ADHD and Seasonal Affective Disorder

ADHD and Seasonal Affective Disorder (SAD): Are they Linked?

Is it possible that ADHD is a seasonally fluctuating disorder? It sounds intriguing, but remember, for diagnostic purposes, classic ADHD symptoms such as hyperactivity, impulsiveness and inattentive behaviors (beyond the normal range of age-appropriate behavior) must persist for a set period of time (the typical cutoff is 6 months for most cases). Nevertheless, it is worth investigating whether there is any sort of seasonal pattern to the disorder. If there is, there could be far-reaching implications such as medication dosages (if diagnosed or initially treated during a "high ADHD symptom" period may result in effects of over-medication for the rest of the year, while initial dosing during a "low-tide" season of ADHD symptoms may prove inadequate in the later months).

Intuitively, we would probably assume that ADHD symptoms would be worst during the dark winter months, but is there any data to support this hypothesis? As it turns out, there may be. Here are the results of a few relevant studies on the apparent connection between ADHD and seasonal related psychological disorders:

• Seasonal Affective Disorder (SAD) symptoms overlap and co-exist at higher rates in those with ADHD: A study by Levitan and coworkers on seasonal affective symptoms in adults with ADHD found that the prevalence of seasonal affective disorders was higher in the ADHD population than in the general population. This study accounted for some of the obvious factors such as geography (someone in Seattle would be more prone to seasonal related disorders than, say, someone in San Diego).
  
  Perhaps not surprisingly, the rate of appearance of seasonal affective symptoms was higher in women with ADHD (in general, depressive-like disorders such as SAD are more common in women in general). However, other interesting comparisons were seen, such as the prevalence of seasonal affective symptoms in the inattentive subtype of ADHD (as opposed to the hyperactive/impulsive or "combined" subtypes of the disorder). While this subtype connection may be interesting, it is important to remember that comorbid depression is often seen more in the inattentive-dominant forms of ADHD than the hyperactive-impulsive forms of the disorder.
  
  
• Overlap in medication treatments for ADHD and SAD: While we should be careful not to simply lump a bunch of disorders together just because they share similar treatment methods, the relationship between SAD, ADHD and medications such as buproprion (Wellbutrin) may be worth noting. Bupropion has shown to be clinically effective in the treatment of a whole spectrum of disorders including seasonal affective disorders.
  
  Additionally, this medication has shown its far-ranging capabilities, due, in part to its success as both an anti-depressant and "pseudo-stimulant" (of course there is a heated debate among professionals as far as whether "Wellbutrin" should even be mentioned in the same sentence as "stimulant", but its unusual, and relatively unknown mode of action keep it from an exclusive anti-depressant label, at least in the classical sense).
  
  The reason I personally use the term "pseudo-stimulant" is that bupropion can function as a dopamine reuptake inhibitor (which is one of the major modes of action of several ADHD stimulant medications and is typically uncharacteristic of most anti-depressants which often predominantly target the brain chemical serotonin). This may be evidenced by bupropion's relative effectiveness in treating ADHD (please note that bupropion or Wellbutrin is still extensively used in ADHD treatment in place of a stimulant if there is some type of depressive related disorder, however, findings such as the one in this previous study seem to indicated that buproprion may be effective for treating free-standing ADHD without comorbid depression).
  
  While again, I should reiterate that similar treatment methods does not necessarily equate to similar disorders or conditions, the relative effectiveness of this medication for treating both disorders at least leaves the door open for the possibility that there exist similar underlying modes of action between ADHD and SAD.
  
  
• The connection between ADHD and circadian rhythms: While SAD, by definition is a seasonal (as opposed to daily) issue of cyclical patterns of time, it is worth mentioning that new research is being done with regards to differences in the chronological patterns in the bodies of individuals with ADHD. In other words, there may be an actual scientific explanation behind the reasons why your ADHD child likes to stay up until three in the morning on a consistent basis.
  
  There also appears to be an affiliation with daily rhythms and ADHD subtype. For example, while impulsivity is often more associated as a "morning" behavior, the inattentive subcomponent of ADHD appears to be more affiliated with the evening. This may factor into the differences in sleep patterns and prevalence of sleep disorders in ADHD children, and may even highlight the daily schedule differences between the ADHD subtypes.
  
  If the hypothesis that individuals with ADHD are at least partially predisposed to different patterns of circadian rhythms compared to the general population, it may stand to reason that these same individuals may also be more susceptible to seasonal fluctuations. Some studies confirm this possible "double" association of ADHD to both seasonal fluctuations and circadian rhythms.
  
  
• Overlapping treatment strategy of Light Therapy for ADHD and SAD?: There has been a recent surge of evidence that light therapy, when administered at the correct wavelengths, is an effective treatment for seasonal affective disorder (and often with measurable levels of success), may now be useful for treatment in the ADHD population.
  
  As an interesting aside, there may be some unusual side effects of ADHD stimulant medications with regards to light therapy. A case study of a single child noted that there may be a possible connection between methylphenidate and photophobia (photophobia referring to fear of or excessive sensitivity to the light). Of course this observation was limited to just one patient, but the correlation of the symptoms with methylphenidate treatment at least suggests the possibility that this is a possible (albeit) rare side effect of one of the most popular stimulant medications for ADHD currently on the market.
  
  Blogger's side note: it is also worth mentioning that this case report was also published by the same individual who brought us the interesting case study which became the topic of an earlier post in this blog: excessive talking as a potential side effect of methylphenidate treatment. I will refrain from making any comments or conclusions about this, but on a personal note, I actually enjoy reading about some of these unique side effect case studies of the popular drug, and wonder if this will result in an increased level of vigilance with regards to monitoring odd side effects of common ADHD stimulant medications in both clinical studies and individual prescriptions.
  
  
• Omega 3 (n-3) fatty acid deficiency: A common underlying factor for both ADHD and seasonal affective disorders? I saved what is perhaps the best explanation for last. It consistently has been shown that individuals with ADHD are often deficient in omega-3 fatty acids. We have even discussed the theory behind omega-3 fatty acid supplementation for ADHD in earlier bloggings. Now it appears that omega-3 deficiencies may disrupt circadian rhythms as well, possibly due to an impairment in melatonin production (melatonin is a hormone which is tightly associated with the sleep-wake cycle and hence has implications on the circadian rhythm patterns in a particular individual).
  
  This may suggest that omega-3 fatty acid deficiencies may either help cause, or exacerbate the severity of both ADHD and circadian rhythm impairments. Interestingly, there is some evidence that omega-3 supplementation may be beneficial in treating seasonal affective disorders as well. In fact, diets rich in omega-3's may be an underlying reason why seasonal affective disorders are relatively uncommon in Iceland, which, due to its far-northern location, experiences exceptionally long, dark winters.
  

While I admit that the evidence for the link between ADHD and Seasonal Affective Disorders is nowhere near as strong as for other ADHD comorbid issues (such as Tourette's, anxiety, conduct disorders, and learning disabilities), I still wanted to pass on some of the information out there supporting a possible link between the two disorders. Given the close associations both between depression and seasonal affective disorders, including the argument that SAD should be labeled as a specific subtype of depression, and the high rate of comorbidity between ADHD and depressive disorders, there is certainly a possibility that the magnitude of overlap between ADHD and SAD is greater than we might imagine.

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Methylphenidate vs. Atomoxetine ADHD Medications: Effects on Sleep

Stimulants are often the primary source of medication for ADHD and related disorders. Medications such as methylphenidate (Ritalin, Concerta, Daytrana), Adderall, Vyvanse and the like are often the first line of defense and choice of prescription for ADHD for many practicing physicians. However, certain drawbacks exist to these medications. Perhaps the three most common concerns are cardiovascular effects, stimulant induced sleep difficulties, and appetite suppression and resulting weight loss.

As a result, some parents and prescribing physicians choose a non-stimulant form of medication for treating ADHD such as Atomoxetine (Strattera). While some of the negative side effects mentioned above are less common for these non-stimulant options, the overall efficacy of reducing core ADHD symptoms is often less extensive than for the stimulant counterparts.

In this post, we will investigate one of the problem areas of stimulant medication by examining a handful of studies comparing and contrasting the different effects of methylphenidate and atomoxetine on sleep patterns in ADHD individuals. Sleep patterns are often analyzed via reports (either the patients themselves, or parents if the patient is a child), actigraphy (less invasive) or polysomnography (more details and quantitative data).

Methylphenidate:

Adult ADHD studies on methylphenidate and sleep quality:

While sleep difficulties are clearly evident in several studies, numerous others have actually shown overall positive effects of methylphenidate on sleep performance. For example, a study by Boonstra and colleagues on sleep activity patterns in adult ADHD showed that methylphenidate administration resulted in a delayed period of sleep onset. However, once subjects did fall asleep, the frequency of nighttime awakenings decreased significantly for the methylphenidate group (keep in mind that all of these individuals had ADHD), and that the overall duration of sleep for the night was less for the methylphenidate participants. These positive results were echoed in a study by Sobanski and coworkers, which found that methylphenidate administration improved efficiency and restorative quality in adults with ADHD compared to non-medicated individuals with the disorder. In other words, it appears that although methylphenidate can delay the onset of sleep, it appears to offer a positive effect in promoting a deeper pattern of less-interrupted sleep in ADHD adults.

ADHD, Methylphenidate and Sleep Quality in Children:

One of the difficulties in assessing the effects of ADHD medications on sleep deficits in children is that it relies heavily on parental reports and observations. Unfortunately, the overall accuracy of these parental (as well as teacher ratings) has been called in to question by several recent findings. More info on this is given at the bottom of the post.

Another key issue, is the relative lack of long-term controlled studies on methylphenidate in children due to a myriad of safety and practicality issues. As a result, obtaining clear-cut and accurate information on ADHD stimulant medications and sleep disorders in children is more tenuous than in the adult model, even though the overall number of studies on ADHD medication effectiveness is much higher in children. In other words, sleep disorders still hold a relatively remote corner amongst the sea of information on pediatric ADHD.

Nevertheless, several studies on the matter have been done in the past few years. I will highlight some of them below:

An investigation by O'Brien and coworkers found a significant increase in sleep disturbances for ADHD children regardless of medication status. These findings suggest a neutral effect of stimulant medications such as methylphenidate for children with ADHD, but cite an often-overlooked characteristic: ADHD children typically exhibit more sleep difficulties than non-ADHD children. Therefore, some of the bad rap attributed to ADHD stimulant medications such as methylphenidate for inducing sleep disorders may simply be due to the nature of the individual's ADHD and not to the medication. This is an important observation to keep in mind, especially when investigating sleep medication studies.

There is even some evidence that the assertion of methylphenidate administration later in the day (afternoon) may negatively impact sleep performance is less pronounced than popularly believed. Many physicians fear that a third daily dose of methylphenidate may cause sleep difficulties and omit the afternoon dosage. However, a study by Kent indicates that this may not be the case. Of course this is just one study, and should be regarded as such, but this may at least open the possibility that a number of these afternoon medication/sleep impairment fears may be less grounded than previously believed. Nevertheless, sleep disturbances are still a concern with ADHD medications such as methylphenidate, but, according to recent findings, the effects are relatively small.

"Do genetics play a role on sleep disorders and the ADHD medication response?"

This is an intriguing question which needs to be investigated further. We have had several previous discussions on the COMT gene and its effects on ADHD. Now it appears that sleep disorders and potential medication response may actually be impacted by an individual variation in this hotbed region of the human genome. A study done by Gruber and coworkers suggests that ADHD children with the Val form of the COMT gene may be more prone to sleep difficulties while on methylphenidate compared to the Met form of the COMT gene (if you are unfamilar with this "Val", "Met" and "COMT" terminology, a good explanation of these terms and how they relate to ADHD and ADHD medications can be found here).

ADHD, Sleep Quality and Strattera (Atomoxetine) in children:

In contrast to methylphenidate, which seems to delay the onset of sleep, individuals on atomoxetine have a much smaller delay in sleep onset. These differences were highlighted in an article by Sangal and coworkers titled Effects of Atomoxetine and methylphenidate on sleep in children with ADHD. Other advantages of atomoxetine over methylphenidate include less irritability, less difficulty getting ready for bed, less difficulty waking up in the morning, and less of an appetite suppression. However, the postive effects of fewer nighttime awakenings seen in methylphenidate were not observed in atomoxetine.

Methylphenidate vs. Atomoxetine: Comparative Effects on Sleep

Here are some of the highlights obtained from the Sangal study. A number of parameters and categories were investigated, but I have only included ones which were either statistically significant or ones which I personally found to be noteworthy:

A comparison of differences between Atomoxetine (Atom) and Methylphenidate (MPH), as well as the effects of both medications compared to unmedicated ADHD individuals are shown above. Quantitative measurements were performed using both polysomnography (polysom) and actigraphy. Some key trends of note:

• A delayed onset of sleep was seen in Methylphenidate.
• However, REM sleep (an important factor in overall sleep quality) was reached faster with Methylphenidate and slower with Atomoxetine.
• Additionally, a slight increase in the percentage of sleep time spent in REM was seen with methylphenidate treatment.
• Fewer sleep disruptions (partial or full, as in awakenings) were seen with both medications, but the effects were even greater in the methylphenidate group.
• When a child did awaken during the sleep cycle, the children medicated with methylphenidate were able to fall back asleep much faster. Note this contrast to the increased time to fall asleep initially for the methylphenidate group.

Overall, it appears that while methylphenidate does slow the onset of sleep initially at a significant level, it appears that once a child does fall asleep, the overall sleep quality is actually improved if the child is medicated with methylphenidate. This data runs against the grain as far as prescription medications for ADHD are concerned, in which nonstimulants such as Strattera (Atomoxetine) are often given in favor of stimulants such as methylphenidate if sleep disorders are a concern. This is likely due to the most obvious parameter (initial difficulty falling asleep), which favors Strattera, while the other parameters, which favor methylphenidate and are more numerous, are less intrinsically obvious.

Why the pronounced difference between the two ADHD medications?

While there is still a fair amount of debate surrounding the exact cause of different impacts of these ADHD medications on sleep, the different biological targets and modes of action may offer some clues. For example, while methylphenidate primarily targets the neuro-signaling agent dopamine in brain regions such as the striatum and nucleus accumbens, Strattera (atomoxetine) instead targets another neurotransmitter called norepinephrine.

It appears that the different neurochemical targets and specific brain regions impacted by the two medications are responsible for the differences. For example, we have previously mentioned in another post on gene variations and attention control that the cingulate region of the brain, which essentially acts as the brain's gear shifter, has a high density of receptors for dopamine, the very chemical that methylphenidate targets. It is possible that changes in dopamine levels from methylphenidate may indirectly impact the "gear shifting" ability of the key brain region of the cingulate. We have previously discussed that an overactive cingulate region can lead to difficulties changing focus or transitioning between topics or activities, while an underactive cingulate can lead to difficulty maintaining focus on a particular thought or state.

Putting this into context of our sleep and ADHD medication discussion, it is also worth noting that the Sangal paper mentioned that children who took the methylphenidate had a more difficult time getting up in the morning and settling down into a pre-bedtime routine than the Strattera group. In other words, it seems like the methylphenidate group had trouble with transitions. As a result, this blogger hypothesizes that the transitions may be caused, at least in part, by the increased activity of the cingulate region of the brain and it's high density of dopamine targets, which see increased activities driven by a boost in free dopamine levels from the methylphenidate. In other words, I suggest the possibility that methylphenidate induces a state of the cingulate "gear" shifter becoming overactive and getting stuck in one routine (either the waking or sleeping state) and having trouble moving to another (getting out of bed or falling asleep). Further supporting this hypothesis is the data from the table above showing that the methylphenidate treatment group appears to be more inert (i.e. fewer sleep interruptions, and a quicker return to a previous sleeping state).

Inconsistencies between parent and teacher reports and actigraphic studies for sleep in ADHD children:

Finally, it is worth noting that the different methods of sleep data acquistion are far from perfect. It appears that there is at least some discord between the methods of measurement.

Compounding the problem of sleep disorders in children is the relative inconsistency between parental reports of sleep disturbances and disorders and results derived from actigraphic studies. This appears to be a recurring problem in the literature, and is confirmed by several other studies of observation. Additionally, teacher evaluations may also be flawed with regards to sleep disorders and ADHD-like behaviors.

Final notes on the methylphenidate vs. atomoxetine debate on ADHD and sleep:

While the current trends in medication prescription still shy away from stimulants such as methylphenidate for fear of insomnia, the findings of some of the recent studies show that overall sleep quality in ADHD individuals may actually improve (in spite of the initial sleep delays) with methylphenidate treatments instead of non-stimulant medications such as Strattera. I personally anticipate further sleep studies in the near future which will confirm several of these findings.

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Iron Levels, Sleep Disorders and ADHD

The aim of this post is to investigate the potential connection between ADHD and sleep disturbances, and how a deficiency in iron levels may in fact be a possible triggering factor for both disorders. We will be drawing heavily from a very recent article by Cortese and coworkers on Sleep Disturbances and Serum Ferritin Levels in children with ADHD. Iron typically does not exist in the body in its free form, but rather in the form of larger complex molecules such as hemoglobin or ferritin (think of iron being "encaged" in these larger complexes).

We have previously dabbled in the field of ADHD and sleep issues in earlier posts, such as a recent one entitled CREM gene, Melatonin and ADHD. I also plan on doing further posts on the connection between ADHD and Restless Legs Syndrome, which is also believed to be connected to low iron levels. It is interesting to note that there may also be an underlying genetic component to this association as well.

Some of the major findings of the Cortese article are listed below:

1. Children with iron-containing ferritin below a concentration of 45 micrograms per liter (don't worry about these numbers yet, we will be discussing them further down) had higher levels of ADHD symptoms as well as sleep disorders than those above this concentration. We must consider the fact that sleep disorders appear at higher levels in individuals with ADHD than in the general population. With regards to ADHD, these results are in agreement with another prominent study by Konofal on Iron Deficiency in Children with ADHD. According to the study, among the different sub-categories of sleep disorders, the only disorders associated with a deficiency of the iron-rich protein ferritin were Sleep Wake Transition Disorders (SWTD). These SWTD's are characterized by "abnormal movements in sleep", according to the Cortese article.
   
   Carrying this a bit further, we find that iron-related sleep disorders are also seen in children with autism, a disorder which shares a fair degree of overlap with ADHD on a genetic basis as well as structure and function of specific brain regions and an overlap of motor problems and other symptoms. It is also important to note that iron is a critical factor for the synthesis of the brain chemical dopamine (which is often at lower levels in the areas between nerve cells in specific brain regions of individuals with ADHD), and that dopamine related functions are connected to motor control behaviors.
   
   
2. While it may be tempting to assume that these problems may be fixed by iron supplements, we need to be careful, especially based on the content of the study. The Cortese article indicated that none of the children had anemia. Keep in mind that anemia comes in multiple forms, with the most common being iron deficiency anemia, which can be caused either by a lack of dietary iron (a possibility) or inflammatory conditions such as parasitic infections (which was not seen in any of the patients). It is interesting to note that serum ferritin is also a bio-marker of inflammatory processes, so the fact that no inflammatory conditions were present was a crucial control for the Cortese study.
   
   While none of the children in the study exhibited outward signs of nutritional deficiencies, diet-related anemia is the result of prolonged deficiency in iron and other supporting nutrients, so it is entirely possible that the children in the Cortese study were simply not far enough along in their iron deficiency situation for anemia detection. However, we must be careful before administering iron supplementation as a potential treatment option. While studies have shown that iron supplementation can effectively reduce the occurrence of periodic limb movements, we must watch out for the toxic effects of rampant iron supplementation (for a general upper limit for iron supplementation, please click here).
   


3. Nevertheless, the effects of an iron deficiency can be drawn out, and symptoms can be delayed. Ferritin, which, mentioned above, is a type of storage protein for holding iron in the body, typically exists at a concentration roughly between 30-45 millionths of a gram (micrograms) of ferritin protein per liter of serum (serum is the watery part of the blood which does not include blood cells) in children, but can be significantly higher in adults. While this number may not mean much on its own to most of us, we should be more cautious about the next number: 12 millionths of a gram per liter of serum. If the concentration of iron-containing ferritin protein falls below this critical level, then hemoglobin synthesis begins to be impaired.
   
   While the difference between the 45 micrograms/liter and 12 micrograms/liter indicates that there is some room to play with between low iron levels and a hemoglobin deficiency, the same study that found the 12 micrograms/liter cutoff point also found that much higher levels than 12 micrograms/liter must be reached before iron stores (and subsequent hemoglobin synthesis) resume to full levels. Therefore, the complex restoration of iron balance is not something that can be typically achieved overnight or even within a week.
   
   Furthermore, the Cortese paper suggested that the transfer of iron stores in the nervous system may also take sufficient time to build back up and may depend on significant iron storage levels. In other words, the effects of iron supplementation and treatment and restoration of iron-containing complexes may not be felt immediately, especially in the brain region and the central nervous system, which is bad news for those suffering from ADHD and related disorders. While no exact quantity was specified, the 30-45 micrograms/liter concentration range seems to be a good starting place for children.
   
   
4. While many comorbid disorders are predominantly connected to one of the three major subtypes of ADHD (inattentive ADHD, hyperactive/impulsive ADHD or combined subtype ADHD), the sleep disorders in the Cortese article showed no particular subtype affiliation.
   


5. Another recent article may shed some light on the subject as far as to why serum ferritin levels and sleep disturbances may occur. We have previously reported the possible connection between ADHD and Celiac Disease and that Celiac Disease can Cause ADHD Symptoms. Picchietti and coworkers reported that treating patients who had restless legs syndrome and low serum ferritin levels but not overtly low iron levels responded well to a gluten-free diet (the most common treatment for celiac disease). Similar associations were seen in other studies involving iron deficiency and celiac disease (as well as generalized intestinal absorption difficulties).
   
   In other words, celiac disease and other digestive issues may be the underlying factor in individuals who exhibit low serum ferritin levels, but not abnormally low overall iron levels, and may contribute to negative symptoms such as restless legs syndrome. Unfortunately, the while generalized gluten-free diets can single-handedly restore the body to pre-anemic conditions, the process can take time, up to 6-12 months.
   
   It would be interesting to see how many of the patients in the Cortese study who exhibited low serum ferritin levels without other forms of iron deficiency have undetected cases of celiac disease or other digestive problems as potential underlying causes to their ADHD and sleep disturbances. This could be a great follow-up study for the population in the Cortese study.
   


6. It is also important to note that a large number of the children with ADHD in the study also had at least one type of comorbid (co-occurring) disorder. Among the most common ones were Oppositional Defiant Disorder (ODD, seen in around half of the patients in the study) and Anxiety Disorders. At the moment, it is unclear as to what the confounding effects of these comorbid disorders may be with regards to iron-related sleep problems. We will be discussing the nature and effects of these comorbid disorders in a later post, but for now, we must keep in mind that these co-occurring disorders have pronounced direct and indirect effects on the symptoms and treatment strategies for ADHD.
   
   
7. Finally, the Cortese paper cited another study in which Methylphenidate (Ritalin, Concerta, Daytrana), and Dextroamphetamine (Dexedrine), both of which are ADHD stimulant medications, decreased the amount of nocturnal motor activity in patients. Cortese suggested that iron supplementation, which can boost free dopamine levels in a manner similar to most ADHD stimulant medications, may possibly accentuate these postive effects. While this is certainly a possibility (which remains to be seen), I also recommend extending this drug/mineral supplementation strategy to zinc, which has been shown to boost Ritalin's effectiveness as an ADHD treatment.

This article ties together well with our recent posts on the numerous ADHD comorbid disorders. We will be having several further discussions on ADHD and sleep disorders, including potential underlying causes, in the near future.

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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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