day, and tend to be a "night-owl", something that I had blamed on several years of second shift work.

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Anonymous said...

The delayed sleep onset problems that have been associated with psychostimulant medications are troublesome for patients and doctors alike. It is important, as studies show that "a tired brain is an ADD brain," meaning, anyone tired enough functions, cognitively, similarly to a person with diagnosed AD/HD. So, a tired AD/HD brain might be trying to function with “double-AD/HD.”

The medical-therapeutic community, presented with someone taking stimulants and complaining of delayed sleep onset, has leapt to the conclusion that this is due to stimulants. Very often, no one has inquired, during the evaluation phase, about sleep habits. So it is an uninformed, illogical conclusion to draw. Too little information about the patient, and overlooking the fact that the stimulants are designed for, and reasonably good at, regulating the abnormal dysregulation of the AD/HD brain.

Still, Patient Information papers and prescription bottles warn of sleep problems as a side effect of the medication. Often, this is far from the truth. When someone diagnosed and treated with medication for AD/HD complains of sleep problems, it may be that with the aid of medication the enhanced awareness “discovers” the sleep habits.

Whenever someone complains of sleep onset problems and thinks the medication is to blame, I ask them to do one simple thing. On a day there are no obligations like work or school, take medications as usual. Some while later, go take a nap. If a person is able to go to sleep, then the medication is unlikely to be responsible for nighttime delayed sleep onset.

Alternatively, some physicians declare that these sleep problems are the result of the wearing off of the medications late in the day, and instruct patients to take their last dose of the day many hours before they need to go to bed and to sleep. This causes other problems, among them the untoward situation wherein one is rendered impaired at day’s end, when routines and kids’ routines and preparations for the next day are mandatory.

Patients who have undertaken my simple experiment have been surprised, since the "facts" given them by doctors, books and articles say otherwise. There are several luminaries in the field who have suggested that stimulants be given to cover bedtime and throughout the night as well. If AD/HD is a 24-hour condition, why do we not, as a matter of course, treat it 24 hours a day?

My favorite 16 year old , who had severe delayed onset problems throughout elementary school (try going to school on 5 – 7 hours of sleep, week after week), used melatonin for a few years, which helped, some. Meanwhile, she had to start her daytime medication an hour before getting-up time, or she'd be unable to function getting ready for school, etc. She finally realized that if she needed it to get to sleep, and to wake up -- well, how many hours are in between?

She took the liberty (at age 10 or 11) of trying medication all night and had no ill effects and many positive ones. Fortunately, her doctor understood and she has, since then, dosed accordingly.

There may be some exceptions to this formulation, but careful inquiry and experimentation – under a doctor’s supervision – are the only ways to find out, for sure.

The ADHD Treatment Guide said...

Well put!

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