ADHD and Vitamin D Deficiency: Any Evidence?

Is there any link between vitamin D levels and ADHD? A review of the current evidence:

We have spent a lot of time looking at correlations between vitamins, minerals, omega-3 fatty acids and amino acids (and their deficiencies) and ADHD. However, it is important to note that just because low levels of a particular nutrient are seen alongside the disorder, it does not necessarily mean that this deficiency is the cause of ADHD (i.e. correlation does not imply causation). In other words, the nutrient deficiency and ADHD symptoms might both be secondary effects of a larger primary cause, such as an enzyme deficiency or metabolic dysfunction.

In the case of vitamin D, the association with ADHD is a lot more muddled than with some of the other nutrients which have a relatively strong connection with the disorder (iron, zinc, magnesium, and omega-3 fatty acids to name a few). The amount of information in the literature is relatively scarce, as well. A search in the journal database Pubmed (where this blogger gets most of his articles and information) for "ADHD" and "vitamin D" turns up only a small handful of search results, the majority of which focus on other disorders and only mention ADHD peripherally.

However, given the fact that vitamin D is such a "hot" vitamin and has been a popular supplement as of late, we should investigate some of its potential benefits with regard to ADHD and related disorders. Please keep in mind that many of these points below are more theoretical or speculative, because most of the hard, concrete evidence in well-documented clinical controlled studies simply does not exist at the moment. Nevertheless, here are some possible ways in which vitamin D may help in cases of ADHD or related disorders:

• Vitamin D can boost levels of the antioxidant glutathione in the brain. One way that vitamin D does this is by regulating an enzyme called gamma-glutamyl transpeptidase, which plays a role in both the metabolism and recycling of glutathione. We have spoken at length about how antioxidant deficits can worsen ADHD symtpoms, and how fatty acids (namely omega-3's) are frequently administered for ADHD and related disorders. Given the high makeup of these omega-3 fatty acids in the brain, and their susceptibility to oxidation and damage in the central nervous system, protecting them by boosting antioxidant levels (either directly or indirectly) is a good bet.
  
  
• One of the current theories surrounding ADHD is that it is (at least partially) an energy deficiency syndrome, or is the result of impaired metabolic abilities in key regions of the central nervous system. While highly debatable, this theory holds that impaired glucose metabolism in various parts of the brain may be a major contributing factor to the presence or severity of this disorder.
  
  While this blogger is currently neutral on this deficiency theory, it is interesting to note that vitamin D can help regulate glucose tranport into the brain, which would (at least in theory) improve this possible cause of the disorder. It is believed that vitamin D works by targeting multiple enzymes involved in glucose transport and metabolism. Much more study needs to be done to confirm this assertion, but this may be another potential benefit of boosting vitamin D levels in the ADHD patient.
  
  
• Vitamin D may play a role in catecholamine synthesis. Catecholamines include the neurotransmitters dopamine and norepinephrine, both of which are believed to be tightly regulated and highly involved in the treatment of ADHD (deficiencies of both dopamine and norepinephrine in the "gaps" between neuronal cells are often seen in cases of ADHD).
  
  
• Vitamin D boosts the effects of an enzyme called choline acetyltransferase in the mammalian brain. This enzyme is used in the manufacture of another neurotransmitting agent called acetylcholine. Acetylcholine is thought to play a major role in maintaining a state of sustained attention, a critical shortcoming in those with ADHD. In other words, keeping adequate levels of vitamin D could potentially help prop up lower levels of this attention-sustaining neurochemical.
  
  
• Learning and memory deficits, both of which are heavily present in the ADHD population, have been tied to prenatal vitamin D deficiencies in the rat model. This involves a process called synaptic plasticity, which relates to memory formation in an individual. If this finding extends to humans, it could have serious implications on maintaining adequate vitamin D intake in pregnant women.
  
  
• Problems with fine motor control are sometimes seen as a secondary characteristic in a fraction of the ADHD population. These problems may be exacerbated in a vitamin D deficient state.
  
  
• Perhaps the strongest correlation, however, may be between vitamin D and depressive-like symptoms, particularly those associated with seasonal affective disorders (SAD). Please keep in mind, however, that studies on vitamin D levels and depression are highly variable; a number of studies have been done on the topic and found no such linkage between the two. We have previously investigated possible connections between ADHD and SAD in an earlier post.
  
  This may make intuitive sense, since vitamin D production is triggered by sunlight, so in the dark winter months, the levels of this vitamin are often much lower (this may also be a major contributing factor as to why illnesses run so much more rampant during the winter months). In other words, vitamin D supplementation may be particularly useful in individuals with ADHD who also have co-occuring depressive or anxiety-ridden symptoms.

To summarize: Vitamin D does not have as many pronounced direct effects on ADHD as do some of the other vitamins, minerals, fatty acids and amino acids we have previously discussed. Nevertheless, the vitamin does seem to have multiple neurodevelopmental and neuroregulatory properties, and may go well with comorbid disorders such as schizophrenia, speech difficulties, memory problems, and (perhaps most strongly) depressive symptoms. Please keep in mind, however, that it may not be possible to simply "supplement these problems away" with extra vitamin D. This blogger just wants to point out that a deficiency in this vitamin often manifests itself in many ways, some of which closely parallel ADHD or related disorders. Nevertheless, supplementing may not be a bad idea, especially if you live in an area that gets minimal sunlight for part of (or all of) the year. Some rough guidelines for vitamin D intake can be found here.

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.

ADHD gene SLC6A4 favors males over females

In our last post, which asked the question "Are ADHD genes Gender Dependent?" we introduced four genes believed to be associated with the disorder of ADHD:

• SLC6A4 gene
• COMT gene
• SLC6A2 gene
• MAOA gene
  

In the next four posts, we will investigate each of the 4 ADHD genes listed above.

SLC6A4 gene, gender effects, and ADHD:

Out of the four genes listed above, the SLC6A4 gene has the least gender-based effects. The authors of the original paper on gender effects of four genes actually concluded that the gender specific influence of SLCA4 gene was not statistically significant. Nevertheless, the authors briefly noted that there was a greater influence on males than females for this particular gene (in the summarizing abstract portion of the paper).

The particular region of investigation on the SLC6A4 gene, which is located on the 17th human chromosome, was at a specific marker rs2066713 (If you are not familiar with this terminology, this is not important, it is just a way of citing a specific region of DNA and can be used to pinpoint a more exact location on a gene for studies on genetic variations, mutations, etc.). According to the study, at this specific marker on the SLC6A4 gene there was a higher likelihood that ADHD boys would receive the DNA base thymine ("T" for short) at this particular location than did ADHD females. This suggests that this "T" form (or "allele", which is a particular form or variation of a gene) at this particular spot on the 17th human chromosome which contains the SLC6A4 gene is more likely to be passed on to males with ADHD than females with ADHD. In other words, this "T" form of the SLC6A4 gene may be more associated with ADHD in males than in females. Of course, we must reiterate, that although a gender difference was observed, it was not sharp enough to be considered statistically significant, according to the original study.

Some other thoughts about the SLC6A4 gene and potential relevance to ADHD symptoms and behaviors:

• The SLC6A4 gene is often referred to by other more common names: the serotonin transporter gene (also abbreviated as 5-HTT, Serotonin Transporter, and SERT) is believed to be associated with a number of depression-related mechanisms. Interestingly, the link between the serotonin transporter gene and depression may also be susceptible to stress and other environmental factors. This gene is responsible for coding for and ultimately producing a serotonin transporter protein, which is frequently implicated in depression-related illnesses and is the target of antidepressant medications, such as Paroxetine (Paxil), Imipramine (Tofranil) and Fluoxetine (Prozac). In addition, the products of the SLC6A4 gene are also affected by amphetamines, which among some of the most common types of ADHD stimulant medications. In other words, the different forms of this SLC6A4 gene may actually play a role as to how an individual acts to a particular antidepressant or amphetamine medication. Again, keep in mind that there is often a fair amount of overlap of depression with ADHD (some experts argue that a "Depressive" form of ADHD should actually warrant its own ADHD subtype), so it is possible that gender based differences in this gene may be related to this hypothetical subtype in particular.

• However, other evidence suggests that the SLC6A4 gene may not be exclusively labeled as a "depressive gene". A study done on multiple genes believed to affect aggression and impulsivity (the latter being a common trademark of ADHD, while the former is occasionally seen extreme cases, although much more rarely, and typically only in the presence of additional comorbid disorders to ADHD), and found a nominal association between this SLC6A4 gene and cognitive impulsivity. Cognitive impulsivity, in essence, is associated with an individual making hasty decisions without carefully considering the consequences of one's actions, which frequently leads to negative or even dangerous outcomes. Not surprisingly, this is seen at much higher rates in ADHD individuals. Similar features are seen in ADHD individuals who have underactive functioning in the right frontal lobe region of the brain (a diagram of this region is given in an earlier blog post on differences in ADHD kids' brain regions), as well as those who have low tryptophan levels (which often correlates with depression and depression-like symptoms).

• There is also a possible connection of this particular SLC6A4 gene and autism, although numerous other studies have shown conflicting results. Nevertheless, given the fact that there appears to be a notable (but incomplete) overlap of ADHD and autistic symptoms, and the fact that autistic disorders are much more prevalent in boys, it is possible that there may be a tie-in between this "male-dominated" SLC6A4 gene form and a possible ADHD-autism connection.

• Finally, studies have linked variations in this serotonin transporter gene to bipolar disorders. This is also of interest because ADHD and bipolar disorders can occur together frequently and can sometimes be difficult to differentiate, especially at the pediatric level.

In the next few posts, we will be investigating three other ADHD genes believed to have gender-specific effects, which each have a potentially greater sex-related differences than this SLC6A4 gene.