ADHD treatments

"Dirty" Electricity and ADHD

2009-11-08T13:10:00.003-05:00

Could fixing your power sources help clear up ADHD symptoms?

We often hear about the health impacts of prolonged exposure to electrical and magnetic fields, including those involving cognitive deficits, neuro-developmental difficulties, and increased cancer risks. We would come to expect that some of these same invisible forces may also be at work with disorders such as ADHD.

In previous posts, we have covered how full-spectrum light exposure (within the context of seasonal affective disorders) can influence ADHD severity and symptomology.

In my reading, I recently came across an article from a few years back that caught my attention. This article was from the journal Electromagnetic Biology and Medicine, and involved a phenomenon known as "dirty electricity". The authors posited that this type of electricity, which occurs when electricity passes through several types of electronic devices such as computers or microwaves, which creates a more "noisy" spectrum (think of the analogy of a river or stream that picks up waste and debris along the way of its course) than "clean" electricity, may be a factor in a wide array of diseases and disorders ranging from diabetes to multiple sclerosis, to asthma, to fibromyalgia to neurological dysfunction (including balancing difficulties as well as ADHD-like behaviors and symptoms).

Although ADHD was not the main concern of the article (which focused more heavily on the diabetic and MS complications associated with this dirty electricity), the importance of maintaining appropriate blood sugar levels to the brains of ADHD patients should at least warrant further investigation into the matter.

By no means do I believe that this "dirty" electricity is a predominant contributing factor to a child's (or adult's) ADHD, but I did want to at least make the blogosphere aware that this may be an overlooked area of treatable potential. Some of the results of the study were intriguing to say the least.

For example, the authors found that:

Fatigue among individuals in a building "sick" from dirty electricity is much more common than previously believed. Due to their size and range of appliances and power consumption patterns, schools are often prime candidates for being vulnerable to this dirty electricity phenomena. Fatigue and overall sickness in students and teachers may be significantly reduced if special electrical filters (called Graham/Stetzer or GS filters) are utilized. Similar results have been found in other related studies (please keep in mind that several of these are somewhat biased, i.e. published by the makers of these electrical filters. For reference, this blogger has absolutely no affiliation with Graham Stetzer and does not receive any type of compensation from the makers of these filters).

Stress from electrical sources reduces the binding ability of insulin to its targets in the body, which can result in lower insulin sensitivity (much like the pattern of insulin resistance seen in the onset of type 2 diabetes).

Furthermore, exposure to higher levels of electromagnetic fields results in an increase in production of "stress" proteins in the body. The degree of this varies, as a number of individuals carry more of a hypersensitivity to electrical fields than others. This high level of inter-individual variability makes it difficult to set concrete limits on safety concerns surrounding electromagnetic exposure.

Additionally, the original article cited a case of significant improvement in balance and walking ability in and individual with multiple sclerosis following the "cleaning" of electricity in his area by using the electrical filters. Much like the phenomena of birds flying into more windows in areas near power lines (which can interfere with the bird's internal magnetic-based sense of direction), it is possible that cleaning up the power supply may have similar effects on humans.

Please note: it's important not to get too excited or attempt to draw too many theoretical conclusions based on these observations. Keep in mind that this individual was diagnosed with MS and it was just a case study. Nevertheless, given the previously mentioned association between ADHD and early infections the inner ear (which affects balance and coordination), the potential influence of electrical fields may somehow tie in to all of this as well. This is simply a working hypothesis of the blogger at the moment.

However, given the fact that abnormal glucose metabolism and blood sugar levels are typically depressed or less stable in the brains of ADHD patients as well as the possible connection between ADHD and areas involved with the balancing regions of the nervous system, the effects of electrical fields on the disorder may be larger than we previously realized.

**As an interesting aside, many of the brain glucose studies of ADHD patients have found that glucose metabolic differences are often more pronounced in girls and women with the disorder than boys or men. It stands to reason (at least on a theoretical basis, but not to prematurely draw any conclusions) that similar gender-based differences may exist with regards to blood sugar levels in the brain as a result of exposure to electromagnetic fields of "dirty" electricity.

Again, to reiterate that this blogger has no affiliation with the filters nor receives any compensation for endorsement of these products, it may be useful to investigate how "dirty" the power in your home, school or office really is, especially if you or a loved one have ADHD or one of the related complications listed in the original article.

**For reference sake, the cost of a meter for measuring dirty electricity runs somewhere from 100 to 150 US dollars (at least based off of what this blogger has seen), and the filters are about 35 US dollars apiece (not surprisingly the companies often recommend sets of 20 for an average home, bringing the grand total up over 800 US dollars. Not a small sum, of course!).

As of now, this blogger is undecided whether the negative impact of dirty electricity is enough to warrant the pricey purchase of these power cleanup methods and devices. The main point for this post was simply bring a lesser-known phenomena of electrical pollution and highlight at least some of the theoretical basis for exacerbating attentional deficits and ADHD symptoms.

Given the widely-encompassing health risks covering various diseases and disorders (listed in the original article and beyond ADHD), it may be worthwhile to spend some time in more personal investigation on the topic.

Nevertheless, these little-known connection (such as those between power lines and blood sugar levels) should serve to highlight the fact that ADHD is a multi-faceted disorder, and its symptoms may be governed by an ever-widening array of influential factors.

Treating ADHD by Floating in Salt Water?

2009-10-20T16:23:00.010-04:00

Can Floating in Salt Water Near Body Temperature be Used as an Effective, Natural ADHD Treatment?

One of the things I enjoy most about researching and writing this blog is that I get a chance to review the literature of some pretty zany diagnostic and treatment methods for ADHD. I often wonder what is going through the minds of some of these researchers as they concoct these seemingly eccentric modes of treatment for the disorder.

This blog has covered some of these seemingly bizarre treatments, including treating ADHD with mirrors, EEG manipulated ADHD treatment, light therapy for ADHD with seasonal affective disorders, and the effectiveness of behavioral therapy measures for ADHD, and hinted at other treatments such as vestibular stimulation for ADHD.

A recent article in Cases Journal on treating a patient with ADHD and Asperger's by flotation sessions in a tank of salt water struck me as particularly bizarre, but piqued my curiosity. However, the justifications and apparent effectiveness of these measures suggests that further investigation may be warranted. Before we all decide to take a prolonged trip to the Dead Sea, we should investigate the methods of this treatment process and check for scientific evidence behind its claims. Below is a summary of the process, and some of the major points the article's authors conjured up to validate the effects of this form of ADHD treatment.

As the name of the journal title suggests, this was a case report on a single individual, and not a controlled clinical study. However, I have repeated given my opinion on how case studies, although statistically inferior to controlled trials, should retain a place in novel medical treatments.

The patient was a 36 year-old woman co-diagnosed with ADHD and Asperger's (although keep in mind that many diagnostic methods forbid the co-diagnosis of ADHD with anything along the Autistic Spectrum, including Asperger's. However, many clinicians often ignore this guideline and have no problem with diagnosing a person with these two comorbid disorders).

The study authors noted that a number of the alternative treatments which previously showed promise hinged on triggering arousal levels (mirrors, EEG, etc.). It is well documented that deficiencies within arousal levels are common in the ADHD population. Hence, a sensory stimulation via flotation in a water tank may possibly show promise as an alternative ADHD treatment.

The flotation device is essentially a covered tank (to minimize the impact of outside sources of stimulation) containing highly concentrated salt water (to enable easier floating and buoyancy) at near-body temperature (to reduce tactile stimulation due to a temperature difference between the person's body and outside environment). Keep in mind that this water is typically only 8 inches to a foot (20 to 30 centimeters) deep, and its high salt content (much higher than the ocean) allows one to float easily without touching the bottom of the tank. This method, called flotation-Restricted Environmental Stimulation Technique or flotation-REST, has been shown to be an effective stress-reliever and relaxation method. A total of 19 flotation treatment sessions were done within the span of about a year.

The authors found five key components (arousal control, inhibition/activity regulation, sensory integration and interpretation, cognitive abilities, and emotional abilities) of ADHD behavior to be positively affected by flotation.

Arousal control: As mentioned previously, arousal levels have been shown to be a significant component of ADHD (and it can be either over or under-arousal). The flotation-REST method apparently addresses the arousal problem and normalizes this state by providing an environment which screens out most visual and tactile environmental stimulants.

Activity regulation/inhibitory control of physical processes: Often a hallmark characteristic of ADHD is the difficulty with inhibition control or impulsivity with regards to physical movements, especially in younger children. Impulsively grabbing at objects or persons is a common occurrence among children with the disorder (as almost any parent of and ADHD child can attest!). The salt water/ADHD treatment case study highlights that the salt water flotation/isolation therapy may alleviate some of this behavior due to it's effect on allowing the individual to "internalize" their focus on their physical movements, which may build up more regulatory ability of motor control and enhance the ability to restrict inappropriate physical impulses.
Sensory integration: We have previously alluded to the possible connection between ADHD and sensory integration (in the context of balance impairment and inner-ear dysfunction on ADHD) disorders. Additionally, numerous studies on fine motor skill deficiencies, such as handwriting and ADHD have been covered this blog and studied in the literature. It appears (at least in theory, according to the case study and journal article) that the flotation experience in a sensory restricted environment enhances the patient's sensory integration abilities by depriving external sensory stimuli, leaving room for the person in the salt water tank more time to focus and coordinate his or her senses.
Improvements in cognitive abilities for ADHD patients: We have discussed cognitive abilities in ADHD (as related to pharmacological treatment strategies) in previous posts, and there are numerous studies on comorbid cognitive deficits in those with ADHD. Furthermore, some posit a cognitive energy deficiency as the underlying cause to ADHD, identified as a cognitive-energetic model of the disorder. These deficiencies are believed to be at least partially remedied or improved by the flotation in salt water treatment, mainly due to the distraction-free environment being conducive to periods of prolonged concentration and enhanced thinking without interruption. According to the article, many of these benefits continue after the individual is out of the tank even for a period of a few weeks (of which these effects then begin to taper off).
Imrovements in personal emotional abilities: Emotional abilities, especially as they relate to inter-personal interactions and relationships can also be a common deficit in individuals with ADHD. The flotation technique is believed to improve this aspect as well, as it provides an environment of personal self-acceptance which can then be transferred to improved relationships with others and their emotions.

In conclusion, we should probably not go running out to buy a big shark tank (minus the shark of course!) just yet. Remember, this was just one simple case study done in Sweden of a 36-year old woman with comorbid Asperger's. Obviously further study is warranted, and there are a number of loose ends that must be tied up before this alternative treatment method is accepted and goes mainstream. Future studies on the effectiveness of this treatment for children with the disorder would be especially useful. Nevertheless, this Flotation Restricted Environment Stimulation Technique (flotation REST) has shown to be useful in other areas of psychological function, including as a relaxation/stress reduction method.

Thus, (in this blogger's personal opinion) this flotation REST technique may be especially good for ADHD'ers who suffer from high levels or irritability or have comorbid anxiety or depressive qualities (perhaps not those with claustrophobia or hydrophobia though!). Individuals with ADHD who have responded well to Wellbutrin or other antidepressant medications may be especially good candidates for this flotation treatment, at least in theory based on our current observations at the time.

Additionally, it is worth the re-mention that the woman of the case study had co-morbid (co-existing) Asperger's and was already on an antidepressant medication throughout the whole course of the study. This may be good news for those who suffer from co-morbid disorders, as well as the fact that this flotation REST technique seems to be relatively compatible with medication treatment. Thus supplemental treatment by flotation in salt water near body temperature may be a good adjunctive measure for individuals with ADHD and a wide spectrum of comorbid disorders.

Drugs, Genes and ADHD

2009-10-11T14:07:00.019-04:00

The Effects Specific "ADHD Genes" Have on Dosing ADHD Medications:

Below is a list of five of the most common medications for ADHD. In order to break down or metabolize these drugs, however, a series of steps must take place for effective absorption, delivery and clearance of these drugs. This process, however, requires a series of enzymatic steps. Generally, when a physician prescribes these drugs, he or she considers factors such as the patient's age, gender, symptom severity and past medication history. However, lost in the shuffle is a lesser-known, but often equally critical factor: the particular genes of the individual. It is these genes which play a large role as to how well these enzymes function (alongside other factors such as the person's nutritional status, as most vitamins and minerals act as chemical "helpers" to these enzymes, and deficiencies can lead to lower enzyme function and sub-optimal metabolic efficiency).

Unfortunately for prescribing physicians, the landscape of enzyme capabilities among the general population is far from uniform. Some individuals naturally possess enzymes or enzyme systems (which are coded for and dependent on the genetic makeup of the particular individual)which are more efficient than others (often by multi fold differences). If these enzymes are essential to drug metabolism (including ADHD medications), then a potentially crucial piece of information may be missing from the physician's repertoire of assessment tools for medicating at the proper dosage.

Much to the dismay of many a frustrated parent of an ADHD child, this often begins the laborious process of adjusting medication dosages through a glorified "guess and check" process. However, due to the need for a relatively small window of effective dosing (especially for psychotropic drugs such as those prescribed for ADHD and related disorders) and unforgiving margins of error in the optimization process, bits of information, such as a child's genetically-dictated levels of drug-metabolizing enzymes could be extremely useful. With the increasing efficiency, lowering costs of and wider availability of genetic screening methods, we may soon be able to predict a child's enzyme levels by their genetic makeup and facilitate the dosing of (and eliminating much of the guess-work from) their medications for ADHD or other disorders, saving both time and money while on the medication circuit.

Given the powerful role of enzymes and enzyme systems (and the specific genes which encode for them) for the delivery, metabolism and clearance of these medications, we should take a look at some of the genetic variations of these enzymes and the implications they may having in assisting the diagnosing physician in the near future for more effectively dosing ADHD medications.

Here are 5 common ADHD drugs (including one which is not prescribed but often used as a "self-medication" tool among the ADHD population), and the genetically-dictated enzymes which can play a role in their metabolism and dosing patterns and levels.

ADHD Drug #1: Strattera (Atomoxetine)

Key enzymes involved and gene of interest: SLC6A2, CYP2D6

We have already investigated another gene believed to have an impact on dosing with Strattera, the SLC6A2 gene. However, in that earlier post, we alluded to another gene responsible for the metabolism of the non-stimulant ADHD drug Atomoxetine. This gene is called CYP2D6. The CYP2D6 gene codes for an important enzyme of the same name (which is an important enzyme produced in the liver). The gene is located on the 22nd human chromosome (the 22q13.1 genetic region to be more specific if you are familiar with genetic markers).

Approximately a dozen different genetic forms (or alleles) of this CYP2D6 gene are seen in individuals of European ancestry. These forms are often designated by a star followed by a number, such as *1 or *4. While these numbers are used for naming purposes, it is worth noting that most individuals of European descent appear to carry either the *1 (the most common), the *2 or the *4 form of this gene. Additionally, *3, *6, and *10 forms are each found in about 1-2 percent of the population.

Interestingly, the *10 form of this gene is found in higher levels in individuals of East-Asian descent. A Chinese study found that a higher frequency of this *10 form in the population (the *10 form shows up in over half of the Chinese population, about 10 times more frequently than in whites), resulted in slower rate of drug metabolism of the ADHD medication Strattera (Atomoxetine) by the CYP2D6 enzyme.

Relevance of the CYP2D6 gene to medicating ADHD with Strattera: The *10 form of the CYP2D6 produces less enzymatic activity than the most common *1 form. This can result in about a 50% increase in Atomoxetine concentration in the blood and duration before clearance, which was seen in the Chinese study. As a result, for individuals with the exclusive *10 form (such as seen in much of the East Asian population), slightly lower or less frequent dosing levels of atomoxetine might be needed to get the same therapeutic effects. This is in agreement with another study suggesting a 50 to 75% dosage reduction of Atomoxetine for those with hepatic impairment (liver dysfunction), as the CYP2D6 enzyme is produced in the liver.

Additionally, this population may be at a slightly greater risk of side effects with the drug due to a slower clearance and greater buildup of the drug. Of course other genes and additional factors in the Atomoxetine pathway certainly play a role, but these genetic variations can still play a significant role in medication dosing strategies.

ADHD drug #2: Adderall (Mixed amphetamine salts)

Genes of interest: Catechol O-Methyltransferase (COMT) gene, Dopamine Transporter Gene (DAT)

In previous posts, we have spoken extensively about a gene called COMT, short for Catechol O-Methyltransferase and its role on dosing for amphetamine-related ADHD medications such as Adderall and Vyvanse. This previous discsussion on COMT and ADHD medication dosing can be found here.

However, there are a few other genes worth noting here for their potential roles in dosing with amphetamine-based ADHD medications such as Adderall. One of these is the Dopamine Transporter gene (DAT), which is located on the 5th human chromosome. This gene also goes by other names such as DAT1 or SLC6A3. The DAT gene codes for an important protein called the Dopamine Transporter protein, which is responsible for shuttling the important brain chemical dopamine in and out of neuronal cells.

A number of stimulant drugs used to treat ADHD and related disorders work, at least in part, by interacting with this dopamine transporter (DAT) to correct a dopamine imbalance (in general, individuals with ADHD often have too little dopamine in the regions between brain cells or neurons in key regions of the brain. Many stimulant ADHD drugs remedy this by blocking the shuttling of dopamine back into the cells, keeping adequate amounts in these "gaps").

Interestingly, on a side note, the DAT gene has been implicated (in conjunction with another dopamine-related gene called DRD4) in IQ levels an behavior problems.

Like the genes mentioned above, DAT exists in a wide number of different forms across the human gene pool. Some forms appear to increase ones predisposition to ADHD and various neurophysiological or behavioral disorders and have earned the moniker "high risk alleles" (remember, an "allele" is simply a specific form of a gene which varies within the population).

A study on families of ADHD children found that a specific form of the DAT gene which included a 480 base pair repeat (simply a repeating section of DNA which is 480 DNA "letters" long) allele was associated with greater severity of ADHD symptoms, especially in the combined ADHD subtype (which includes high levels of both inattentive and hyperactive/impulsive symptoms as opposed to a predominance of one).

Potentially, individuals with ADHD who carry this "high-risk allele" of the DAT gene (which is a substantial portion of the general population) may require slightly higher levels of medication dosage with amphetamine-based stimulants than their "lower-risk" counterparts. These differences may be even more pronounced if the individual carries the "Val" form of the COMT gene, mentioned in a previous post (given the current body of research on the subject, the contributions of the COMT gene dwarf those of the DAT gene with regards to governing amphetamine dosage levels).

ADHD drug #3 Vyvanse (lisdexamfetamine dimesylate)

Gene of Interest: Trypsinogen

Due to its chemical proximity to amphetamines (Vyvanse is essentially an "inactivated" form of the drug Dexedrine, which is an isolation of one of the potent components of Adderall). A special chemical "tag" is linked to the active part of the drug, which must be chemically cleaved to release the active form of Vyvanse (think of it as essentially breaking a seal to free up the drug) into its functional amphetamine-based product. Naturally, the genes listed above (and the enzymes which they encode) which metabolize amphetamines are of substantial interest for potentially influencing the effectiveness of ADHD treatment with Vyvanse as well.

However, the actual cleaving process of releasing the active component of Vyvanse is equally as important. If the drug is not freed, then it cannot be effectively metabolized.

Several enzymes which are called upon to metabolize the other ADHD drugs in this post do NOT appear to have a significant effect on Vyvanse. These include CYP2A6, CYP2B6 (both for nicotine), and CYP2D6 (for Strattera). This is good news for those who are already taking medications, as Vyvanse's relative independence of these drug-metabolizing enzymes means fewer adverse drug-drug interactions.

As far as genetics go, the genes coding for the breakage of de-activating chemical tag placed on Vyvanse may be of most importance, especially since this breakage (or "hydrolysis") is believed to be the slowest (or rate-determining) step in metabolizing Vyvanse for ADHD. The de-activating "tag" attached to Vyvanse is none other than the amino acid lysine. While the exact mechanism of cleaving this link is not fully known, one enzyme in particular may be extremely relevant to this process.

Trypsin is an extremely common digestive enzyme produced predominantly in the pancreas. It is responsible for breaking up chemical linkages much like that of the one used to de-activate Vyvanse. Thus, a genetically-governed deficiency of the trypsin enzyme could lead to a severely hampered absorption (and subsequent metabolism and clearance of the ADHD drug Vyvanse).

Trypsin is actually coded for by a series of enzymes, often referred to as Trypsinogen, which located on the 7th human chromosome (in the "q35" region of the chromosome to be more exact). Individuals with pancreatic deficiencies, including pancreatitis have been tied down to having mutations in this trypsinogen gene.

Therefore, while this genetic region on the 7th chromosome hasn't been sufficiently studied with regards to Vyvanse (at least to the best of this blogger's current knowledge), this blogger personally believes that aberrations in the region of the Trypsinogen gene on this 7th human chromosome may be a worthwhile place to look for genetic response-based differences to the ADHD medication Vyvanse.

ADHD drug #4: Concerta/Ritalin/Daytrana/Biphentin (methylphenidate)

Genes of Interest: Carboxylesterase 1 (also referred to as "CES1"), DAT (refer to ADHD drug #2: Adderall section for DAT's genetic location)

Carboxylesterase 1: Although the affected form of this enzyme, which is coded for by a gene on the 16th chromosome, is relatively rare, some key studies have indicated that deficiencies in the CES1 enzyme can be coded from specific forms of this gene. These rare, low-functioning gene-mutation forms of Carboxylesterase 1 result in extremely poor methylphenidate metabolism, resulting in a buildup of abnormally high levels of the drug in individuals with this enzymatically-deficient form.

In addition to their effects on amphetamines such as Adderall or Dexedrine, variations (often referred to in the literature as "polymorphisms") in the DAT gene also play a role in the response to methylphenidate. A Korean study found that a specific allele (the 10-repeat allele, which is the same form as the "high-risk" 480 base-pair allele mentioned earlier in the amphetamines section) predicted a poor response to methylphenidate.

Interestingly, however, several Irish studies suggest the exact opposite: the "high-risk" 10-repeat 480 base pair form of the DAT gene may produce larger amounts of the DAT protein (which shuttles essential dopamine out of the gaps between the cells, the opposite effect of what one wants if they suffer from ADHD), so the higher levels of expression of this transporter may make it a better candidate for methylphenidate.

Another Irish study may help resolve some of this discrepancy. It found that individuals with the so-called "high-risk" form of the DAT gene mentioned above exhibit a more positive response to treatment with methylphenidate with regards to treating their attentional symptoms based on the left side of the brain. Left sided inattention can be a reflection of brain damage or brain asymmetry, the latter being a common trait in the ADHD population. It should be worth noting that methylphenidate has been an effective treatment method for improving cognitive processes for those suffering from traumatic brain injuries.

Given the fact that in the amphetamine section we mentioned that the DAT gene was more connected to the Combined ADHD subtype (the original article specifically stated that the association did not hold for the strictly inattentive ADHD subtype). If this holds true, then we may have discovered a potentially significant gene/medication/ADHD subtype association.

It is this blogger's current hypothesis that the "high-risk"/480 base pair/10-repeat allele form of the DAT gene might predispose one to a MORE FAVORABLE response to methylphenidate treatment if inattention is the most persistent ADHD symptom (as in the predominantly inattentive ADHD subtype). Conversely, if the hyperactive/impulsive behavior either predominates or is largely present in an individual (such as in the hyperactive/impulsive or combined ADHD subtypes, respectively), then the "high-risk" label holds for this particular gene type, and the methylphenidate response potential goes down.

In other words, if large amounts of hyperactivity are present (which is the case in most ADHD children, as the combined subtype is by far the most common form), then this "high-risk" form of the DAT gene hampers methylphenidate's effectiveness, whereas if hyperactivity is largely absent, then the response to methylphenidate is actually more favorable. If this hypothesis were to hold true, then we could screen youngsters for this form of the gene and keep them far away from methylphenidate if they were bouncing off the walls, whereas if the exhibited more of an inattentive "space cadet" type of behavior then methylphenidate might be a good first choice of pharmaceutical treatment. Of course this theory could be completely off-base, but given this blogger's current knowledge and exposure to the current literature, this may be a plausible explanation.

Another possible explanation for this discrepancy between Irish and Korean studies: We have already seen that specific forms of certain genes can be found at considerably higher levels such as the *10 form of the CYP2D6 gene mentioned above with regards to the East Asian population. Keep in mind that this gene form was associated with the metabolism of Strattera (which exhibits a significantly different mode of operation than do stimulants such as methylphenidate or mixed amphetamine salts). However, there are a number of so-called ADHD genes which have been implicated with the disorder. The current thought here is that some genes exhibit a more powerful influence on physical or behavioral traits than do others. In other words, some genes simply act more "powerfully" than others. This is known as epistasis ("Epistasis" roughly means "standing upon").

***As a side note, please don't confuse "epistasis" with the whole dominant/recessive "big A/little a" (Aa) gene thing you probably learned about in middle school biology. Dominant/recessive refers to different forms of the SAME gene, whereas epistasis refers to DIFFERENT genes. For example, let's say, hypothetically that there was a rare gene for green hair located on the 20th human chromosome. However, a more "powerful" gene, say on the 14th chromosome codes for brown hair. This brown hair gene in this case would be epistatic, meaning that it would overpower the effects of the green hair gene altogether. This phenomena is quite common in genetics.

Getting back to our discussion, this blogger hypothesizes that there may be one or more other unidentified genes in either the Korean or Irish population which are epistatic to the DAT gene with regards to the methylphenidate response. If this was true, then it's quite possible that the effects of these hypothetical yet-to-be-identified genes might "mask" or override the effects of the DAT gene, and that the association with the "high-risk allele" may be largely coincidental rather than causative. Given the state of the current research on current "heavyweight" genes such as the COMT gene mentioned earlier, it is entirely possible that the overall level of contribution among specific "high-risk" DAT alleles might be less significant than many of these studies seem to indicate.

Of course the discrepancy could just as easily be attributed to small sampling sizes, slight differences in experimental methods or uncontrolled variables in the experiment (or a complete lack of true association between methylphenidate and the DAT gene at all, although given the current body of literature, this last assertion seems highly unlikely).

ADHD drug #5: Nicotine:

Genes of interest: CYP2A6, CYP2B6

I have included this drug due to the high rates of smoking among those with ADHD. As with alcohol, nicotine is often widely used as a form of self-medication for those with ADHD. Some research even suggests that individuals with ADHD exhibit a different response to nicotine and that nicotine withdrawal may produce different patterns in certain critical brain regions between ADHD'ers and the general population. Interestingly, there are some genetic regions which may tie into this behavior.

With regards to nicotine metabolism, 2 genes appear to stand out in particular: CYP2A6 and CYP2B6 (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism CYP2D6. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the CYP2A6 (hereafter abbreviated as "2A6") enzyme is responsible for the lion's share of nicotine metabolism. It is coded for by by a gene of the same name, located in the "q13.2" region on the 19th human chromosome.

Like the 2D6 gene for Strattera, the 2A6 gene can exist in multiple different forms. Some 2A6 gene forms produce higher levels of the 2A6 enzyme than others. Other forms of 2A6 are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. As a result individuals with these less efficient forms (called "slow metabolizers") of the 2A6 genes are less likely to develop nicotine addictions.

The relevance of these 2A6 genes on ADHD: The stimulating effects of nicotine are believed to be a major contributing factor to the higher prevalence of smoking among the ADHD population. If this is true, then slow metabolizers of nicotine may not derive the full effect of nicotine self-medication for attentional deficits, at least not as immediately as the fast metabolizers. On the flipside, they have lower cravings (like with virtually all stimulant drugs, the speed and rate of uptake and clearance of nicotine is a major factor in its addiction potential) and are exposed to less tobacco and often find it easier to quit smoking.

At least two alleles or forms of the 2A6 gene (using the "star/number" nomencalture us used in 2D6 for Strattera earlier in this blog), have been shown to coincide with slower rates of nicotine metabolism. They are 2A6*2 and 2A6*4 (these two forms are actually referred to as "null alleles" meaning that the 2A6 enzyme they code for has no activity).

Additionally, there are noticeable differences in the frequencies of these forms across different ethnicities among the global population. For example, these "slow metabolizing" gene/enzyme forms of are found in higher percentages in individuals of Asian ancestry (around 20%) compared to those of European descent (around 8%).

With regards to ADHD behavior, it is likely that people possessing these *2 or *4 forms of the CYP2A6 gene, may be less likely to use nicotine as a self-medication tool for their ADHD, or at least use the drug in lower doses, due to its lesser effects. On the flipside, however, there is another allele of the 2A6 gene, referred to as CYP2A6*1B. This version of the 2A6 nicotine metabolism gene actually promotes greater activity of the nicotine metabolizing enzyme, and speeds up the processing and clearance of the drug. As a result, individuals who possess this relatively rare CYP2A6 form may be more prone to more frequent use and abuse of nicotine, and individuals with ADHD who attempt to self-medicate with this drug may cycle through their nicotine more rapidly if they carry this *1B form of the gene.

Interestingly, another drug, bupropion (Wellbutrin), which is an anti-depressant often used off-label to treat more "depressive" forms of ADHD is a relatively common anti-smoking drug. Given the fact that a number of ADHD'ers who typically do not respond well to stimulants, but do respond to Wellbutrin may fall in this smoking category, it is possible that the fast metabolizers (i.e. the *1B individuals), may be good candidates for Wellbutrin, not only to stop smoking, but possibly also to treat unwanted ADHD symptoms.

Alleles of the CYP2B6 gene and enzyme with regards to nicotine and ADHD:

Shifting gears for a minute, we see that the CYP2B6 gene (as well as the enzyme which it encodes) also may also play a unique role in ADHD. The CYP2B6 gene is located on the 19th human chromosome (in the 13.2 region of the 19th, to be more specific). For individuals who lack CYP2A6 enzyme activity because of the reduced-activity or even "null" alleles, the enzyme CYP2B6 can metabolize nicotine in its place (it turns out that CYP2D6, the enzyme responsible for Strattera metabolism can also do the trick). For those who need to metabolize nicotine, but lack an effective CYP2A6 enzyme system, this is good news (however, this "B6" enzyme only functions at about 10% of the level of the "A6" enzyme, so B6 is not a very efficient "backup" for A6).

Beyond its role as a "backup" for the CYP2A6 enzyme, CYP2B6 may also be of clinical significance with regards to ADHD and similar disorders. In contrast to "A6", whose enzymes are predominantly generated in the liver, the CYP2B6 generated enzymes are expressed in brain tissue. With regards to the differences in neurochemistry and neurological functioning of the ADHD brain, the role of CYP2B6 is therefore potentially noteworthy.

Additionally, as we have discussed in earlier posts regarding ADHD and alcoholism, the 2B6 enzyme apparently also plays a role in alcoholism, and individuals who express higher levels of this genetically-encoded CYP2B6 enzyme in their brains may be more sensitive to alcohol, nicotine and other centrally acting drugs. The study even suggests that individuals with high levels of this gene-coded enzyme may be more prone to damages induced from these common chemical agents, including possible higher susceptibility to cancer.

For reference (using the "star" notation again), genetic forms of CYP2B6 which typically yield higher levels of this enzyme in the brain include the CYP2B6*4 (which shows up in about a third of the European popluation) form and the CYP2B6*9 (which is present in about a quarter of those of European descent) form. Again, don't worry too much about the specifics of these "starred" variants, just know that if you were to get a genetic screen and had one of these two enzymatic forms, you may be more sensitive to nicotine as a self-treatment ADHD "medication".

What this means is that ADHD individuals who harbor the higher-expressing "*4" and "*9" forms of the CYP2B6 enzyme in their brains may be more sensitive to chemical agents such as nicotine, and these same individuals may be more likely to suffer the toxic effects of this popular form of ADHD "self-medication".

In conclusion, we should note that some of these genes (such as DAT) have been well-studied and have repeatedly shown to be associated factor in proper dosing of ADHD medications. Others, however, such as the trypsinogen gene for Vyvanse are more at the theoretical level at the moment. However, this blogger believes that in the next couple of decades, (due in part to our expanding knowledge of the human genetic code and functional genomics), genetic screens will become foutinely more commonplace as a necessary tool for both prescribing and dosing medications. With regards to this general trend, psychotropic medications for disorders such as ADHD should be no exception.

Omega-3 Oxidation in ADHD: A Problem with Supplementation?

2009-09-08T23:18:00.009-04:00

Here are 4 reasons why omega-3/fish oil/flax seed oil often fails for treating ADHD and how some simple strategies can maximize omega-3 supplementation's effectiveness for therapeutic treatment of the disorder:

One of the most common recent trends in the natural treatment world of ADHD is omega-3 fatty acid supplementation. A number of studies appear to provide at least a theoretical basis for omega-3 fatty acid supplementation for ADHD as a valid natural treatment option. Fish oils, flax oils, and a variety of marine and seed oils are are showing up and rapidly disappearing off the shelves in grocery and health food stores.

Along with all of the pronounced cardiovascular improvements, a number of concerned parents are reaching for these omega-3's as natural treatment options for other dysfunctions, including ADHD and depression. A number of journal articles and research studies seem to support the use of omega-3 fatty acid supplementation as a viable alternative treatment method for attention deficit and or hyperactivity disorders (although not, perhaps at the complete level of stimulant medications).

Lost in the shuffle, however, is the million dollar question: Does omega-3 supplementation actually work in practice?

A number of parents will quickly jump to one side or another on this issue. Some swear by the effects, while others have written off this treatment alternative altogether.

I would like to distill some of the information I have gathered on the subject for this blog post. I personally believe that manipulation and treatment strategies for disorders such as ADHD using dietary fats is still in its infancy. Beyond their caloric content and to a degree beyond most other foodstuffs, fatty acids are often capable of making or breaking our systems hormonally and metabolically. Omega-3's are no different.

Recent findings suggest that fatty acid imbalances in children with ADHD may not be due as much to fatty acid intake, but rather a difference in metabolism of these fats.

In my personal line of work, I have seen at least 4 major factors (there are certainly more beyond these 4, for sure), which can severely hamper the effectiveness of omega-3 fatty acid treatment for ADHD and related disorders. They are:

Insufficient nutrient cofactors (or "helpers" for the enzymes that metabolize fatty acids). These include key vitamins and minerals, many whose supplementation, coincidentally, is often linked to improvement in ADHD symptoms.
Genetic factors in which lower amounts of of active enzymes key in the omega-3 metabolic pathway are present: A relatively new body of research suggests that individuals with ADHD manufacture different levels of these enzymes than the general population. This is one of many ways in which genetics may play a factor in the disorder.
Multiple fats competing for the same enzymes and pathways: The metabolism of different types of fatty acids can be complex. Different fats often share the same enzymes to form their respective products, so an imbalance in dietary intake of certain fats often means an imbalance in their products. This can have wide-reaching effects, such as a heightened state of inflammatory processes and disorders (such as heightened allergies), which coincidentally or not, are often seen at higher rates in ADHD patients. In other words, supplementation with omega-3 fats may be offset if a person's diet also contains high levels of "competing" fats.
Fatty acid oxidation: One of the most damaging negative side effects. Omega-3's, as great as they are for overall cell health, are often especially prone to oxidative damage. This damage, of course, can be at least partially stopped by ensuring that the body has adequate stores of antioxidant nutrients which are capable of acting on cell membranes and other common destinations of omega-3's.

Having highlighted these 4 factors on how well we can maximize the "omega-3 effect" on ADHD and related disorders, we can see that one of them (genetics) is largely beyond our control. However, we can also see that 3 of these 4 factors do fall under our control, at least somewhat, by dietary intervention. Add on these 3 helping factors, and you increase the chance of reducing unwanted ADHD symptoms and behaviors through omega-3 manipulation.

Before we begin, let's get a brief background on omega-3's and other fatty acids and how they relate to disorders such as ADHD.

A background on fatty acid ratios and ADHD:

You may be familiar with some of the following fatty acid "buzzwords" being thrown around recently: ALA, DHA, EPA, etc. These are simply abbreviations of much more lengthy names of major types of fatty acid which are either obtained in the diet or produced by metabolism of other fats.

Here is a quick summary on some of these important fatty acids and why they may be important with regards to ADHD and related disorders:

ALA: Short for Alpha Linolenic Acid, ALA is an omega-3 fatty acid. It can be obtained via dietary means including green vegetables, walnuts, soybeans and several types of seeds (kiwi seeds, flax seed or linseed are especially high in ALA).

One of the main reasons ALA is so important is that it can be converted to other key fatty acids such as EPA and DHA, which will be addressed shortly (essentially it acts as starting material for these other fats). It is therefore relatively versatile among the omega-3's, so maintaining adequate levels of this fat is important. It is important to keep in mind, however, that this conversion process is relatively inefficient, even with the help of important enzymes. As a result, many choose to supplement with these other fats which occur "down the line" directly. Nevertheless, due to its nutritive properties and versatility, maintaining adequate pools of ALA through consumption of the above-mentioned dietary staples is of great potential use.

DHA: Short for Docosahexaenoic Acid, DHA is another important omega-3 fat. It is found in green vegetables as well, as well as several types of meat and animal products (including milk from free range animals who graze on greens instead of feed lots). Of the omega-3's DHA is one of the most critical fatty acids for optimal brain health and nervous function. Low levels of DHA have been linked to cognitive decline and neurodegenerative diseases such as Alzheimer's Disease. DHA is also important for eye health, but is also susceptible to oxidation (which will be discussed in the last section). Interestingly, DHA is believed to play a role in protecting the nervous system from oxidative stress.

EPA: Short for Eicosapentaenoic Acid (not the Environmental Protection Agency, although this fat does play a protective role in several key functions!), EPA is another important omega-3 fatty acid. It is found in significant levels in breast milk (another major plus to breast-feeding) and oily fish such as sardines, mackerel, cod liver and salmon. Most of the fish oil treatments for ADHD rely heavily on this omega-3. It is important to note that this omega-3 is not often found in high levels in farmed fish who obtain their food primarily from non-algae sources. This is because it is the algae itself, which contains most of the EPA.

EPA is unique in that it's effect may be more far-reaching than many other omega-3's. At least some research suggests EPA has a protective effect against depressive disorders including suicide, inflammatory conditions (DHA does this as well, making both EPA and DHA good potential candidates for ADHD patients with a concurrent inflammatory condition such as allergies), and may even combat certain types of cancer.

As an interesting aside, there is also some evidence that EPA (at very high doses) may interact with an important type of enzyme called CYP2D6. This enzyme is actually responsible for metabolizing a number of drugs including amphetamines (for ADHD) and a number of antidepressants (including Prozac or fluoxetine as well as Tofranil or imipramine), so extremely high doses of EPA may actually interfere with these medications. Additionally, some studies suggest that higher levels of EPA may reduce levels of natural killer cells (which play a big role in fighting off invading foreign bodies) in older adults. However, to reiterate, most of these observations were seen at high doses beyond the common range of dietary or supplemental levels.

Blogger's note: I found an excellent review article about ALA, EPA and DHA for those of you who are interested. It can be found here. Although a bit lengthy and technical, it greatly expands on our above discussion.

Now that we have given some background into some of the key omega-3 fatty acids and their functional roles, let's return to the four factors listed in the beginning of this blog on how omega-3 supplementation's effectiveness can be hindered.

Factor #1: Insufficient supporting nutrients for the conversion process:
The ALA to DHA and EPA conversion process involves a number of steps and a number of enzymes. These enzymes, however, do not function in a vacuum, but rather rely on a number of common vitamin and mineral "cofactors" to optimize their function. Some of these cofactors necessary to optimize function of these fatty acid conversion enzymes include magnesium, zinc, vitamin B6, and vitamin C. We have seen in previous posts how magnesium, zinc, and vitamin B6 supplementation may be helpful in ADHD cases, especially if nutrient deficiencies are suspected.

Factor #2: Deficiencies in the enzyme systems themselves:
Another possibility in the fatty acid metabolic differences in individuals with ADHD may be due to malfunctioning or lower enzyme activity, even if the above mentioned cofactors are in place. Lending credence to this hypothesis is the fact that certain forms of genes responsible for "coding" for these important enzymes are seen at higher levels in ADHD patients. One of these genes is called fatty acid desaturase 2 gene, or FADS2.

It's important to note 2 things here:

1. The FADS2 gene is believed to code for an important enzyme delta-6 desaturase. This enzyme is critical in several fatty acid conversion processes, such as ALA to DHA. As we will see in the next section, this same enzyme, delta-6 desaturase is also used in another fatty acid conversion process, LA to AA.

2. At least some genetic evidence suggests that some forms of the FADS2 gene are seen at abnormally high rates in individuals with ADHD. This hints at a potential association between ADHD and the FADS2 gene.

Please keep in mind that these genetic factors are a bit more tenuous than the other ones. This is good news, because it suggests that even more control of the disorder may lie in the diet instead of the genes (at least with regards to omega-3 levels and ADHD). However, it is also important to note that the body of research on this topic is constantly shifting and changing.

Factor #3 on omega-3 supplementation for ADHD: Different fats share the same enzyme (delta-6 desaturase):

Factor #1 tells us that if we want to be serious about getting the most out of omega-3 supplementation for ADHD and related disorders, we had better make sure that we are supplying the enzymes which churn out this important omega-3 conversion process with the necessary nutrients or "cofactors" (vitamins C and B6, magnesium and zinc, to name a few). Without these helping nutrients in place, the enzymes cannot do their job nearly as effectively, and many of the nutritionally based benefits of omega-3's may be lost.

Factor #2 states that expression of some of these enzymes (and the subsequent activity level of these fatty-acid metabolizing enzymes, such as delta-6 desaturase) is contingent on specific genes, such as the FADS2 gene. Certain forms of this gene are believed to appear at higher levels in the ADHD population. Unfortunately, this is a genetic factor, meaning that there is little we can do about this process.

However, a third factor with regards to manipulating enzyme systems involved in omega-3 fatty acid supplementation and subsequent metabolism is within our control, at least to a certain extent. This involves tilting the scale or balance of dietary fats which compete for the same enzyme system. Let me explain:

The typical conversion of the omega-3 fatty acid ALA (alpha linolenic acid, see description at the top of this post) to the important fatty acid DHA utilizes the enzyme delta-6 desaturase. Yes, this is the same delta-6 desaturase enzyme which is coded by the FADS2 gene in factor #2 (and whose expression may, at least indirectly be associated with ADHD by genetic factors). However, the conversion of other fats in the body also share this enzyme for their conversion process (think of 2 construction workers who need to share the same power tool at the same time, but for completely different sections of the project). One of these other "competing" fats is linoleic acid (abbreviated as "LA", be careful, unlike alpha linolenic acid, this fat is spelled without the "n"). LA requires this same enzyme delta-6 desaturase to undergo a conversion process to another important product called arachidonic acid (AA).

Please don't get too tripped up on all of these lengthy names, terms and abbreviations. The important thing to remember here, is that many different processes, including metabolizing different types of fats, often share the same enzyme systems. As a result, these different fats often "compete" for the same enzymes, and significant dietary imbalances of one type of fat over another may often lead to an imbalance of "output" or products of these fatty acids.

Arachidonic acid (a non-omega 3 fatty acid) is responsible for a number of necessary processes, including some of the inflammatory responses described earlier, but it is important to note that it is possible to build up an over-abundance of this, which can play a role in the buildup of unnecessary or chronic levels of inflammation. This is believed to be at least partly responsible for inflammatory diseases and disorders such as allergies (as an interesting side note, allergies are seen at higher levels in individuals with ADHD than within the general population).

To summarize this point, the conversion of alpha-linolenic acid (ALA, which is an omega-3) to DHA must "compete" alongside the Linoleic acid (LA, a non omega-3) to Arachidonic acid pathway for the same enzyme (delta-6 desaturase). If excessive amounts of non omega-3 fatty acids are consumed (which is typical in most Western diets), then this crucial ALA to DHA process is hampered. Of course an imbalance on the other side (too many omega-3's) is also a possible, but given the dietary makeup in much of the industrialized world, this is often highly unlikely.

So, to summarize Factor#3: Omega-3 supplementation, such as with fish oil, flaxseed oil or ALA is often compromised by the concurrent intake of high amounts of other fats, throwing off the delicate balance of dietary fatty acid intake.

Finally, there is one other extremely important factor, which is the main topic of this post. Factor #4 involves the fatty acid oxidation process.

Factor #4: Is ADHD an "oxidative" condition?

While numerous studies have linked ADD and ADHD to lower blood level ratios of of omega-3's and various essential fatty acids, some others are suggesting that the actual oxidation of these fatty acids may also be a problem in children with attention deficit disorders.

Omega 3's are especially prone to fatty acid oxidation (as anyone who uses pure, untreated omega-3 rich oils can attest, these oils quickly become rancid and have a much shorter shelf-life than the processed "partially hydrogenated" oils). This is actually one of the main reasons why trans fats came about. They are tougher to oxidize by bacterial systems than the "natural" fats and thus have a longer shelf life. Unfortunately, a lot of the health problems stemming from trans-fats is due to many of the same reasons (our bodies aren't quite sure how to process, break down or metabolize these fats).

One of the major targets of omega-3's is that they are able to incorporate into cell membranes. In general, omega-3 fatty acids make the cell membranes more flexible or fluid, while other fats often make these same membranes more rigid or hard, which can compromise the integrity of the cell membrane and the overall cell health. However, like omega-3 cooking oils, these cell membranes are constantly exposed to oxidative damage. This includes cells in the nervous system, which are highly "fatty", and thus extremely susceptible to oxidative damage. This is why it is so important to not just provide the nerve cells with abundant supplies of omega-3's to incorporate into their membranes but also protected omega-3's (that is to say, omega-3 fatty acids accompanied by adequate antioxidant protection).

Therefore, for disorders involving the nervous system, including ADHD, it is imperative that sufficient antioxidants are available to protect these key cell systems. Simply taking omega-3's, fish oils, etc. in an antioxidant-deficient state is less effective at best, and neuro-damaging at its worst. I personally believe that omitting antioxidant protection is the single-greatest saboteur of omega-3, fish oil, or flax oil supplementation's effectiveness for treating diseases and disorders such as ADHD.

So which antioxidants should we be taking?

Vitamin C readily comes to mind as one of the cheapest and most well-known antioxidants. However, one strike against this vitamin is that it typically exists in a water-soluble form (that is, it mixes well with water, and is why it is easily flushed out of the system and needs to be replaced on a daily basis. It is also a main reason why it difficult to overdose on vitamin C, since excess amounts can simply be flushed away with water). Remember that omega-3's are still fats, and that fatty substances often do not mix or interact well with water. Thus, vitamin C, at least in isolation, is not the best option for protecting these essential fats. A fat-soluble antioxidant may be a better option here.

Enter vitamin E. Unlike vitamin C, vitamin E is a fat-soluble vitamin, which has a greater potential to interact with fatty substances such as omega-3-laden membranes in the nervous system and other cells. Even better, vitamin E and vitamin C work well in tandem, helping recycle each others' antioxidant pools after countering oxidative-damaging agents in the nervous system and other parts of the body. This is evidenced by a number of studies which indicate that vitamin C can help recycle vitamin E levels.

Recommended daily amounts (and toxic levels) can be found here for vitamin C and vitamin E.

Finally, I would like to address one of the more recent "wonder-nutrient" brain foods which may pose therapeutic benefits for ADHD and related disorders: Pycnogenol/pine bark extract. There is some debate as to why this may be an effective natural ADHD treatment, but much of the evidence suggests that the effectiveness of pycnogenol for ADHD lies in its antioxidant properties.

So the key take-home messages from this post are as follows:

Omega-3 fatty acids show a significant amount of potential as natural ADHD treatment options (although they are often not nearly as potent as medication treatments in a number of cases).
Omega-3's rely on enzyme systems to do their job. Genetics can play a role in the functionality and effectiveness in some of these key enzymes.
In order for these omega-3 metabolizing enzymes to function, nutritional "cofactors" are required. These include most of the B vitamins, vitamin C, and important minerals or metals such as zinc or magnesium. Other cofactors, such as biotin (found in eggs) are also necessary agents to make many of these enzymes run smoothly. Deficiencies in these nutrients compromise enzyme integrity and can ultimately limit the effectiveness of omega-3 supplementation for ADHD and related disorders.
Omega-3's compete with other fats for many of the same enzymes and enzyme systems. They often produce competing products, so an overall balance of fatty acids is imperative. Taking a couple of fish oil capsules will not be enough to offset a diet chock full of unhealthy saturated or trans fats. Chronic inflammation disorders such as allergies, asthma, etc. can be a sign of (but are by no means the exclusive reason of) omega-3 deficiencies or an indication of an imbalance in fatty acid intake or metabolism.
It is imperative that these omega-3's be protected by adequate antioxidant levels in the body, as omega-3 fatty acids are often extremely prone to damage by oxidation, especially in the nervous system. Vitamin C/E combos, as well as other powerful antioxidants such as bio-flavonoids in colorful fruits, vegetables, teas, etc. are especially helpful in this regard, and should be taken as seriously as the omega-3's themselves as natural treatment strategies for ADHD.

ADHD gene ADRA1A: A good target for clonidine?

2009-06-01T22:37:00.006-04:00

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.

Modafinil: An alternative treatment for ADHD and comorbid substance abuse?

2009-05-30T20:55:00.011-04:00

Can Modafinil (Provigil) Replace Stimulant Medications in Adult ADHD where stimulant drug abuse is a concern?

It is a Catch-22 of the ADHD world. An individual is suffering from severe ADHD symptoms and appropriate stimulant medications may help remedy some of the negative side effects of the disorder. However, due to the high prevalence of substance abuse in ADHD (some officials put the rate of comorbid substance abuse as high as to 30% in the ADHD population), including stimulant medications such as amphetamines, treatment of ADHD symptoms via stimulant medications cannot, by nature of the comorbid substance abuse disorder, be a treatment option.

The appearance of (relatively) novel non-stimulant medication alternatives such as Strattera (atomoxetine), have offered individuals with ADHD another treatment alternative. However, the results are often mixed. Strattera often works well with the inattentive-dominated forms of the disorder, but the positive results are often not as pronounced for the more hyperactive or impulsive forms of ADHD, especially if comorbid disorders such as conduct-related issues surface.

Another alternative may be a completely different type of drug, which, while not a stimulant in its own right, can act on or exhibit pseudo-stimulant properties. It appears that in at least some cases, Modafinil (Provigil) may be the type of drug we're looking for in these cases.

**Blogger's note: The extent of the study highlighting this case for Modafinil treatment for ADHD and comorbid amphetamine abuse is intended for adult treatment only. Given the relative scarcity of research on medication options for adult ADHD symptoms (compared to those designed more for children), this post is designed for offering a possible treatment alternative for ADHD in adults. Nevertheless, some recent studies have shown promising results of Modafinil as an ADHD treatment method for children and adolescents.

It is important to note, that while not initially designed as an ADHD-specific medication (and not a stimulant in its own right), Modafinil does share at least some degree of overlap with several stimulant agents for ADHD treatment. One is its regulation of catecholamines (important neuro-signaling chemical agents, whose balance in and out of neuronal cells is crucially important for regulating attention, hyperactive and impulsive behaviors, and locomotor control). As far as its mode of action and metabolism (clinical pharmacokinetics of Modafinil) are concerned, drug-drug interactions between Modafinil and several ADHD stimulant medications such as methylphenidate or dexamphetamine (Dexedrine) appear to be limited.

A background note on addiction potentials of ADHD drugs: This section is an aside, and is meant to serve as some background information and to clear up potential confusion surrounding ADHD medications and their addiction potentials. The next four paragraphs may be skipped if you are pressed for time.

While I cannot stress enough the importance of regulating neuro-chemical balance for both the onset of ADHD as well as drug addiction (which are affected by pharmacological agents such as ADHD medications, in varying forms), it is the rate of action for which these chemical changes take place which typically drives a particular drug's addiction potential.

Unfortunately, this last fact is often lost in much of the literature surrounding ADHD treatment (especially those which promote non-pharmaceutical treatments for the disorder). For example, many "natural" ADHD treatment books and websites frequently start out by asserting (erroneously) that methylphenidate is the equivalent of crack cocaine, and promotes later drug abuse and addiction.

While this blogger is a personal advocate for natural approaches to treating ADHD whenever possible (and without compromising overall treatment effectiveness in ADHD treatment), he wants to make it clear that significant differences do exist between ADHD medications and stimulant street drugs. One of the most telling signs of this is the rate of uptake and clearance of drug-like agents into and out of the brain, respectively. In general, the quicker a substance is taken up into the central nervous system and the faster it clears the brain, the more likely this chemical agent will elicit a "high" and an increased tendency towards substance dependence.

ADHD medications like Ritalin, while having some degree of overlap in structure and net effects of action as cocaine, are specifically designed to have a much slower rate of release and clearance, significantly reducing their abuse potential compared to cocaine. We have previously discussed Ritalin (methylphenidate) vs. cocaine addiction potentials in earlier posts.

Modafinil: Modes of action and addiction potential:

The reason I am providing all of this information is the fact that the successful regulation and softening of rapid spikes and clearances of chemical peaks is a crucial component to curbing the drug addiction process. It is believed that modafinil may work so well at reducing drug cravings by targeting this very mechanism. Unlike many stimulant medications which can produce some type of "high" (especially if abused by snorting or injection, or taken at abnormally high doses), Modafinil has a low abuse potential, and offers several other advantages over methylphenidate.

Modafinil does have a relatively positive track record for mitigating substance abuse disorders. For example, the administration of Modafinil can attenuate cocaine dependence. In contrast, methylphenidate (Ritalin, Concerta, Metadate, Daytrana), while being very effective as an ADHD treatment, does little to curb comorbid substance abuse disorders in ADHD patients. Unfortunately, the effectiveness of Modafinil on treating comorbid substance abuse disorders in individuals with ADHD may be limited to specific drugs. For example similar positive effects of Modafinil on nicotine dependence appear to be less pronounced.

Modafinil may also offer advantages over traditional stimulants as well. As a cognitive enhancement type of pharmacological agent, modafinil may be useful in improving the work performance of adults with ADHD by improving short-term memory and visual recall, impulse control, and spatial skills (all of which are frequent deficits in children and adults with ADHD). Additionally, similar improvements were seen in individuals with schizophrenia, suggesting the diversity of modafinil's range of performance in cognitive improvement. These improvements are typically not seen in individuals unaffected by psychological disorders, further supporting the evidence that modafinil is less likely to be abused recreationally in the general population.

The potential implications of modafinil for ADHD treatment may be further reaching than the details outlined in the original article (and basis of this post, highlighting the effects of modafinil on amphetamine abuse in adult ADHD). For example, modafinil, as a vigilance-promoting medication, can offset an afternoon dip in arousal state (which has implications on many of the shorter-acting stimulant medications, which begin to wear off around this time). This may be useful for individuals with sleep disorders (which are common in ADHD), as well as regulating circadian rhythms. In a post earlier this month, we investigated the relationship between ADHD and seasonal affective disorders, and hinted at the association between ADHD and disruption in circadian rhythms.

Potential future implications of Modafinil as an ADHD treatment alternative:

Additionally, while Modafinil may offer benefits for the whole ADHD spectrum, this blogger hypothesizes that it may be most useful for treating the inattentive subtype of the disorder. Some reasons for this are as follows:

Activity patterns and circadian rhythms may often be associated with ADHD subtype. For example, "morning people" with ADHD may have a tendency to fall into the more hyperactive/impulsive group, while "eveningness" is more of an inattentive ADHD trait, suggesting more of a disruption in the circadian rhythms of inattentive ADHD'ers.
Additionally, non-stimulants often have somewhat of a better track record with the inattentive subtype of ADHD compared to the more hyperactive/impulsive subtypes. The uses of the non-stimulant atomoxetine (Strattera), highlight this general trend. While atomoxetine treatments often result in drastic improvements in all ADHD subtypes, negative side effects are often less seen in the inattentive subtype.
Compared to stimulants, non-stimulant medications for ADHD often do a better job at not exacerbating comorbid disorders such as obsessive compulsive or anxiety disorders (which are often more common to the ADHD inattentive subtype). Additionally, Modafinil treatment can be useful in treating adults with ADHD and a history of mood disorders.
Modafinil offers advantages over methylphenidate as far as fewer side effects including appetite suppression, sleep disturbances and heart rate dysfunction (orthostatic tachycardia, which essentially is significant changes in heart rhythms based on postural changes, such as standing up quickly from a seated position).
Anecdotal evidence, as noted by the Modafinil and amphetamine abuse study mentioned earlier, also suggests that Modafinil may be a useful treatment method for "refractory" cases, or individuals who have consistently shown poor response to other treatment medications and interventionary measures.
Finally, it is important to note (and this was also touched on in the Modafinil and amphetamine abuse study), that Modafinil treatment may be better suited for the more "controlled" abusers of stimulants. In other words, better effects might be seen for adults who regularly take illegal stimulant drugs such as amphetamines as a conscious effort to "self-medicate" for their ADHD, as opposed to an out-of-control drug addict who craves the drugs on a non-scheduled basis.

Given the high propensity of comorbid disorders when deciding on treatment for ADHD, as well as practicality issues concerning the administration of medicinal agents for treatment of the disorder in adults, I see a fair amount of potential for Modafinil's "off-label" usage as a treatment alternative to stimulants in adults with ADHD.

Does Blood Type Affect ADHD?

2009-05-29T22:01:00.004-04:00

This blog has often discussed the wide range of genetic influences on ADHD and related disorders. Some of the ADHD genes we have previously investigated include:

DAT1 gene (often referred to simply as "DAT", possibly related to Tourette's and eating disorders such as bulimia)
MAOA gene (likely has gender-specific effects, also tied to autism, bipolar and anxiety disorders)
COMT gene (can affect dosage levels of ADHD stimulant medications, and possibly have an impact on brain regions responsible for attentional control)
SLC6A2 gene (also called "NET" or "norepinephrine transporter gene", may affect the response to Strattera, also related to posture and eating disorders such as anorexia)
SLC6A4 gene (often has a greater potential effect on males with ADHD, associated with autism)
Protogenin gene (possibly related to ADHD and reading disabilities)
DRD4 gene (also may be related to schizophrenia, alcoholism, and resistance to Parkinson's)
Fatty acid desaturase genes (may play a role in deficiencies in omega-3 levels in ADHD)
CREM gene (may be related to hormonal regulation, including the sleep-related melatonin)
Serotonin receptor 1B gene (may be more associated with the inattentive subtype of ADHD)

Additionally, some of these genes may work together in combo. For example, a combination of specific variations in the DAT1 gene and the DRD4 gene may associate with IQ and behavioral disorders as they relate to ADHD.

The main point of all of these examples was not to overwhelm anyone, but rather to highlight the intricate relationship between genetics and ADHD heritability.

Adding to this extensive list may be a new set of genes related to blood types and ADHD.

**For a quick synopsis of blood types, please consult the italicized paragraphs below. Otherwise you may skip to the next paragraph highlighting a new study on blood type and ADHD.

Human blood types are often classified by the "ABO" system. "A" and "B" refer to immune-regulating factors and play a major role in blood transfusions. These blood types are acquired from our parents and can come in dominant and recessive forms. Genes for blood type can be found on the 9th human chromosome.

They are the two main (or dominant) forms of immune-regulating blood factors. Additionally, A and B can be "codominant", that is an individual can have a mixture of the two. For these "codominant" individuals, their blood type is labeled "AB". If an individual has neither "A" nor "B", he or she is labeled as an "O".

In essence, if you have a specific letter(s), you can donate blood to individuals who share your same letters (there are actually other important factors and donor restrictions besides this, such as the "Rh factor", but for sake of simplicity, we will just discuss "ABO" for the moment). For example, a person with type "A" blood could donate to another person who has "A" or "AB" because both "A" and "AB" would recognize the "A" component. They could not donate to a "B" or an "O" blood type because these individuals' bodies would not be able to recognize the "A", resulting in a severe immuno-rejection problem.

An "O" could donate to and "A", a "B", an "AB", or another "O" (again, there are detailed exceptions to this generalization), because "O" does not have either of the "A" or "B" markers on it, so the recipient's body would not see anything "foreign" about this. This makes "O" carriers better candidates for blood donation. On the flip side, and individual with type "AB" could take blood from and "A", a "B", an "AB" or an "O" since their blood already recognizes the "markers". This makes AB candidates better recipients for blood.

In addition to an individual's blood type governing the blood transfusion process, blood types may also confer resistance or susceptibility to certain bodily dysfunctions or diseases. For example, type "A" individuals may be naturally more prone to cancers of the digestive system, and individuals with type "O" are more prone to cholera, plagues, or even malaria (interestingly, they may be more prone to be preferred targets of mosquitoes, compared to the other blood types).

Overview of an original study on ADHD and blood types:
Returning to our main discussion, it appears that certain blood types may also be related to an increased likelihood of childhood ADHD or related disorders. A Chinese study recently came out which sought to investigate whether certain blood types were actually more likely to be affiliated with ADHD. The results, while preliminary, should nevertheless pique some interest on the topic among professionals.

Here are some of the major highlights of the study:

Blood types (using the "ABO" format) were taken from 96 children and their parents, to determine the heritability patterns of blood types.
Both ADHD and non-ADHD children were observed in the study, and their blood types were broken down.
The study found that children who did have ADHD were more likely to have inherited either the "A" or "O" type blood from their parents.
Conversely, children who inherited the type "B" blood (which would include either the "B" or "AB" form) were less likely to be diagnosed with ADHD.

** A caveat concerning the findings and reproducibility of this study: It is important to note that the study population was relatively small, especially for a study of this magnitude which seeks to identify general trends between blood types and their relative association with co-existing disorders. Some blood types can be relatively rare, for example, in the United States, only around 10% of the population has type "B" blood and only about 15% has the "B" in any form (types B or AB). Although blood types vary extensively all over the world, certain types tend to predominate, which requires large populations to be studies to ensure all groups are sufficiently represented. Thus, small population studies can easily produce skewed results. Nevertheless, I personally believe this study was a good starting point.

**Blogger's personal notes/opinions on these findings:

I found this study to be interesting. Unfortunately, I could not read the whole article (the majority is in Chinese!), but the possibility of blood typing being related to ADHD would be a major breakthrough, if these results are able to be consistently replicated with larger population studies.

My first thought was that maybe some nearby gene related to ADHD might be influencing the blood type/ADHD connection, but no significant genes associated with ADHD exist on the 9th chromosome (at least to the best of my knowledge after conducting a search of OMIM for the term "ADHD", a national database which ties down diseases and disorders to known genetic regions). However, genes which are located far apart from each other, even on completely different chromosomes can also work in tandem, so genetic relationships between ADHD genes and blood type genes cannot be ruled out entirely.

Another option may be some type of indirect connection between blood type and ADHD. For example, the article notes that individuals who have the "O" or "A" blood type alleles are more prone to ADHD. Other sources note that individuals with type "O" are more prone to developing intestinal and gastric ulcers, and that individuals with type "A" are more prone to cancers of the digestive system (such as cancers of the esophagus, pancreas and stomach). This may signify that these blood types (compared to those who have "B" or "AB" blood) may be more prone to digestive problems.

Digestive disorders can result in poor nutrient absorption (we have discussed nutrient deficiencies in ADHD in number of previous posts), which may leave one more prone to ADHD symptoms. Additionally, digestive dysfunctions can actually lead to an increased likelihood of developing food allergies, as potential allergens are less likely to be broken down or "chewed up" than by a properly-functioning digestive system. Furthermore, we have also explored the possibility that acid accumulation can make its way into the brain regions and have an impact on neurological symptoms including ADHD-like behaviors. This was discussed in a recent post investigating the high prevalence of ADHD in children who suffer from frequent ear infections.

While these possibilities are strictly hypothetical at the moment I firmly believe that we should further explore the possibility of specific blood types as possible underlying causes or risk factors for developing ADHD.

ADHD and Balance Impairment: Visual and Inner Ear Deficiencies

2009-05-27T20:24:00.011-04:00

Balance dysfunctions and visual or vestibular deficiencies: Uncommon comorbids in the ADHD spectrum:

When we think of comorbid disorders to ADHD, we often envision disorders which can be diagnosed psychiatrically. Common examples such as depression, anxiety, Obsessive Compulsive Disorders (OCD), oppositional defiant disorders, and conduct disorders often come to mind. In addition, it is perhaps no surprise that learning disabilities are relatively common in children and adults with ADHD. If we do delve into physical comorbid disorders, things like Tourette's and tics may come to mind. For those skilled in the diagnosis and treatment of ADHD, even non-trivial comorbids such as bedwetting and sleep disorders may be apparent.

However, there is another impairment that often goes along with the ADHD population, especially in children. Sensory processing disorders are often seen in the ADHD population, especially in children. This includes more "physical" dysfunctions including the ability of the child to maintain balance and equilibrium. To the frustrated parent of coach of an ADHD child, this may introduce another complication with regards to sports or other activities which involve coordination and balance, such as basketball, baseball, tennis, soccer, gymnastics, musical instruments, dance, etc.

The aim of this post is to investigate and discuss impairments in balance function in children with the disorder, We will be citing and highlighting some key studies in the overlap between ADHD and balance dysfunctions (especially relating to functions derived from visual and tactile signals) and look for possible underlying causes and treatment methods:

Brain regions involved in Balance Dysfunction in the ADHD Child:

Most experts often cite specific "hot spot" regions of the brain for the ADHD patients. Among these, the prefrontal cortex part of the brain often receives the most attention. Less pronounced, however, are the studies associating the cerebellum, and their implications on ADHD. For a reference to the Prefrontal Cortex and Cerebellum brain regions, please consult the brain diagrams below:

Shown above is a human brain. The Cerebellum region, which plays a major role in governing balancing functions and may be compromised in a significant subsection of ADHD children, is shown in purple in the top picture. The area highlighted in orange in the bottom drawing roughly corresponds to the prefrontal cortex region of the brain, which plays a major role in impulse control. Deficiencies in blood flow and overall activity of this prefrontal cortex region of the brain are often seen in children (and adults) with ADHD, and may be responsible for some of the difficulties in filtering out comments and actions for appropriateness.

The inter-relationship between attention and balance/coordination: The strong association of the prefrontal cortex and cerebellum regions of the brain:

Many studies involving brain regions and ADHD often miss this connection. The relationship between these brain regions may go a long ways in explaining ADHD comorbid disorders as well, especially the more "physical" ones such as speech complications, developmental coordination disorders, etc. While perennial "hot spot" brain regions, such as the prefrontal cortex, are frequently mentioned in studies involving brain activity in ADHD, this particular brain region is actually intricately interconnected with the cerebellum (as well as another key brain region, the basal ganglia. The role of the basal ganglia in kids with ADHD has been discussed previously in other postings, but in general, the basal ganglia tell how fast a person "idles". 'Type A' personalities, such as workaholics, individuals with OCD and overly focused individuals typically have overactive basal ganglia, whereas many with ADHD often exhibit underactive basal ganglia.).

We have already mentioned that the balance-governing regions of the brain (the cerebellum) is interconnected with a key impulse-control region of the brain (the prefrontal cortex or PFC). We also mentioned that impulsivity is a characteristic of the Hyperactive-impulsive and Combined ADHD subtypes (as opposed to the more inattentive forms of the disorder). Interestingly, the prevalence of balance dysfunction cases seems to predominate in the combined subtype of ADHD (main paper as reference source). This correlation lends further credence to the hypothesis that the balance-governing and impulse-governing regions of the brain may be "co-affected" in the case of the balance-deficient, hyper-impulsive ADHD child.

Key points concerning balance related deficiencies and ADHD:

ADHD is often associated with developmental delays. Indeed, studies highlighting a delay in cortical maturation in children with ADHD suggests that children and teens with the disorder may fall "behind the curve". By its own very nature, the vestibular system often does not fully develop until the age of 15, so immature development in this brain region may result in deficiencies in this system throughout almost the entire span of childhood in an individual with ADHD.

Additionally, EEG and imaging studies have also demonstrated relative deficiencies in both size and activity (by measuring blood flow patterns) in various brain regions of ADHD children. These include the cerebellum and the caudate nucleus. Both are interconnected and associate with the "ADHD region" of the prefrontal cortex (PFC). This PFC region plays a major role in the impulse-control process and deficiencies in its function can result in a weak self-regulatory system of impulsive behaviors (which are hallmark characteristics of ADHD, especially in the hyperactive/impulsive and Combined subtypes).

The cerebellum gathers input from visual, vestibular (inner ear), and somatosensory (mainly tactile senses, such as perceived through the skin and internal organs) systems. As we can imagine, a defect in one or more of these information-obtaining sensory systems, and the cerebellum (as well as the interconnected region of the PFC) may be compromised. Thus ADHD and sensory deficits may be intricately related.

Taking this one step further, we may wish to explore the link between ADHD and sensory disorders, including processing disorders and sensory integration disorders. One thing is for sure, however: ADHD is not simply limited to deficits in the PFC!

The vestibular system also plays a crucial role in what is known as "gaze stabilization" (i.e., stabilizing the focus on a particular fixed object when you yourself are moving). The very nature of "gazing" obviously has visual implications as well, so a deficiency in the vestibular component of gaze stabilization may also affect visual input success as well. Interestingly (an perhaps not surprisingly), visual input deficiencies are also seen at high rates in children with ADHD.

This may actually serve as one of the key contributing factors as to why maintaining attention (to, say, a teacher), may be so difficult for ADHD kids, because they literally are having trouble focusing their visual attention (gaze) on their target of interest (i.e. a teacher standing up in class giving a lecture), especially if the child is already fidgeting around in their seat. In other words, there may be some inherent deficiency in this particular component of the attention span, and needs to be addressed further in the near future.

Investigating the sources of balance impairment in children with ADHD:
In order to clarify where I am coming from on this, I will highlight an extremely recent publication in the Journal of Pediatrics by Shum and Pang. This study investigated the different systems of balance in children, including somatosensory (balance governed by tactile features), visual, and vestibular (inner ear and the sense of equilibrium). They tested approximately 50 children (ages 6-12) with ADHD for balance discrepancies by isolating each of the three systems listed above to test sensory organizations of balance. A highlight of the study can be seen below:

Instruments/Methods of the study:

A platform which can induce a feeling of motion on a child who stands upon it (this disrupts the somatosensory component of balance, forcing the child to use their visual or vestibular functions to compensate for the somatosensory impairment).
Surrounding scenery which can visually give the illusion of motion. This forces the child to use their vestibular and somatosensory methods of equilibrium, as the visual sense is disrupted. Another variation of this is to have the child perform with their eyes closed.
A combination of the two methods above will isolate the vestibular component of balance, as both the somatosensory and visual sources of balance are now both compromised.
A total of six different environmental conditions were performed to isolate one or more senses of balance. The researchers noted which of the three modes of balance were most likely to be compromised in the ADHD children. The findings are highlighted below:

While balance-related issues can stem from visual discrepancies, somatosensory issues (i.e. the sensations of touch and pressure from the skin and even internal organs), and vestibular (inner ear) imbalances, it appears that ADHD children are most likely to suffer from visual imbalances. This is closely followed, however, by deficits in vestibular function. Somatosensory difficulties appear to occur in ADHD children as well, but the role of this system is likely to be much smaller than for the other 2.

Possible academic implications of balance dysfunction and ADHD: Does the source of an ADHD child's balance deficiency affect his or her sensory learning style? The following points are simply the result of this blogger thinking out loud. Nevertheless, these might be some good topics of future study, as balance difficulties may be useful in evaluating academic strategies.

These findings on balance may even extend to the classroom and affect the learning environment of an ADHD child. Given the above, abnormalities in these areas may even affect a child's mode of learning and learning style. While these assertions simply remain personal hypotheses of this blogger, a child with visual discrepancies leading to balancing difficulties may also be deficient in visual perception and therefore struggle in a visual-dominated learning environment. He or she may gravitate towards a more auditory or kinesthetic style of learning.

Conversely, it is also possible that vestibular-regulated balance dysfunctions, which stem from the inner ear may actually extend to a child's auditory learning capabilities. Again, this remains a hypothesis, but given the fact that severe childhood ear infections can affect both balance and hearing (as well as ADHD symptoms, see previous post on childhood ear infections and ADHD), a child with vestibular-related balance deficiencies may also have more difficulty in a predominantly auditory-based learning environment. This may spell bad news if an ADHD child's teacher engages in more auditory discussions or as the child moves up to high school and college courses where an auditory lecture is the more common form of teaching and communication.

A double-whammy?: Given the fact that children with ADHD may suffer from both vestibular and visual (and even somatosensory) information processing for balance, it leads us to wonder if the child may also have learning deficits in 2 of the 3 major forms of learning (visual, auditory or kinesthetic). If this is the case, trying to accommodate an ADHD child's education could be extremely difficult, if he or she must heavily rely on only one predominant mode of acquiring and processing information.

For example, if a child were to undergo a study similar to the one listed above, and it turns out that he or she is weak in both the visual and vestibular forms of balance, and (this is a big "if" and is only hypothetical at the moment) the whole balance governing/learning style hypothesis holds true, he or she may have to rely on a predominantly kinesthetic form of learning. While this child may succeed in hands-on learning subjects (i.e. frog dissection or wood shop class), he or she may have an exceedingly difficult time in other subjects such as algebra or history where hands-on-learning opportunities are more difficult to implement.

The role of balance and sensory stimulation may have even greater-reaching academic implications. Another study just came out recently investigating the role of posture stability (i.e. how well a person stabilizes their center of balance) on ADHD and dyslexia. The study found that comorbid ADHD symptoms greatly influenced the effects of posture stability in dyslexic individuals, which may even have implications to affecting the reading environment of the individuals with dyslexia. It's important to keep in mind that this study involved adults instead of children, but the fact that ADHD may play such an integrated role into sensory modulation of other disorders into adulthood may signify the deep level of inter-relationship between cognitive function and sensory motor stimulation.

Vestibular Stimulation as an alternative form of ADHD Treatment?: As an interesting aside, there has been some pronounced effect on treating ADHD symptoms with a non-pharmaceutical alternative method called vestibular stimulation. We will be addressing the validity of these findings and their potential for practical usage in a later discussion.

Childhood Ear Infections and ADHD: Why the link?

2009-05-22T22:24:00.003-04:00

When we scan the literature for statistics on ADHD and search for early warning signs or tip-offs that a young child may be prone to the disorder, a few common trends seem to pop up again and again. One of these is the high rates of ADHD and attentional difficulties in kids suffering infection of the middle ear (Otitis Media) in early childhood.

During early childhood, the actual positioning of the ear canal is still adjusting, the pathway into the middle part of the ear is actually at a flatter angle than in a mature adult. This difference in positioning actually makes younger children much more prone to ear infections than older children or adults. Unfortunately, these infections may increase the risk of further complications down the road, including an increased onset of attentional difficulties, including ADHD. Here is what some of the literature has to say about the ADHD/ear infection connections:

Relationship between middle ear infections and inattention: The basis for inattentive ADHD?

The main culprit for attentional deficits is often believed to be the result of hearing loss (even mild), early in a child's life due to complications with the middle ear, including infections, allergy-related causes or build-up of fluids in the canal. As a result, the child begins to miss out on verbal cues, and does not develop the same level of response to an adult voice. Auditory deficiencies (including auditory processing disorders) may stem from this key development period, even if the hearing difficulties are only temporary.

Not surprisingly, there is a wealth of data associated with hearing loss due to middle ear complications can lead to language processing difficulties. We have seen how auditory processing disorders can often occur as a comorbid factor in ADHD, and may be linked to seemingly unrelated behaviors including comorbid anxiety and conduct-related disorders.

It is important to note, however, that other early childhood studies have not seen a link between infection and attentional difficulties (observed by parents, teachers, or clinicians).

Interestingly, environment may play a huge role in explaining this discrepancy between study results. One study found that children who had middle ear complications early on along with poor home environments were significantly more likely to develop attentional difficulties (along the lines of what would be classified as ADHD). Therefore, the effects of early ear infections on compromised attentional difficulties may be significantly reduced if a supportive home environment is maintained for a child. This is good news for parents of children with ear infections. But what about the hyperactive component of ADHD?

The link between hyperactive behaviors and middle ear complications: The basis for hyperactive/impulsive or combined subtype ADHD?

While it seems more intuitive that ear infections could lead to auditory problems and subsequent attentional difficulties (especially to auditory cues), the relationship between ear infections and hyperactivity is less inherently obvious. This association would be more relevant to the hyperactive/impulsive and combined subtypes of ADHD.

For over 30 years, researchers have linked high rates of ear infections and hyperactivity (this study used the term "minimal brain dysfunction", a phrase which this blogger has personal objections, nevertheless, it is a relatively common term in the literature). Later studies confirmed these findings, including one which reported the majority of children medicated for hyperactivity had a past history of 10 or more childhood ear infections. These numbers were in sharp contrast to the prevalence of ADHD in non-hyperactive children.

One thought may be that ADHD which includes a significant hyperactive component (as opposed to the more inattention-dominated form of the disorder) is more likely to be associated with comorbid disorders that correspond to ear infections. We have seen previously that comorbid disorders to ADHD are often related to particular subtypes.

For example, anxiety and depressive-like symptoms are often more likely to co-exist with primarily inattentive ADHD, while conduct disorders are more likely to co-exist if there is a high hyperactive/impulsive behavior (especially in the combined subtype). In general, the prevalence of more severe learning disabilities is often more associated with the inattention-dominant form of ADHD, while motor tics are more likely to be a hyperactive/impulsive trait. Carrying these associations in mind, are the studies linking early ear infections to hyperactivity simply due to associations with hyperactive subtype-dominated comorbid disorders?

One particular study found that children with hyperactivity vs. children with learning disabilities (and not hyperactivity, remember, learning disabilities are often seen at higher rates in the inattentive forms of the disorder) had similar numbers of total childhood ear infections. However, the timing of the infections did seem to matter. Children with hyperactivity experienced more recent ear infections (within the previous year) compared to the learning disability kids.

In other words, the question surrounding hyperactivity and ear infections may be more of a "when" question than a "how many" question. This may also suggest the possibility that hyperactivity due to middle ear troubles may be more of a temporary condition (this is supported by trends as an individual with ADHD ages, typically, the hyperactive symptoms of the disorder begin to subside as a child gets older and reaches adulthood, while the inattentive symptoms are more likely to plateau) as opposed to inattentive problems stemming from ear infections. Severity of the infections may also be a triggering cause or associated warning sign of an increased risk of developing hyperactive behaviors. The same study found that earaches and upper respiratory tract infections were higher in the hyperactive group than in the less-hyper learning disability group.

So what's going on with the connection between ear infections and ADHD-like hyperactivity?:
Although none of the above studies mentioned this possibility, as a blogger I have a few ideas on the subject. One of the most probable reasons for the ear infection/hyperactivity correlation may be due to the treatment process of ear infections. Let me explain:

Ear infections are typically treated with antibiotics. While these drugs work wonders for most infections, they also can disrupt the healthy bacterial counts in the digestive tract (that is, they kill off many of the "good" bacteria in our digestive systems in addition to the "bad" bacteria which may be causing our infections).

If the "good" digestive bacterial counts fall too low, the digestive process is compromised. The absorption and digestion process may suffer, as key nutrients may now be compromised (even if no major dietary changes occur). We have spoken extensively about nutrient deficiencies and ADHD as well as ADHD-related nutrition strategies in earlier posts.

Additionally, if good bacterial counts fall low, incomplete digestion results, which can lead to byproducts such as higher concentrations of organic acids, as well as incomplete breakdowns of potential allergens (which can increase sensitivity to food allergens, among others). These allergens and acids can actually begin to penetrate the blood brain barrier and show up in higher concentrations in the brain. Neurological disorders, including abnormal hyperactivity may actually be triggered by digestive imbalances (to a degree beyond what most of us realize). We are just beginning to recognize the huge degree of inter-relationship between the nervous and digestive systems, including brain-gut interactions.

There has been a longstanding "hot" discussion surrounding food allergies and ADHD (as well as possible connections between food allergies and disorders like fibromyalgia and chronic fatigue syndrome), and the disrupted bacterial balance in the digestive system due to frequent antibiotic usage for recurrent ear infections may be a governing factor. This seems to make sense, especially considering the fact that hyperactivity was more linked to recent ear infections (and resultant antibiotic treatment), while the more inattentive behaviors and learning disorders seem to be a more long-standing symptom. Since bacterial counts begin to re-stabilize following antibiotic treatment (if a proper diet is maintained), the food-related hyperactivity may begin to subside, but for recent infections and treatments, the digestive bacteria may still be imbalanced, triggering an onset of ADHD-like hyperactive behaviors.

Of course this is just the blogger's personal hypothesis, but it at least seems plausible that the actual treatment for ear infections may play an equally strong role on the high rate of occurrence between ADHD and ear infections.

Ginkgo biloba for ADHD: A natural herbal treatment alternative?

2009-05-17T21:00:00.004-04:00

A few weeks ago, I discussed the merits of ginseng for treating ADHD. What I did not mention is the fact that this special herb often works even better in tandem with another important "brain herb", Ginkgo biloba. It's benefits also extend beyond the nervous system, and the Ginkgo has been used to treat everything from increasing blood flow to Alzheimer's to glaucoma to hormone replacement to protection against neuronal degradation. While somewhat wary (personally) of using generalized "brain booster" nutrients for ADHD (it is a highly variable disorder of complex etiology and treatment methods), I am interested whenever new research publications arise on the topic. Just this week, a new paper came out on the merits of Ginkgo biloba as an ADHD treatment option.

Here are some of the major points of the publication:

Irritability is an often overlooked side effect of ADHD. Medications, especially over-prescription with stimulants such as methylphenidate and amphetamines can increase this unwanted side effect. However, Ginkgo exhibited a positive mollifying effect on irritability for the individuals in the study.
While one of the knocks against Ginkgo biloba is that it can sometimes result in sedative effects, the study found these to be extremely mild. However, to go along with the irritability-reducing benefits above, Ginkgo was able to improve the individuals' tolerance for frustration (to the degree that this behavior could be measured).
We have seen previously that oppositional defiant behaviors are often comorbid to ADHD (which can often manifest themselves alongside seemingly unrelated disorders such as auditory processing disorders or even bedwetting). One of the strongest suits of Ginkgo biloba may actually be in curbing these oppositional behaviors. This suggests that Ginkgo may be effective for the more Hyperactive/Impulsive or Combined Subtypes of ADHD, where comorbid oppositional behaviors are more often seen (as opposed to the predominantly inattentive subtype of the Disorder).
Nevertheless, Ginkgo biloba appeared to boost symptoms of attention and working memory as well. This may suggest Ginkgo's versatility, and that it could be used universally across the ADHD "spectrum", including for the 3 classic or traditional subtypes of the disorder.
The study highlights the relative success for co-treatment with methylphenidate and clonidine for individuals with ADHD and comorbid anxiety disorders. The authors suggest a functional comparison between Ginkgo and clonidine, and hint at its use as an alternative to clonidine/methylphenidate treatment (of course, it is also possible that Ginkgo may be used alongside lower doses of stimulant medications, which could be very useful in reducing unwanted side effects, which are often mild for low doses of stimulants, but typically begin to appear with greater frequency when stimulant dosing is increased). Thus, Ginkgo could possibly act as a side-effect-saving alternative to higher doses of medication.
As a precautionary measure, due, in part to some of its anti-clotting properties, there is some concern about Ginkgo triggering internal cerebral bleeding. Indeed, other studies have also addressed this possible concern, highlighting issues such as haemmorrhage risks, as well as herb-drug interactions with Ginkgo and anti-coagulant medications.
Keep in mind the extremely small nature of the study (only 6 individuals) should be met with healthy skepticism. However, the results were still notable. Statistically significant reductions in some of the trademark ADHD symptoms (fidgeting, restlessness, inattention, etc.) upon Ginkgo biloba treatment definitely highlight its potential as a more "natural" alternative treatment method for ADHD.

Why the Menstrual Cycle may affect ADHD Medication Dosing Levels

2009-05-16T20:07:00.006-04:00

Do hormonal fluctuations result in variable ADHD medication dosage levels across the menstrual cycle?

We have investigated the impact of gender on ADHD in a number of earlier posts. We have covered topics such as:

Gender Based Metabolic Differences in ADHD brains

Gender Dependent ADHD Genes, including MAOA, SLC6A2, SLC6A4 and COMT

ADHD subtypes and Comorbid Disorders

Clearly, there are a number of boy/girl differences in the root causes, diagnoses and treatment methods for the disorder.

However, we need to investigate whether intra-individual differences are also an important factor, especially where medication treatment and medication dosing levels are concerned. Based on a number of studies, it appears that women may actually require different medication dosing levels depending on where they are in their menstrual cycle. Additionally, post-menopausal drugs such as estradiol patches may also alter the drug effects of certain ADHD medications such as amphetamines. The main culprits are most likely fluctuating levels of estrogen and progesterone.

Here are brief summaries on some of the relevant studies and their findings. Wherever possible, I will include a link to the original studies:

The link between Estradiol treatment and amphetamine medications: This study focused on whether pretreatment with estradiol played any role in the reaction to amphetamines. The drug used in this study was D-Amphetamine, which would correspond to the medication Dexedrine, however, this is also the predominantly active compound in medications such as Adderall or Vyvanse (once this "pro-drug" is metabolized). It is unclear at the moment whether chemical "cousins" to amphetamines, such as methylphenidate (Ritalin, Concerta, Daytrana, Metadate), also exhibit these fluctuations when combined with estradiol-releasing drugs.

The study found that for females who took estradiol-supplementing treatments during the early follicular phase (pre-ovulation) of the menstrual cycle experienced an overall greater "stimulating" effect of the amphetamine medication (taken as 10 mg of amphetamine). This may suggest that a slightly lower dosage during this stage of the menstrual cycle might be warranted, and (as this blogger's personal hypothesis) may actually affect the addiction potential of ADHD stimulant drugs such as amphetamines.
Another study by the same group found that estrogen may be responsible for some of the heightened euphoric effect felt from amphetamine-based drugs. However, the hormone progesterone may actually counteract some of this euphoria. During the luteal phase of the menstrual cycle (after ovulation), high levels of both estrogen and progesterone are seen (although levels of both of these taper off going into menstruation), so the effects of estrogen may be curbed. During the late follicular phase, where progesterone levels are low and estrogen levels begin to spike, the "high" may be at its peak, especially if stimulants are involved.
A case study found that an increase in inattentive symptoms coincided cyclically with the menstrual cycle for a patient who was undergoing treatment for newly-diagnosed ADHD with a twice-daily dosing regimen of the stimulant medication Concerta.
The findings from these two studies suggest the possibility that a slightly smaller dosing schedule with amphetamine-based ADHD medications (such as Adderall, Vyvanse or Dexedrine) may be warranted during the follicular phase. However, during the luteal phase, when progesterone levels are higher, the amphetamine-based effects are less pronounced. This may correlate to a slightly higher dosing regimen for amphetamine-based treatment for ADHD and related disorders.
While there is a relatively good theoretical basis for this assertion above, practical consideration measures must also be considered. Based on the relative scarcity of studies (besides the 2 mentioned above) on the amphetamine-menstrual cycle interactions, it is unclear as to how pronounced the medication change should be.

For instance, should someone taking 10 mg of Adderall during the follicular phase boost up to 15 mg for the luteal phase? 20 mg? 30 mg? Additionally, hormonal fluctuations vary during the phases themselves, such as the estrogen spike during the late follicular phase. Questions abound, especially when dealing with the brief ovulatory phase as well.

This blog post hopefully introduces what may be a new consideration to women who have ADHD and are currently taking stimulant-based medication treatments. Perhaps this posting simply confirms what you have already experienced.

Nevertheless, given the fact that administering variable levels of medication based on cyclical patterns such as time of day (like ramping up methylphenidate concentrations via controlled release formulations to offset "acute tolerance" based effects), and the fact that individuals with ADHD may experience seasonal variations in symptoms, at least suggests, that variable dosing of medications across the near-monthly period of the menstrual cycle may prove to be beneficial treatment strategy for females with ADHD.

Long Wave Infrared Imaging: A new detection method for ADHD?

2009-05-14T12:42:00.006-04:00

Detecting ADHD using the long-wave infrared spectrum:

I always enjoy covering new breakthroughs in the diagnosis and treatment methods in the medical field. A new study just came out which may have a number of potential applications to aid in the diagnostic process of ADHD, which I believe is worth sharing. Called Long-Wave Infrared Imaging, this method utilizes the infrared spectrum to detect biological activity (namely bloodflow patterns) via the differences in radiation emitted by these activities. The study, titled Sensitivity and Specificity of Longwave Infrared Imaging for Attention-Deficit/Hyperactivity Disorder, found that this method may be a surprisingly powerful way of separating ADHD from other related disorders, aiding in the always-difficult process of differential diagnosis.

The basics of Long-Wave Infrared Imaging:

The term "long-wave" is a relative term, of course, referring to wavelengths of approximately 10 nanometers (or only one one-hundred millionth of a meter). Differential bloodflow patterns can result in temperature differences by a full degree (Celsius), making this technology useful in tracking bloodflow disorders. A recent publication in the Journal of Medical Physics by Bagathaviappan and coworkers suggests describes how this long-wave infrared imaging can detect areas in the circulatory system where bloodflow activity is sluggish or reduced. Typically, these areas appear "cooler" on the spectrum, due to the lack of a new, replenishing blood supply.

Applications for ADHD:

A number of studies have confirmed the hypothesis that individuals with ADHD have reduced bloodflow levels marking a recuction of activity to multiple key brain regions. Additionally, while several disorders have a number of overlapping symptoms (which can make the diagnostic process more complicated, especially if multiple comorbid disorders are present), differential blood flow patterns to the brain may be able to help make these distinctions. For example, blood flow patters to the brains of ADHD and OCD (Obsessive Compulsive Disorders) can show pronounced differences, which can aid the diagnostic process between these two disorders (while ADHD and OCD are often considered to be on "opposite" ends of the spectrum with regards to neuro-chemical signaling levels, these two disorders can often exhibit similar symptoms, such as a severe impairment in the response to verbal directions. This is especially true in younger children).

This technology may even be extended to measuring or predicting which medications may work for an individual diagnosed with ADHD, based on blood flow in specific localized brain regions. Cerebral blood flow patterns may help predict the response to common ADHD drugs such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana). For example, a study by Cho and coworkers found increased blood flow in at least three different brain regions for individuals who showed poor response to methylphenidate treatment compared to their peers who did show improvements under the drug.

While the medication response study was done utilizing a different type of brain imaging device known as SPECT, which utilizes gamma rays and radioactive tracers to detect brain activity in 3-dimensional patterns. While SPECT has proven to be an extremely powerful and effectively safe method of detection (the radioactive isotope used in this method is relatively non-invasive and breaks down quickly, and the gamma rays are carefully controlled), concerned parents may still have an inherent fear of the terms "radioactivity" and "gamma rays" tend to shy away from this powerful detection method on their kids.

While this blogger personally has a very high opinion about the use of SPECT as a diagnostic tool for ADHD and related disorders, it is at least worth mentioning the possibility that long-wave infrared imaging methods may be a viable alternative method in at least some of these imaging cases (SPECT technology has been around for over 30 years, but the recent advances in computational power resurrected this technology in the very recent past, similar possibilities may abound by this infrared technology, which has been around even longer).

Keep in mind that the studies utilizing this range of infrared imaging technologies for detecting and differentiation disorders such as ADHD are still relatively scarce. Nevertheless, long-wave infrared imaging appears (at least in this blogger's personal opinion) to be a powerful diagnostic tool for ADHD and related disorders in the near future.

ADHD and Seasonal Affective Disorder

2009-05-09T23:38:00.006-04:00

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.

Methylphenidate, Anxiety and ADHD: How do they fit together?

2009-05-08T22:48:00.005-04:00

Effects of Comorbid Anxiety on Methylphenidate Treatment in the ADHD Child:

Medication with stimulants such as methylphenidate has consistently proven to be a popular and relatively effective mode of treatment for the ADHD child. However, questions arise regarding its side effects. In particular, the effectiveness of methylphenidate (Ritalin, Concerta, Daytrana, Metadate) can be jeopardized if the child with ADHD also has some type of comorbid disorder (such as depression, obsessive compulsive behaviors, Tourette's and a host of other common associate disorders) which may be negatively impacted by the ADHD treatment. Anxiety-related disorders are seen in up to 35% of ADHD individuals, according to some studies.

Typically, treatment is met with some type of adjunctive medication to treat the comorbid disorder (which can be quite tricky, as it introduces the problem of potential drug-drug interactions, as well as a possible impairment in the effectiveness of the ADHD treatment medication), a non-stimulant method of treatment such as Strattera (atomoxetine), or non-drug alternatives (behavior therapy, EEG, nutrition and dietary strategies, etc.). While isolated behavioral therapy has limitations for treating ADHD (especially in cases of "refractory" ADHD), it has proven to be a beneficial mode of treatment for childhood anxiety disorders.

In the case of anxiety disorders alongside ADHD, treatment with stimulant medications such as methylphenidate can also be tricky. However, recent findings seem to indicate that methylphenidate is a safe mode of treatment for ADHD with comorbid anxiety. However, a new publication notes that there may be a significant distinction between the effects of anxiety on methylphenidate's effectiveness from a behavioral standpoint vs. a cognitive standpoint. Let me explain further.

When attempting to determine whether a child should be diagnosed and treated as having ADHD, the supervising physician often gives out rating forms to both parents and teachers of the child in question. Numerical rating scales with regards to classic ADHD symptoms (i.e. impulsivity, hyperactivity, inattentiveness, etc.) comprise the majority of the rating forms, and these results are tabulated and typically used in the diagnostic process. Additionally, these rating forms are often administered after a specific period of time following treatment (with medication, nutritional therapies, counseling or ADHD coaching programs, etc.) to assess the effectiveness of these treatments.

While the level of agreement between parent and teacher rating forms is generally high, significant differences may often be seen. In other words, how a child's perceived behavior in the home may be notably different than his or her behavior in the classroom. While there are an array of possible factors and explanations for this, the presence of comorbid anxiety may be an important but often overlooked reason for this discrepancy.

In the study titled: Predicting Response of ADHD Symptoms to Methylphenidate Treatment Based on Comorbid Anxiety, the researchers found that the behavioral improvements in children with ADHD were similar regardless of whether the child also had an accompanying anxiety disorder. In other words, a notable decrease in symptoms of hyperactivity, impulsiveness and behavioral annoyances was frequently seen. Since these symptoms are often more of the obvious tell-tale signs of the disorder, it would be easy to conclude (especially from a parent's standpoint) that all is well again.

However, on the opposite side of the coin, the side dealing with the cognitive deficits of ADHD (which, not surprisingly have immense academic implications), may tell a different story. The study found that for the ADHD children without an accompanying anxiety disorder, methylphenidate treatment often contributed to vast improvements in their cognitive function (and subsequent academic achievement potential). However, if the ADHD child did have an accompanying anxiety disorder, the methylphenidate treatment was significantly less effective (and possibly even counter-effective). This may serve as a possible explanation for at least some of the variability between parent and teacher evaluations of the same ADHD child.

This leads to the question: does comorbid anxiety affect the cognitive ability-enhancing effects in all academic areas or just in some of the sub-fields of academic-related cognitive functioning?

The study investigated this by administering a Weschler Intelligence Test (WISC III) to the children and examined the effects of comorbid anxiety and methylphenidate medication on three subcomponents of the test: Coding, Arithmetic and Symbol Search. An explanation of the results in these three subcategories with regards to what they measure, possible implications of these subcategories, and the effects of anxiety and methylphenidate treatment are summarized below:

Arithmetic: This is a timed test in which arithmetic questions are orally presented to the children and the responses are measured, assessing both speed and accuracy. Methylphenidate treatment produced a slight improvement in the ADHD children without comorbid anxiety. However, for the children with comorbid anxiety, the use of methylphenidate was ineffective (in fact, a slight decrease in performance was seen, but this was exceedingly small. It should be concluded that methylphenidate treatment had no reasonable positive effect for the ADHD children with comorbid anxiety for this particular subcategory).

This should lead to an array of questions, including ones such as "does anxiety hamper one's performance in math, if one is ADHD (or even if one is not ADHD)?". Intuitively, we would expect the answer to be "yes", as evidenced by the huge number of children (and adults) who have self-reported "mathphobia". However, some well-reputed studies seem to indicate that methylphenidate treatment can actually help with mathematical abilities. Is there something else going on here?

One potential explanation (not mentioned in the study) may reside in the possible presence of a third comorbid factor, such as an underlying comorbid auditory processing disorder. Auditory processing disorders are relatively common in individuals with ADHD, however, since the two disorders often exhibit symptomal overlap, comorbid auditory processing disorders are often missed in ADHD children.

Interestingly, some recent evidence has come out that there may be a connection between auditory processing issues and anxiety disorders. This possible link between anxiety and auditory processing disorders has been addressed previously in another section of this blog. Note that the arithmetic subsection is administered orally in the WISC III test.

If the theory that auditory processing difficulties are seen alongside anxiety disorders, it is entirely possible that the discrepancies in the ADHD with comorbid anxiety performances me be largely due to the nature of how the arithmetic portion of the test is administered. It would be interesting to see if any improvements were seen in the arithmetic scores were improved in the anxiety subgroup if the questions were presented in a written, non-auditory format.

Coding: This section of the WISC III test measures skills involving visual-spatial coordination, speed and concentration. The individual (for those over 8 years old) is instructed to copy a line of code substituting a number for a symbol (this would involve something along the lines of writing, say, a "1" where a star is presented, "2" for a "circle", "3" for a smiley face, etc.). A high performance in this section has implications for advanced academic tasks that involve utilizing tables and formulas (think of solving chemistry problems using data from a periodic table at the top of the page, etc.).

In addition, a strong visual-spatial aptitude may have implications for things such as note taking skills and the like. As a result, a strength in this area may be particularly useful in upper-level courses involving the sciences, foreign languages and anything that requires an individual to "decode" and translate new information quickly. With regards to the anxiety vs. non-anxiety ADHD groups, both showed some degree of improvement with methylphenidate treatment for this subsection.

However, the non-anxiety group showed a significantly greater positive response (around twice as big of an increase in scores for this subsection following methylphenidate treatment as the comorbid anxiety group) to the methylphenidate treatment, suggesting that comorbid anxiety was a relative impediment to methylphenidate-mediated improvements in this area as well.

Symbol search: This subsection involves picking out or identifying whether a particular symbol is present in a row of symbols. It has direct implications on one's ability to pay attention to detail as well as the ability to quickly scan through information to find what is relevant. Both the anxiety and non-anxiety groups showed slight improvements following methylphenidate treatment, however, once again, the improvements in post-methylphenidate scores were about twice as large for the non-anxiety group of ADHD children.

Of the 3 subtests, methylphenidate treatment helped the most in the coding section, had minimal effects in the symbol search section and little (for the non-anxiety group) to no or negative (for the anxiety group) effects for the arithmetic section.

Other studies have also investigated the effects of comorbid anxiety on cognitive task performance in ADHD children. By and large, it appears that memory-based tasks are the hardest hit by an accompanying anxiety disorder when methylphenidate is administered as an ADHD treatment. Other studies have confirmed this finding on anxiety disorders impeding memory enhancement via methylphenidate treatment. This seems to agree with the data on the coding section, which involves a type of working memory for the symbol deciphering process.

Based on what we have covered here, it would be reasonable to scrutinize significant differences between parent and teacher ratings and behavioral and attentive improvements for the possibility of an accompanying anxiety disorder to go along with an ADHD diagnosis in a child. While anti-anxiety medications can be useful, and co-administered with ADHD stimulant drugs under the watchful eye of a carefully trained physician, there is also evidence that

These findings suggest that comorbid anxiety can be a serious handicap to achieving cognitive and academic-related improvements in response to stimulants such as methylphenidate. However, please note that, based on the main study of our discussion on ADHD, anxiety and methylphenidate, notable behavioral improvements were seen from methylphenidate treatment in both the ADHD + anxiety and the ADHD minus anxiety groups.

The implications of this discrepancy can be noteworthy. To the parent who is only marginally involved with their child's academic progress, and is simply concerned with getting more manageable behavior out of their ADHD child, the sharp reduction of negative behavioral symptoms may lull the parent into a false sense of security that all is well on the home front. This stratified response to the methylphenidate medication may be lost to the unassuming parent.

However, it may be possible that an accompanying anxiety disorder (and maybe even an auditory processing disorder) may be lying there dormant to the oblivious parent. For the teacher, however, an improvement in classroom behavior due to medication, but a lack of improvement in academic work (especially in memory-related tasks) may be a tip-off that an undiagnosed accompanying anxiety disorder may be in place in this ADHD child. Thus this discrepancy in medication-derived improvements may actually serve as a potentially powerful diagnostic tool for detecting an accompanying anxiety disorder in a child being treated for ADHD.

ADHD, IQ and Gene Combinations

2009-05-05T23:47:00.004-04:00

How combinations of 2 "ADHD genes" increase the risk of verbal IQ deficiency and behavioral disorders:

We have spoken at length on the matter of genes and their effects on the disorder of ADHD. The vast majority of the numerous ADHD gene studies we have previously discussed have looked at these genes in an isolated manner. However, it begs the question as to what the implications are of having more than one "ADHD gene". For example, does having 2 genes of the "ADHD form" double the risk of having the disorder? Quadruple it? What about having 3 or more of the "at risk" genes? Do certain specific ADHD genes have a dominating influence in the likelihood of inheriting the disorder?

A recent publication came out in the past few days examining the inter-relationship between ADHD, genetics, IQ and behavioral symptoms. It is worth noting that the two genes implicated in the study and their association with ADHD are ones we have previously discussed, the Dopamine Receptor 4 gene, (DRD4) and the Dopamine Transporter 1 gene (DAT1).

ADHD gene #1: DRD4: This gene, called the DRD4 (short for dopamine Receptor gene 4) is located on human chromosome #11. In addition to its association with Attention Deficit Hyperactivity Disorder, this gene is also believed to be associated with schizophrenia, alcoholism and drug abuse, Parkinson's (namely a resistance to this disorder, associated with a specific form of the gene), mood disorders, and novelty-seeking behaviors (which have obvious implications to the impulsive nature of ADHD). Additionally, the proteins coded for by this specific genetic region appear to be major targets for the antipsychotic drug clozapine.

ADHD gene #2: DAT1: This gene, called DAT1 (short for Dopamine Transporter gene 1) is located on human chromosome #5 (in the p15.3 region of the chromosome to be specific, if you are not familiar with this terminology, this is simply a more specific location on the 5th human chromosome). This gene also goes by the name SLC6A3 or simply DAT (without the "1"). Like the DRD4 gene mentioned above, the DAT1 gene has also been implicated in ADHD as well as a number of other disorders. These include (but are not limited to): Tourette Syndrome, cigarette smoking (interestingly, this includes a form of the gene which apparently offers "genetic protection" against the risk of nicotine dependence), bipolar disorders, substance abuse and Tourette Syndrome.

**Blogger's note: The fact that so many psychological and behavioral disorders are also believed to be connected to genes associated with ADHD is simply not a matter of coincidence, especially in this blogger's personal opinion. The majority of the disorders listed above are frequently seen alongside ADHD as comorbid disorders. While no one can deny that environmental factors do play a critical role in the development of these disorders, it is worth repeating the fact that certain individuals, because of the forms of these two (as well as several other "ADHD genes") inherently have at least some degree of genetic predisposition to these inter-related disorders.

Childhood externalizing behaviors:

Childhood externalizing behaviors cover a wide spectrum of behavioral disorders. These include behaviors such as excessive aggression, antisocial behaviors towards peers or authorities, defiant behaviors (in excess of the typical range of expected age-dependent behavior range), excessive hyperactivity, conduct disorders, etc. These should not be confused with the more "internalizing" behaviors, such as anxiety and related disorders. With regards to ADHD subtypes, the externalizing behaviors such as conduct disorders are often more likely to be seen with the hyperactive-impulsive and combined ADHD subtypes, while the internalizing childhood behaviors such as anxiety are more frequently affiliated with the inattentive subtype of ADHD.

IQ: Although IQ is often thought of as one specific number which hovers around 100 for the majority of the population (i.e. 110, 97, etc.), it is actually comprised of multiple subcategories. Generally, the scores in each of these subcategories also generally centralize around 100 and most individuals scores show slight to moderate differences between the subcategory scores. However, in the case of most learning disabilities, this is not the case. Typically, children and adults with learning disabilities have average or above average scores in many of the IQ subtypes, but often have glaring deficits in one or more areas, in which the IQ for that particular area is significantly lower than the rest. In the case of this study relating IQ, externalizing behaviors and the DAT1 and DRD4 genes, the particular IQ subtype most in question is the verbal IQ.

The study found some interesting points with regards to IQ, externalizing behaviors, and the 2 "ADHD genes" (keep in mind that when we are talking about these genes, we are only talking about specific forms, or alleles, of these genes, which are seen only in a fraction of the population. For reference sake, the "at risk" forms of the two genes are referred to as the 7-repeat allele for the DRD4 gene and the 10-repeat allele for the DAT1 gene. Don't get caught up too much in the specifics, these "repeat" describe specific DNA patterns that are seen in these "at risk" forms of the DRD4 and DAT1 genes). The results can be summarized in the following points below:

For ADHD children who had only the "at risk" DRD4 (but not the DAT1) gene form, there was no significant increase in the likelihood of having a low IQ or behavioral disorders.

Likewise, for the children who only had the "at risk" DAT1 (but not the DRD4) gene form, there was no significant reduction in IQ or increased risk of behavioral disorders.

Additionally, the actual correlation between low IQ and increased risk of deviant behaviors (which is often seen in multiple other studies, especially with regards to the IQ and criminal behavior link), was not observed if the child only had one of the two "at risk gene forms" either for the DRD4 or DAT1 genes.

However, for ADHD children who had both the "at risk" forms of DRD4 and DAT1 (please note that this study investigated children who had inherited these gene forms from both parents, i.e. they had 2 copies of each "at risk" gene) showed a significant level of association between low verbal IQ scores and increased likelihood of having increased expression of externalizing behaviors.

It is also worth mentioning that the IQ/behavior connection was only seen in the verbal IQ subcategory and "externalizing" behavioral subcategory. In other words, other forms of IQ (such as more "performance" ones such as motor coordination and kinesthetic types of intelligence) and "internal" behavioral disorders (such as anxiety-related disorders), were apparently not factors affiliated with either of these gene forms.

These findings potentially highlight the complexities of disorders such as ADHD, behavioral disorders and personal characteristics such as genetics, and may also explain some of the incongruities between studies. For example, if one particular genetic study finds a specific form of a certain gene to be associated with ADHD, another one will typically find there to be no genetic linkage (even if the studies are conducted in the same manner with similar study numbers, subjects, and experimental methods).

This may be due to the fact that most of these psychological, behavioral, and functional connections are associated with multiple genes and do not pop out unless more than one "at risk" gene forms are in place. In other words, multi-gene analysis studies (although much more difficult to conduct and analyze) may be our best bet for finding the real genetic basis for ADHD occurrence and related behaviors. This may stress the fact that gene-gene interactions may be as powerful as gene-environment interactions for assessing the risk of an individual acquiring attentional and behavioral disorders such as ADHD.

Treating ADHD with....Mirrors?

2009-05-05T19:18:00.009-04:00

Using mirrors may help ADHD kids retain focus in school-related tasks:

One of the major goals of this blog is to examine as many different treatment methods as possible for ADHD, with the hopes of informing individuals with the disorder and parents and teachers of ADHD children to allow them to make the best possible decision for them and their child. This search has brought me to some interesting treatment methods, including the one described below. We will be examining the theory and potential effectiveness for the use of mirrors in treating ADHD. The majority of this information comes from a 1998 study done by Zentall, Hall and Lee, entitled Attentional Focus of Students with Hyperactivity During a Word-Search Task.

Please note: Psychology and behavioral modification strategies are not my personal forte, this blogger's strengths typically lie in the chemical, genetic and physiological aspects of ADHD and treatment of the disorder. Nevertheless, I was so intrigued by this paper, I have decided to give my best stab at reviewing the study and explaining the effects and overall practicality of its findings.

Some major highlights of the study are as follows:

Earlier studies suggest attempts to regulate ADHD behaviors using self-control methods often fail. This is likely due to a number of factors, such as the relative differences in ADHD children to be motivated by delayed rewards or gratification (although I personally have seen several cases to the contrary. At my school, we offer a special ski trip which must be earned by behavior, and a number of kids, including those with ADHD are able to modify their behavior to remarkable degrees to earn a trip five weeks away. Nevertheless, rewards of less magnitude, especially ones further down the road have often been largely ineffective, at least based on my personal experiences). However, physiological studies do suggest some sort of absence or difference in the intrinsic reward system and motivation in ADHD children.
Instead, ADHD children typically respond better to external stimuli, either good or bad. In other words, a child with ADHD will often show an improvement in response if he or she can see his or her behaviors or actions partly regulated from an outside source.
The use of mirrors is geared towards this externally-driven stimulus method, by allowing the ADHD child to observe or see themselves from a third-person perspective. They are essentially taking cues from an external source in lieu of self-regulating their behaviors. In other words, they may perceive reinforcements better from the "child in the mirror" than internal reinforcements from themselves.
The study even hints that children with ADHD may have a type of delay in the development of self-awareness. While this blogger's opinion is currently neutral on the validity of this assertion, the fact that neuro-developmental and cognitive delays are so prevalent in children diagnosed with ADHD, it is entirely possible that the rewiring and brain maturation processes responsible for developing a mature sense of "self" may also be behind the curve age-wise in ADHD children. If this is the case, then we would expect the mirror trick to lose effectiveness as the child ages and finally develops this sense of "self".
Boosting states of arousal, including through the use of emotional states has been shown to increase a child's attentional focus. Several theories for hyperactivity, such as those by Zentall, support this assertion, claiming that excessive activity (beyond the perceived age and gender-appropriate amounts) may be a way for the child to achieve these heightened levels of arousal necessary for the performance of cognitive tasks, including school work.

If this is the case, attempting to merely calm this hyperactivity via behavioral or pharmaceutical treatment may, in essence, be detrimental to the ADHD child, as it robs him or her from achieving a state of arousal necessary to achieve the desired state of focus. This may even play a significant role as to why a number of children with ADHD are predominantly kinesthetic learners (as opposed to the more "passive" auditory of visual learning styles). **Please not that the previous two italicized statements are simply personal opinions and musings of the blogger at the moment, however, note the potential effects that medication may have on this mirror treatment at the bottom of this post.
Numerous adult studies confirm what may seem intrinsically obvious (but relevant to our current discussion): the presence of external "observers", including an audience, cameras, or even mirrors, significantly increase attentional focus (and subsequent self-control) in the individual being observed. However, limited study has been done on this phenomena in children. Nevertheless, it appears to make inherent sense that a child who is under the "watchful eye" of someone (even if that someone is their personal reflection in a mirror), may exhibit higher levels of attentional behaviors.
The study highlights a work by Carver and Scheier called Attention and Self-regulation: A control therapy approach to regulating human behavior (1981) in which the use of mirrors increased the effectiveness of academic-related methods such as copying letters (which has practical uses in note-taking), persistence in problem-solving tasks (which has direct uses in academic areas such as math and science), and the extent of response generation exercises (which have direct implications in brainstorming activities and subjects such as creative writing assignments). Thus, the possible benefits of mirror usage are far reaching for the ADHD child.

The experiment comprised of giving both ADHD and non-ADHD children a word puzzle (which was unsolvable, as a handful of the words the child was instructed to find did not exist in the puzzle. The children were notified of this fact, but were not notified on the number of words that were missing. When the child believe that he/she had found all of the words in the word search, he/she notified the experimenter and stopped the task. In other words, this study was tailored to track attention and persistence for a particular task). Both the ADHD and non-ADHD children worked on the puzzle in either one of two conditions: in front of a mirror (approximately 2 feet by 3 feet in size, on a wall in front of the table where the child was performing the word-finding task), or without a mirror.

ADHD children showed noticeable improvements when working in front of the mirrors (i.e. finding more words). In contrast, the non-ADHD children who worked in front of mirrors were either unaffected or showed decreased levels of performance on the word finding task.

Additionally, the study examined when a child looked up at the mirror or ignored it. It appears that looking up at the mirror improved the performance of the ADHD group but either did not effect or decreased the effectiveness of the non-ADHD'ers. Therefore perception of being "watched" appeared to improve the focus of the ADHD group, but may have overwhelmed the non-ADHD group. Interestingly, several of the ADHD children who were placed in front of the mirror but did not look up at it had significantly lower levels of performance than those that did look at the mirror. The study suggested that these children may have already developed strong "internalizing" behaviors of self-focus, such as vivid daydreaming.

These findings may be interesting, due to a number of reasons. In previous posts, we have recently alluded to the fact that a particular region of the brain called the basal ganglia, which essentially governs how fast an individual "idles" (i.e. a "type A personality" such as a workaholic, obsessive-compulsive individual typically has higher basal ganglia activity, while individuals with ADHD often have lower levels of activity in this brain region).

The basal ganglia activity is also increased when there's a sudden change in external stimuli, especially when the sudden change is perceived as dangerous or harmful. Under conditions such as these, the basal ganglia can become so overwhelmed, that the individual temporarily "freezes". Under a highly unpredictable or stressful situation (such as witnessing a traffic accident, crime or heart attack), ADHD individuals are often the first ones to react to the situation. It is believed that this is due to the fact that they have lower baseline levels of activity than their non-ADHD counterparts, and therefore have more capacity to accommodate to this new-found stress before either freezing up or becoming overwhelmed.

Tying this in with our mirror discussion, the difference in response to the feeling of being "observed" by the mirror, may be due, at least in part, to heightened basal ganglia activity, which may begin to overwhelm the non-ADHD group but help optimized the basal ganglia activity in the ADHD group of children. This assertion remains the blogger's personal hypothesis, and was not mentioned in the study, however, I believe that there is sufficient groundwork to warrant a mention of this possibility.

The results of the word-finding task may extend into other academic areas as well. The authors cited another study in which mirrors used as part of a larger classroom setup experiment (such as music, color settings, activity breaks, etc.) significantly improved performance, accuracy and completion on math assignments.

Finally, there was a small side-study involving children who did not fit into either the ADHD or non-ADHD group (often due to medication). It appears that for the medicated group, the presence of the mirror was actually detrimental to performing the word finding task at hand. Therefore, the combination of mirror and medication for ADHD, especially in the academic or classroom setting, needs to be further investigated.

ADHD, Methylphenidate and Blood Sugar Levels

2009-05-04T21:56:00.007-04:00

ADHD medications may interfere with blood sugar levels and glucose metabolism:

When we think of common side effects of ADHD medications (especially of the stimulant variety), we often consider things such as cardiovascular risks (increased heart rates and blood pressure), appetite suppression (which may subsequently result in temporary growth impairment), interference with sleep, dampening of creativity and emotions (i.e. taking on a zombie-like state), irritability, moodiness, and the like.

However, it appears that another equally important, but often less-considered side effect of many ADHD medications is a change in blood sugar and glucose metabolism. The first part of this post will investigate some of the research out there on the effects of common ADHD medications on brain glucose metabolism. The second half will zero in on some of the general metabolic differences between the ADHD brain and the non-ADHD brain, and will also investigate possible effects of age, gender and co-existing disorders:

A drop in blood sugar following methylphenidate treatment: A case study involving a diabetic woman who underwent a surgical operation for a brain tumor. While we cannot make any logical conclusions about the population based on one individual of unique needs, the fact that a pronounced drop in blood glucose (over 25%) following methylphenidate treatment is at least worth noting. It is unclear as to whether the effects were due merely to the methylphenidate (common forms of this drug include Ritalin, Metadate and Concerta), or rather to a drug-drug interaction.
Methylphenidate reduces required brain glucose amounts to perform cognitive tasks: A study done at the National Institute of Drug abuse found that the administration of methylphenidate reduces the amount of glucose (the brain's desired energy source) needed to perform a thinking task. It is believed that this lower energy requirement is mainly due to less "wasted" energy from a constantly wandering and side-tracked mind, such as one seen in individuals with ADHD.

Interestingly, this same study also found that during non-cognitive tasks, the differences in brain energy requirements did not change with or without the drug. This may at least call into question the merits of ADHD stimulant medication usage if higher order cognitive tasks are not required. Furthermore, if the brain is already focused, the utilization of methylphenidate may even be overkill. The authors concluded that this may be a primary reason why adverse effects in concentration and focus can be seen when methylphenidate is administered to "normal" functioning brains.
Methylphenidate's influence on brain metabolism may be regio-specific: Another study done by the same author as in study #2 found that the effects of methylphenidate on brain glucose metabolism may depend on individual subregions of the brain. For example, this study found that for the basal ganglia region of the brain (this brain region essentially governs how fast a particular individual's brain "idles"), the relative activity of this brain region was typically reduced following methylphenidate treatment, compared to activities in other brain areas. This may be a bit counter-intuitive, since basal ganglia activity is typically lower in individuals with ADHD and higher in individuals with obsessive compulsive or anxiety-ridden behaviors.

However, other brain regions such as the frontal and temporal regions of the brain (which are responsible for filtering out unimportant external stimuli and inhibiting impulsive behaviors, and, perhaps not surprisingly, often show lower levels of activity in the ADHD brain), experienced a boost in metabolic activity following methylphenidate treatment. It is believed that these responses are modulated through categories of receptors for the brain chemical dopamine (called Dopamine D2 receptors, which help control levels of this important neuro-signaling agent, which is often deficient in key regions of the ADHD brain).

In this blogger's opinion, this dual action of inhibiting impulsivity (which can potentially dampen creativity) and shutting down some of the basal ganglia activity may actually be a reason why "zombie-like" behaviors are sometimes seen in children medicated or overmedicated with stimulants for ADHD.
The "Energy Deficient" Hypothesis of ADHD: While still in the hypothetical stage, there is a fair amount of evidence suggesting that ADHD may be due, in a large part, to a lack of energy to specific neurons in key brain regions such as the prefrontal cortex (part of the "frontal" regions of the brain discussed in the past point). This ADHD as an energy-deficiency hypothesis carries that astrocytes (star-shaped cells that provide energy and nutrition for growth and repair of neuronal cells) may be starved of some of their important nutritional needs for glucose and related nutrients. As a result, they are unable to effectively "feed" the neurons in these key brain regions associated with governing attentional and impulsive behaviors in the brain. Should this hypothesis hold true, it would stand to reason that regulating and improving glucose levels either via either medication-manipulated, or alternative dietary methods may help offset some of the energy deficient imbalance in ADHD. Some natural supplemental options to boost glucose levels in the ADHD brain may include ginseng and carnitine.
Reduced brain metabolism in teenagers with ADHD: The results of this study on metabolic differences in teenage ADHD brains agree with many of the findings discussed in point #3 above. This study investigated the effects of an auditory-based attentional task on rates of brain glucose metabolism in adolescents with ADHD. It found that there was minimal differences between glucose metabolic patterns in the brains as a whole when comparing the ADHD and non-ADHD individuals.

However, it is also worth mentioning that in other related studies on brain metabolism in teens with ADHD, it was found that metabolic deficits were seen at significantly lower levels throughout the brain as a whole. Interestingly, according to the second study mentioned, these differences in brain metabolism were only seen in the girls with ADHD and not the boys, which suggests possible gender-specific differences in the etiology of the disorder.

However, upon investigating for the more hyperactive forms of the disorder in the first study (remember that ADHD behaves as a spectrum, in which some individuals have the predominantly inattentive symptoms, while others exhibit the hyperactive and impulsive symptoms more readily, these different predominant features are typically grouped together as unique subtypes of ADHD), it was found that the hyperactive component of ADHD corresponded to a significantly reduced level of glucose metabolism in the whole brain. This brings up the question as to whether these metabolic differences exhibit any sort of subtype-dependent effects with regards to ADHD.

Also, as in point number 3 above, metabolic deficits were apparent in more specific brain regions such as the left frontal lobe regions of the brain. Even more remarkably, there appeared to be somewhat of a sliding scale with regards to the relationship between reduced glucose metabolism and increased symptom severity in this particular "hot spot" (the left frontal lobe) region of the ADHD brain.

The following sidenote is a personal comment by the blogger regarding some of the methods of the previous study. As mentioned above, the test for this adolescent ADHD study involved an auditory based attention task. However, as discussed in earlier posts on this blog, we have seen that auditory processing disorders sometimes accompany ADHD.

Furthermore, due to a high degree of symptom overlap, a comorbid auditory processing disorder can often be missed in an ADHD child or adolescent. Because of this, we should not rule out the possibility that comorbid auditory processing issues may interfere with the results of studies such as this one.

We can see that auditory processing takes place in multiple regions throughout the brain, many of which do not have significant overlap with the "ADHD brain regions". One would expect the brain of an individual with an auditory processing disorder to work harder to achieve the same results as that of a non-auditory disordered individual. Thus, a confounding processing disorder could, in theory result in an increased demand for energy utilization to the portions of the brain responsible for stimulatory processing, which could leave less available energy for the frontal lobe regions of the brain responsible for modulating hyperactive and impulsive ADHD behavior. These assertions remain hypothetical at the moment, but this blogger feels that the presence of undetected comorbid disorders can easily skew the results of these metabolic studies on the ADHD brain.
Age-Dependent Decline in Brain Glucose Metabolism in Adults with ADHD: Apparently, metabolic differences in ADHD brains are not limited just to children, adolescents, and young adults with the disorder. Some of the findings of this following study may seem inherently counterintuitive at first. While ADHD symptoms often decline as an individual with the disorder ages, we would expect that an accompanying level of improvement in glucose metabolism in ADHD-specific brain regions would hold true. However, according to this study on brain glucose metabolism in older ADHD adults, it appears that the opposite is actually the case.

The authors hold that the decrease in glucose metabolism may actually be markers of a more efficient process of brain metabolism (i.e. these older ADHD brains may somehow conform to an efficient energy-conservation state allowing them to function more optimally, thereby decreasing the prevalence of ADHD symptoms), although this finding is somewhat suspect in this blogger's personal opinion.

As an interesting side note, the decrease in brain glucose metabolism in adults is apparently gender-specific, according to the study. This parallels the findings from some of the adolescent ADHD brain metabolic studies. The notable metabolic decreases were observed in women with the disorder to a much larger degree in men. The authors of the study suggested this may be due to hormonal influences, such as changes in post-menopausal women.

Given the anecdotal evidence supporting the association between ADHD and higher onsets of neurodegenerative diseases later in life, this blogger finds the results of this study to be of particular interest. There may even be some claims that genetics may be partly to blame for the overlap between ADHD and neuro-degenerative diseases. For example, a gene referred to as DAT1 (short for dopamine transporter gene 1, located on the 5th human chromosome) may be connected to both ADHD and parkinsonism (a secondary or alternate form of Parkinson's disease). DAT1 also helps regulate dopamine function, (although via a different method than the dopamine receptors mentioned in point #3), by coding for an enzyme that helps transport or shuttle dopamine into and out of neuronal cells. We have discussed these dopamine transporter genes in earlier posts.

We have covered a number of works on the metabolic differences of glucose in the ADHD brain, and how they differ from the brains of non-ADHD individuals. There is the distinct possibility that stimulant medications used to treat ADHD, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana) can significantly alter brain glucose requirements. It appears that significant differences in brain glucose utilization patterns and efficiency may affect the entire brain, but certain ADHD "hot spot" regions of the brain may be particularly hard-hit. It is unclear whether this is due to preferential metabolic differences of the ADHD brain (compared to the "normal" brain), or whether it is due to an all-out brain energy shortage.

It is also worth noting that significant gender-specific factors may also affect this process, with ADHD girls in particular showing the greatest metabolic deficits. It also appears that these effects are also being observed across the lifespan of the ADHD individual. Finally, there is at least a hypothetical possibility that sensory processing difficulties or other comorbid disorders commonly seen alongside ADHD may also play a role in these metabolic differences of ADHD brains.

Can ADHD be Treated with Ginseng?

2009-05-03T11:55:00.006-04:00

The Theory Behind Ginseng as an ADHD Treatment Option:

Ginseng is well-regarded for its memory boosting, sleep improving, and brain-saving longevity benefits. In a general sense, it appears that it would be a good potential treatment method for ADHD and related disorders. Although successful clinical study publications on the specific use of ginseng for ADHD are relatively scarce, it appears that on at least a theoretical basis, this popular herb could work for treating ADHD and related disorders. I would like to highlight some of the biochemical and physiological reasons supporting its use as an alternative treatment for ADHD:

Compound diversity in ginseng: Ginseng is not simply one isolated compound, such as an individual drug, but rather a mixture of substances of potential pharmaceutical benefit. Among these are a family of compounds called ginsenosides. One of the underlying benefits this (and herbal treatments in general), is that many of these related compounds can work together in a synergistic fashion, nature's own alternative to drug cocktails. Given the fact that absorption, metabolism and utilization of biochemical agents for the treatment of disorders is rarely due to one isolated substance of pharmaceutical value, this multi-compound treatment method certainly has potential advantages over a single-drug treatment method for ADHD or related disorders.
Ginseng, dopaminergic activity, and ADHD: It has been demonstrated that herbal extracts of ginseng can exhibit activities that target the dopaminergic (dopamine-related) pathway and can exhibit neuro-protective benefits for these pathways. This is important, because ADHD is often chemically characterized by deficits in this pathway, which typically include reduced dopamine levels in the regions between neuronal cells throughout various key regions of the brain (ones that, among other things, are responsible for attention span, screening out irrelevant stimuli, and impulse control). There are even implications that ginseng compounds can accelerate the neurodevelopment process from stem cells.
Boosting of "synaptic plasticity": During the learning process, a certain amount of "agility" is necessary in the regions in between the cells as the brain begins to rewire itself to conform to the newly learned material. The ability of neurons to form new connections is referred to as synaptic plasticity. It appears that ginseng contains several key elements which helps maintain this "pliable" learning-friendly state. Essentially, compounds isolated from ginseng can moderate long-term potentiation, (long term potentiation refers to a learning and memory process in which communication between two neuronal cells is improved or made more efficient by stimulating both cells at the same time. This plays an important role in the development and maintenance of long-term memories). Given the fact that learning disabilities are frequently seen in ADHD (often more on the inattentive side of the ADHD spectrum), it stands to reason that ginseng may be useful in some of these comorbid learning-related deficits as well.
Ginseng boosts aerobic glucose metabolism in the ADHD brain: The ADHD brain typically contains deficits of glucose and oxygen (as determined by multiple imaging and brain scanning studies) in many of the key brain regions which modulate attentional control, impulsivity, and concentration. It is even postulated that ADHD may be an "energy deficient syndrome". Brain metabolic studies indicate that aerobic glucose metabolism is typically improved in the presence of ginseng isolates. Not only does this reduce some of the potentially brain waste products associated with oxygen-deprived brain activity, but this enhanced aerobic form of glucose metabolism in the brain is a more efficient process.
Ginseng may boost dopamine and norepinephrine levels: As mentioned previously, individuals with ADHD are typically deficient of the important neuro-signaling agent dopamine in key regions of the brain. However, a deficiency in another important neuro-signaling agent called norepinephrine is also frequently seen in the ADHD brain. Imbalances of both dopamine and norepinephrine are seen in ADHD patients, and can lead to disruptions in physiological processes such as attention span, complex cognitive processes, auditory processing delays, and motor behavioral dysfunctions. It is believed that the ginsenoside compounds (see point #1) may help alleviate some of these ADHD-related symptoms by boosting levels of dopamine and norepinephrine in these key brain regions, several of which are affiliated with ADHD.

Interestingly, many stimulant meds for ADHD work by boosting levels of these same two compounds, meaning the effects of ginseng may approximate those of a stimulant medication used to treat ADHD. We will see in the next post how another natural brain supplement, Ginkgo biloba, may better approximate the action of non-stimulant ADHD medications. It is also worth noting that isolates of ginseng and ginkgo may work in tandem to boost memory and other related functions.

On a side note, fatty extracts of the ginseng plant have been used to alleviate the dopamine-dependent "high" of cocaine, which supports the use of ginseng as a potential treatment agent for cocaine addictions. Similar results support the use of ginseng for treating nicotine addiction as well. This further validates the dopamine-dependent regulatory benefits of ginseng and its ability to stabilize fluctuations in neuro-signaling agents of relevance to ADHD.
Ginseng may protect against brain damage from excess iron: I have personally advocated the use of iron for treating ADHD in several other posts. It can counteract toxic effects of lead and other metals, improve the synthesis of dopamine from the dietary amino acid tyrosine, and improve sleep quality in ADHD children. However, there are several dangers associated with excessive iron supplementation, one of which is neuronal death and neuro-degenerative diseases such as Parkinson's. However, there is some evidence that ginseng can counteract this iron-related neuronal damage by regulating specific iron-transporting proteins in the brain. If these findings hold true, then ginseng might be of use as some type of "insurance measure" against potential damage from excessive amounts of iron supplementation designed to treat ADHD.
Promote nerve growth in brain regions typically under-developed in ADHD: We have reported earlier on some of the delays in maturation and development of specific brain regions in ADHD. Some research suggests that ginseng compounds may promote neuronal growth and development in the early stages of life. While currently a bit of a stretch, findings such as this may lead to the use of ginseng compounds to offset ADHD-associated neurodevelopmental delays somewhere down the road.
Neuroprotective effects of ginseng for the aging ADHD brain: This may be especially relevant to adults with ADHD as they age. In addition to its ability to help with neuronal cell development in the early stages of life (mentioned in the previous point), evidence suggests that the active ginsenoside "Rd" compound in ginseng can alleviate inflammatory damage and death to neuronal cells. Given the fact that early neurodegenerative effects are often present in ADHD-like mammalian systems, these results at least suggest that ginseng may be a potential life-long treatment option for individuals diagnosed with ADHD.

ADHD Gene Falls Inside Reading Disabilities Genetic Region

2009-05-02T15:17:00.006-04:00

ADHD and learning disabilities are often seen alongside each other (many actually label ADHD as a learning disability itself, but most of the medical community considers ADHD a separate entity). Now there is some evidence that ADHD and reading related learning disabilities may be genetically linked:

A quick background of genetics: The human body consists of somewhere around 30,000 to 50,000 genes (the numbers actually vary, as actual genetic regions are not fully pinned down, and various regions of DNA called pseudogenes, exhibit genetic qualities themselves). These genes are spread across 23 pairs of chromosomes (one copy per each pair), and have a relatively wide degree of diversity among individuals. These genes are essentially lined up nearby each other, such as houses in a neighborhood. When the genes are transmitted from parent to offspring, the closer two genes are to each other, the more likely they will be passed on together. Thus if an individual has an "ADHD gene" form located right next to, say a gene which has certain forms which increase one's susceptibility to color blindness (this is just a hypothetical example), we would likely expect a greater than normal co-occurrence of ADHD and color blindness.

The ADHD gene in question is often referred to as the Protogenin Gene, located on the 15th human chromosome. If falls in a region flanked not only by what is considered a genetic region implicated for reading disabilities. In addition, this gene is also believed to aid in the physical developments of the nervous system and neuronal cells at the embryonic stage of life.

While these findings are preliminary, they suggest a possible genetic factor for the connection between ADHD and reading disorders (of course we should not overlook the obvious fact that having attentional or concentration difficulties also has a negative impact on one's reading capabilities, especially if required to read complex material for long periods of time). It also lends credence to the growing body of evidence that suggests the role of developmental delays in the onset of ADHD.

ADHD and Handwriting: What's the Connection?

2009-05-01T23:51:00.003-04:00

The link between ADHD and Poor Handwriting (Dysgraphia):

It has been well-known for years that individuals with ADHD are often more prone to problems with penmanship, that is, they have trouble producing legible handwriting. But why is this the case? There are several theories out there, and multiple studies showing how effective ADHD treatments can also result in major improvements with a person's handwriting. I will review some of the current findings on the topic:

A group in Israel sought to investigate whether the problem with handwriting in ADHD children was due more to underlying language problems (i.e. spelling, formulating sentences, etc.) or more due to the mechanical problem of the physical writing process. While they concluded both were at play, the results of their study seemed to indicate that underlying language difficulties played only a secondary role to the writing difficulties and that the primary cause was due to "non-linguistic deficits". Interestingly, the group did find specific patterns to the frequent mis-spellings of words, instead of a host of random, unrelated errors. This blogger personally found the conclusion of the article's summary to be particularly amusing, as it recommended a "judicious use of psychostimulants".
Continuing on with the "judicious use of psychostimulants" theme, we must investigate the effectiveness of one of the most common types of stimulants for ADHD, methylphenidate (Ritalin, Concerta, Metadate). This drug has elicited a number of positive effects as far as improving both the cognitive and physical aspects of handwriting, as concentration or attentional lapses subside, allowing the thought process and physical act of writing to be performed simultaneously.

However, another study found that even medication with methylphenidate had its limits, and that handwriting gradually deteriorated as the child continued with the writing process. This suggests that for long essays or standardized tests (such as the writing portion of the SAT's, or A.P. exams), medication with methylphenidate or other stimulants may only be useful early on.
Specific Genetic Factors may underlie both ADHD and handwriting problems: There was an interesting study done by a Dutch group which suggests that there may be some sort of genetic factor that inhibits fine motor movements (such as those required for writing) which then make their way over to ADHD. In other words, this study seems to suggest that ADHD is a secondary problem to fine motor problems such as dysgraphia (typically, it's the other way around, where ADHD is considered the primary disorder). This study discovered that non-ADHD siblings (who, by definition, share half of the ADHD child's genes, provided they are not identical twins) of the ADHD children also had difficulties with more complex forms of the writing process, compared to the general population. In other words, these siblings had some degree of impairments with the writing process, but not to the degree of their ADHD siblings.

This suggests that these non-ADHD siblings may have enough genetic "impairments" to share some of the comorbid writing problems as their ADHD counterparts but not enough to manifest an outright diagnosis of ADHD themselves. In other words, the comorbidity (co-occurrence of) ADHD and dysgraphia is apparently not an all-or-nothing phenomena.
Differences in hand-eye coordination and motor control problems are more pronounced in the left hand for ADHD vs. non-ADHD children: We have previously investigated key brain regions commonly associated with ADHD, including differences in relative brain region size, use of brain regions, bloodflow patterns, brain electrical activity patterns, sense of smell, the relationship to alcoholism, brainwave patterns, and genetic differences targeting specific brain areas.

However, it is worth noting that these brain regional differences are often not laterally symmetric, that is they may only be on the left side or right half of a particular brain region. This lopsidedness may play a role in manual dexterity and motor coordination differences between ADHD and non-ADHD individuals, which appear to be even greater in the left hand (which, in most cases the non-dominant one).

The article which found this discrepancy between the different sides of the body goes on to suggest that testing for fine motor coordination in ADHD kids would be better suited for the left hand, since the effects are more pronounced. This leads to this potentially intriguing question: If handwriting is done with the dominant hand, does it stands to reason that handwriting difficulties are just the tip of the iceberg with regards to immensely greater fine motor difficulties? In other words, if an ADHD child is having trouble writing with his or her dominant right hand, how bad would the fine motor deficits be if they needed to use their left hand for something like catching a baseball, or shooting a left-handed layup in basketball?

Based on this finding, it appears that poor handwriting may be just one aspect of a much larger fine motor disability. Another possibility, however, is that using one's non-dominant hand requires a higher order cognitive process than utilizing one's dominant hand for a routine task. This possibility may actually carry some weight, as we have seen in previous posts how discrepancies between ADHD and non-ADHD individuals begin to balloon as the cognitive processes become increasingly more difficult.

This also seems to jive with the underlying genetic component of these disorders proposed by the ADHD sibling study in the previous point, in which the non-ADHD siblings had trouble only with the higher-order writing processes and not the more automatic ones (such as doing a simple task with one's dominant right hand). Unlike the Israeli study, this seems to favor more of an underlying cognitive discrepancy as the main culprit of poor handwriting in ADHD, as opposed to a more "mechanical" one.
The genetic discrepancies in ADHD and fine motor impairments may be one of motor timing: Going back to the genetic aspects of ADHD and motor impairments such as dysgraphia for a moment, it is worth mentioning another finding by a group investigating difficulties in timing fine motor applications in ADHD children. This study utilized tests such as pressing a button on self-determined one second intervals (and measuring how close the child's perceived timing matched up with "real" one-second intervals), tapping one's finger as many times as possible within a given time limit (a relatively common test for individuals with ADHD and related disorders) and tests which measured reaction timing to moving objects and visible changes (which may have direct implications as to how well a child would perform in a sport involving reacting to moving objects, such as baseball, lacrosse, or tennis). Based on these tests, the authors concluded that the motor impairments in the ADHD children were more likely due to timing issues as opposed to generalized motor problems.

As a blogger's note, this might explain some of the difficulties in the handwriting mechanics, such as crossing "t's" and dotting "i's", which essentially involves hitting a "target" on the paper, or keeping up with a teacher while taking notes (which is a very time-dependent process which often requires a fast execution of handwriting numbers, letters, diagrams, and symbols).

A number of books on the subject of ADHD and writing disorders show actual handwriting samples of children on and off medication for ADHD. The differences are astounding. Additionally, differences in complexity and eloquence in creating stories are often extremely pronounced depending on the mode of expression. For example, actual cases involving gifted children with ADHD have highlighted how a child can concoct an thorough, detailed, and well-rounded story orally, but when asked to write out the same story, he or she is scarcely able to construct even a single, legible, coherent paragraph.

This brings up the important issue as to whether children with ADHD should be afforded opportunities to use different modes of communication for their assignments, such as dictating or typing as opposed to handwriting. It appears that for many, the actual process demanded of ADHD children for actually writing may rob or ferret away the majority of their cognitive capacity, resulting in a barren landscape of creativity or eloquence.

Given the fact that many children with ADHD respond positively to alternative learning or expressive styles such as predominantly auditory (dictating) or kinesthetic (typing) means of expression, numerous questions surrounding the degree of accommodation for these ADHD children must be addressed. It is my personal hope that the findings of some of these studies will shed some light onto the mechanical and cognitive impairments of the physical writing process for children with ADHD will help shape an educational environment to help these children to flourish.

Bedwetting ADHD Kids and Depressed Dads: Is there a connection?

2009-04-30T21:51:00.004-04:00

ADHD and Bedwetting (Nocturnal Enuresis): How are the two related?

There is a relatively recent publication that came out within the last couple of weeks on the relatively high rate of occurrence in bed wetting (enuresis) among ADHD children, which I believe is worth sharing. We have previously investigated this ADHD and bed wetting connection (note that bed wetting may be more likely to be seen alongside the inattentive subtype of ADHD). However, this study offers some additional insight into this strange association between the two disorders. Here are some important points worth mentioning:

Overlapping Drug Treatment for ADHD and bedwetting: It stands to reason that if a particular drug or agent is effective in treating multiple disorders, there may be a distinct possibility that those two or more disorders may share some type of underlying cause(s) or defect(s). For example, Tofranil or Imipramine, a drug used to treat enuresis and depressive disorders can possibly be useful as a treatment option for ADHD. We have also investigated the potential role of Reboxetine as a potential ADHD treatment in previous entries. Some work has found Reboxetine to be useful in treating therapy-resistant enuresis as well.

Prevalence of Enuresis in ADHD: Enuresis refers to urinary incontinence which is limited to the night-time. Additionally, the term is typically limited to individuals over the age of 5 (i.e. a 3-year-old child who frequently pees in their pants would not be considered as suffering from enuresis, at least in the context of this study). The article cites other studies in which the rate of bedwetting (enuresis) in ADHD is as high as 30%, although other studies have it down around 10-20%. Still, compared to the general population, (factoring in things such as the age of the child, of course)the high rate of bed wetting in ADHD is especially noteworthy. There is some evidence from other studies that ADHD and enuresis may be more intricately linked than previously imagined. For example, one particular study has shown that treating urinary incontinence has a higher rates of failure in children with ADHD vs. non-ADHD children.
The role of Oppositional Defiant Disorder (ODD) on Bed wetting: The study examine several different psychiatric disorders which frequently occur alongside of (or are comorbid to) ADHD. These include depression, anxiety disorders, obsessive compulsive disorders, tic disorders, nail biting, bruxism (teeth grinding), conduct disorders and oppositional defiant disorders. However, out of all of these different disorders which often appear alongside ADHD, the only one which exhibited a statistically significant correlation to increases in bedwetting was oppositional defiant disorder. Interestingly, oppositional defiant disorders have been associated with bedwetting in other ADHD studies.

As its name suggests, Oppositional Defiant Disorder is a disorder in which a child exhibits disobedience, irritability and hostility towards authority figures beyond the range of normal age-appropriate behaviors. Of course there is a significant gray area with regards to what is age appropriate, especially when the child's environment is considered. Nevertheless, Oppositional Defiant Disorder (or ODD) is much more than just routine temper tantrums. Oppositional Defiant Disorders may also be associated with auditory processing issues and ADHD. It is somewhat interesting that anxiety disorders, which have also been correlated to oppositional behaviors, did not elicit a significant positive correlation to bed wetting.
The autonomic nervous system as a potential underlying cause of ADHD, bedwetting and Oppositional Defiant Disorders: The autonomic nervous system is the part of the nervous system responsible for involuntary muscle actions such as digestive processes, blood vessel contraction, etc. It is subdivided into the sympathetic and parasympathetic nervous systems, which often act in a sort of "push-pull" opposition to each other. For example, the sympathetic nervous system does things such as boosting heart rate and constricting blood vessels, while the parasympathetic nervous system is in charge of activities such as reducing heart rates and relaxing sphincter muscles (which plays a role in bladder control).

Typically, the sympathetic and parasympathetic components of the nervous system are kept in balance, but this balance may be thrown out of whack and result in numerous disorders. For example, it is believed that the parasympathetic nervous system is over dominant in cases of Oppositional Defiant Disorders (ODD). The study found that for ADHD and Oppositional Defiant Disordered children, functions such as heart rate were controlled excessively (if not almost exclusively) by the parasympathetic portion of the nervous system (while non-ODD and non-ADHD children had both sympathetic and parasympathetic controls operating on their heart rates. This suggests a common underlying imbalance among the different components of the nervous system which is common to ADHD and ODD individuals and often separates them from the non-ADHD'ers. Interestingly, other studies have indicated that bedwetting or generalized incontinence problems may also be caused by an overactive parasympathetic nervous system, which suggests that ADHD, ODD and night-time bedwetting may all share some underlying causes within the nervous system.

Connection to Parental Depression: I personally found this observation to be interesting. The study found that the prevalence of bedwetting in ADHD children was higher if the father (but not the mother) of the child was suffering from some sort of major depressive illness. The article did not express an opinion as to whether these depressive symptoms were due in part to the child's bed wetting problems or whether there was some underlying mechanism at work.

ADHD medications may Influence Enuresis: The authors highlight some other works in which popular ADHD medications may either increase or decrease the risk of bedwetting in ADHD children. For example, the article highlighted a case study (by the same author) in which treatment with methylphenidate induced nocturnal enuresis. Methylphenidate is one of the most common ADHD drugs, and often goes by the common trade names Ritalin, Concerta, Metadate and Daytrana (the patch form of the drug). Of course this is based on only one individual case, but for those of you who have read this blog on a frequent basis, will know that I like to report on some of these abnormal occurrences (for reference sake, here is an earlier blog post I have done on the possible connection between methylphenidate and excessive talking. While based on an isolated case report, I believe that this zany potential side effect was at least worth a mention). On the flip side, however, the non-stimulant alternative ADHD drug, Atomoxetine (Strattera) can be a useful treatment for enuresis. This blogger would personally like to see additional studies on whether ADHD children with a comorbid bedwetting condition actually saw a better reduction in their ADHD symptoms while on Strattera than while on methylphenidate. If this were the case, then bedwetting may actually served as a useful tip-off as to which type of ADHD medication would work best for that particular child.

Strattera (Atomoxetine) response may be affected by SLC6A2 gene

2009-04-26T15:04:00.004-04:00

About a month ago, we were discussing the ADHD gene SLC6A2. Located on the 16th human chromosome, different variations of this SLC6A2 gene are believed to play at least somewhat of a determining factor as to the genetic predisposition towards attention deficit hyperactivity disorders (ADHD). We saw that this gene was also correlated to anxiety and depression-like symptoms (which commonly occur along many ADHD patients) and that these genetic factors were slightly stronger in girls.

Atomoxetine (Strattera) is a non-stimulant alternative to medication treatment for ADHD. Unlike most stimulant medications, which interfere and regulate the pathways of the neurotransmitter dopamine, atomoxetine acts upon the pathway of the neuro-signaling agent norepinephrine. While dopamine-related stimulant medications for ADHD can worsen accompanying anxiety and depressive-like disorders (extreme caution is necessary when prescribing stimulants if a severe co-illness of anxiety or depression is present alongside ADHD), Strattera has shown to extremely beneficial in the co-treatment of depressive-like illnesses, especially when used alongside the SSRI class of antidepressant drugs.

A recent publication in the journal Neuropsychopharmacology highlights the potential connection between variations of the "ADHD gene" SLC6A2 and the effectiveness Strattera (Atomoxetine) for treating ADHD.

It is important to remember that for most genes, there are slight variations in the different forms within the human population. For most, these small changes in DNA do not result in any major physiological differences, but for some, even a change of one or two units of DNA can make a huge impact on biological functions, such as response to a specific medication. We have previously discussed how both the Catechol O-Methyltransferase (COMT) and CREM genes, may both dictate different dosing levels for ADHD medications.

Based on the SLC6A2 and Strattera study, it appears that individuals with specific gene variations of the SLC6A2 gene had a significantly more positive response to atomoxetine (based on a common behavioral rating process typically used to assess ADHD and related disorders), than were others with different variations of the gene. These effects were seen even when another gene (the CYP2D6 gene, located on the 22nd human chromosome and is responsible for the metabolism of atomoxetine/Strattera) was taken into account.

We will hopefully discuss these findings in more detail later, but the main point to drive home from all of this is the concept of how individual gene variation (i.e., which specific forms of a particular gene one has), can play a major role in predicting whether:

An individual will even respond to particular drug (such as Strattera for ADHD), and
Whether that individual's particular forms of these genes predispose him or her to requiring a higher (or lower) than normal dosage level than otherwise physiologically similar individuals to achieve the desired effects.

This blogger personally believes that we have just begun to scratch the surface in investigating the power of gene-medication interactions, and how these interactions will shape the landscape for ADHD treatment.

Phenylketonuria (PKU) or ADHD?

2009-04-23T16:36:00.006-04:00

ADHD vs. Phenylketonuria: A possible misdiagnosis?

If you’ve never heard or seen the term phenylketonuria (PKU) before, you are not alone. However, here’s a quick experiment. Go look at the back of a 2-Liter bottle of diet soda. Near the bottom of the back label, you will probably see a small warning label that says something along the line of “Phenylketonurics: contains phenylalanine” (individuals with phenylketonuria are often referred to as phenylketonurics).

The reason that this warning is on the back of only diet sodas and not regular ones is because the artificial sweetener Aspartame (Nutrasweet) contains the amino acid phenylalanine as one of its two primary components. When phenylketonurics, take in large amounts of this artificial sweetener, they get a large buildup of this amino acid in their bloodstream which they have trouble clearing. As a result, they often suffer a number of physiological problems, in, but not limited to, the nervous system.

The conversion process of phenylalanine to dopamine and how it relates to ADHD:

Phenylketonurics are those individuals who, for typically genetically predetermined reasons, are unable to break down and process the amino acid phenylalanine. This process actually has several implications that can relate to ADHD. We have spoken extensively about the neurochemical dopamine in various other posts. In general, chemical imbalances of this important neurotransmitter are frequently at the helm of ADHD and related disorders (typically shortages of dopamine are found in the "gaps" between neuronal cells, and most stimulant medications for ADHD work by resetting dopamine levels within these gaps). As we can see below, the body can actually manufacture this important brain chemical from various sources or starting materials, including phenylalanine (providing that the individual is capable of manufacturing all of the necessary enzymes in the conversion process. For PKU patients, this conversion process is hindered, and typically leads to shortages of dopamine). A rough sketch of the conversion process is listed below:

So what’s the point?

I have highlighted the chemical changes above, using different colors to represent the enzymes used and the chemical changes that these enzymes are responsible for (note the red and blue colors). As we can see above, the first step of the metabolism of phenylalanine to dopamine is done by adding a hydroxyl ("OH") group to phenylalanine, converting it to another amino acid, tyrosine. The chemical change is highlighted in red. (As an interesting side note, tyrosine is sometimes used as an ADHD supplement or auxiliary to medication treatment, even though the effectiveness of tyrosine for treating ADHD is questionable. Note that if one with PKU were to start with tyrosine, they would bypass the step of the chemical process of converting phenylalanine to tyrosine, which would help with the deficient enzyme phenylalanine hydroxylase. This enzyme will be addressed further down in the post).

Further modifications carry it to the product dopamine, which require two other enzymes (as a side note, the conversion of tyrosine to dopamine, in addition to the two enzymes listed above, also requires an adequate supply of iron. This is one reason why maintaining ample iron stores is necessary in combating ADHD and related disorders, and why an iron deficiency can elicit some of the negative behaviors characteristic of ADHD patients). As an aside, we have previously investigated how iron deficiency can affect both ADHD and sleep disorders and how iron supplementation can potentially offset the toxic effects of lead in ADHD patients.

You'll notice that the first step of the conversion process is blocked for individuals with PKU. This is due to a mutation in the gene that codes for this enzyme, the phenylalanine hydroxylase gene. For reference sake, the phenylalanine hydroxylase gene is located on 12th human chromosome. Remember that it is the mutated form(s) of the gene that can lead to PKU, the vast majority of the human population carries the regular form.

Fortunately, phenylketonuria is a rare genetic disorder, affecting less than one percent of the population. This is due, in part, to the fact that it must be present in both parents to be passed on to a child. It is almost always detected in most newborn screenings. However, it is possible to be missed, especially if a milder form is present. While there are several key differences, some of its symptoms mimic problems that correlate with attention deficit disorders. These include:

Hyperactivity
Erratic Arm and Leg Movements (can be similar to tics or Tourette's-like behavior, which often accompanies ADHD individuals as a comorbid disorder)
Social immaturity and impairment of mental skills
Learning disabilities

As we can see, these four traits are classic behaviors seen in many children diagnosed with ADHD. The first two are more characteristic of the hyperactive/impulsive or combined subtypes of ADHD, the fourth is more tied to the inattentive form of the disorder, and the third can fall into any of the categories. Interestingly, both ADHD and PKU disorders share a common brain region of deficit, the prefrontal cortex.

Key Differences Between ADHD and PKU:

IQ: Most individuals with ADHD typically fall within the normal range on most IQ tests (however, cases of abnormally high or low IQ scores certainly exist). For individuals with PKU, however, a depressed IQ is almost always seen (PKU is a relatively common cause of mental retardation). For example, in a British study, it was found that IQ scores for children with PKU hovered around 90. The IQ scores were closely correlated to the ability of the individual treatments to keep the phenylalanine levels below a specific benchmark in the blood. In addition, differences in subscores, indicate a possible deficit in spatial processing. Interestingly, visual-spatial deficits are often present in ADHD and its comorbid disorders as well.
Head size: Abnormally small head sizes are often seen in PKU. While smaller relative volumes in specific brain regions are often seen in ADHD, the overall head size differences are typically not as pronounced as for PKU. Interestingly, the effects of smaller head sizes and brain regions for both PKU and ADHD, respectively found the differences to be much more pronounced in boys than in girls. Note that we have previously discussed several other gender differences in ADHD.
Onset of symptoms: In general, PKU symptoms are fully manifested in the first two years of life. These include both mental and physical impairments. While symptoms of ADHD can often begin to appear early on, they often do not fully appear until much later in life. As a result, difficulties in pinning down age-specific aspects of ADHD persist.

As we can see, there are a number of features and methods in place such that the possibility of misdiagnosing ADHD as PKU and PKU as ADHD by a skilled professional is relatively small. However, in addition to PKU, there are genetic deficiencies which result in compromised activity of the phenylaline hydroxylase enzyme by around 5 to 10%. While these deficiencies are milder than in full-fledged phenylketonuria, it does bring up a critical point that intermediate states do exist between being diagnosed with PKU and not having PKU. It is possible that individuals in this potentially vulnerable intermediate state of enzyme deficiency may be more susceptible to disorders such as ADHD. Of course, this is just a personal hypothesis.

Nevertheless, the main goal of this post was to highlight some of the key genetic, physiological and behavioral overlaps of the two disorders. It is my personal belief that looking for common underlying trends between even the most disparate disorders can offer a wealth of information into some of the underlying causes of the individual disorders that we would otherwise miss. In other words, I think we often sell our selves short by not digging "deep" enough in our investigations of the fundamental causes of diseases and disorders such as ADHD and phenylketonuria.

10 Ways Carnitine can help treat ADHD

2009-04-17T18:16:00.006-04:00

Carnitine: The missing link to omega-3 supplementation for ADHD

Carnitine is one of the new "trendy" supplements out there today, due in part to the number of heart-healthy benefits that can be derived from it's usage (often alongside other new popular supplements such as Coenzyme Q10). I am not here to discourage these supplements, I definitely see a number of positives from taking them, but for this post I would like to address the topic on Carnitine and ADHD: Can Carnitine, with all of it's heart-healthy benefits, actually be useful in treating ADHD? Here are 10 possible reasons why carnitine may be a powerful new treatment option for ADHD and related disorders:

As a quick aside: Carnitine, like many other nutrients, can exist in different forms, one of which is acetylcarnitine. This form, actually has a number of metabolic roles, but for the sake of simplicity, I will not go into too much detail about the different forms of carnitine unless absolutely necessary.

Potential for boosting the effectiveness of omega-3 fatty acid supplementation: We have already discussed the theory and applications of omega-3's and their possible benefits as alternative non-pharmaceutical treatment options for ADHD. Nonetheless, despite the recent surge in population of omega-3's (including the ever-popular fish oil supplements), only marginal amounts of improvements as far as behavior and symptom reductions are often seen. A big possibility for this limited effectiveness may actually stem from missing pieces of the puzzle with regards to omega-3 metabolism. This may include a deficiency in carnitine. There is even some speculation that abnormalities in fatty acid metabolism may play a role in autism, and that carnitine levels may play a role in this. Given the degree of inter-relationship between autism and ADHD, this possible connection may be at least worth mentioning. In particular, carnitine plays an important role in the synthesis of the docosahexaenoic acid (DHA), and a carnitine deficiency can result in a reduction of this key nutrient. Like several other important fatty acids, DHA deficency is often seen in ADHD individuals.

Carnitine may be beneficial for "refractory" ADHD (unresponsive to conventional pharmaceutical treatment): This one is somewhat surprising. Typically supplementation and "natural" measures can be tried, but if they fail, the more "heavy-hitting" pharmaceutical treatment options for ADHD are often employed. However, a Dutch study done by Van Oudheusden and Scholte which investigated the efficacy of carnitine in treating children with ADHD mentioned that carnitine was found to be effective in treating ADHD in children who were previously unresponsive to methylphenidate, clonidine or behavioral therapy treatments.

What's interesting is that this group found a strong connection between plasma carnitine levels and a reduction in behavior problems (i.e., those children who were able to build up higher levels of carnitine in the blood were more likely to show direct benefit with regards to ADHD symptoms, while those with lower blood levels exhibited more severe ADHD-like behavior). This strongly suggests the carnitine/ADHD connection and also highlights the fact that there is a relatively wide degree of variation among individuals as far as carnitine storage and metabolism is concerned. Even more interesting, this same group found that when carnitine treatment was discontinued, the negative ADHD symptoms re-appeared relatively soon (within 3-4 weeks), but upon re-administration of the previous carnitine doses, the behavioral problems quickly subsided again.

Potential for use for both inattentive and hyperactive/impulsive ADHD: The same study on carnitine treatment for ADHD noted that a decrease in aggression and conduct problems (which are often comorbid to or co-occur with the more hyperactive/impulsive side of ADHD) upon treatment with carnitine. Not to be outdone, another study found that carnitine was more useful in treating the inattentive subtype of ADHD. Interestingly, the inattentive ADHD study found that individuals with the combined subtype ADHD subtype (which includes high levels of both the inattentive and hyperactive/impulsive behaviors) actually showed a worsening of symptoms upon treatment with carnitine.

It's important to note that the Dutch study did see some improvement in inattentive symptoms as well, so it appears (at least for now), that carnitine may be more of benefit towards treating the inattentive aspects of ADHD. This may actually be in line with other studies which link carnitine treatment to increased energy (individuals with the inattentive form of ADHD are often more likely associated to be more lethargic as opposed to the bouncing-off-the-walls behavior typically exhibited by the hyperactive/impulsive or combined ADHD subtypes).

Carnitine as a memory booster: I am personally hesitant to suggest supplementation with generalized memory boosters for ADHD (multiple ADHD websites love to do this), due to the distinct nature of the disorder. Nevertheless, individuals with ADHD do typically exhibit deficiencies in working memory, and some studies on carnitine on memory improvement are of interest. There is evidence that memory improvement from carnitine treatment may be seen in certain sub-populations. For example, carnitine treatment improved visual memory and attention in Down Syndrome patients, but the same effects were not seen in non-Down Syndrome individuals. Additionally, carnitine has also been shown to be useful in Alzheimer's dementia. The possibility that unique subsections of the population may be particularly receptive is intriguing, to say the least.

Carnitine may play a role in reducing toxicity of other psychiatric medications: We have previously addressed the possible association of ADHD and epilepsy. Valproic acid, an anti-epileptic medication (which is also used in treating bipolar disorders, which often has a fair amount of overlap with ADHD itself) has risks of toxicity. However, carnitine treatment of Valproic acid toxicity has been shown in a recent study. In general, carnitine can also help the body clear toxic carboxylic acids from its cells.
Carnitine's lack of addiction potential compared to stimulant ADHD medications: One of the classic problems with many medications (including ADHD stimulant medications) is the potential for addiction. In general, addiction potential is increased by rapid uptake into and rapid clearance by the brain. Although much more rare than prescription medications, herbs and supplements may also be addiction forming. However, there is a relatively slow uptake of carnitine into the brain, which reduces its addiction potential to virtually zero. While not entirely significant (addictions of similar types of nutrients are almost non-existent), it is worth mentioning, if for no other reason than to inform those who are looking for non-prescription alternatives to ADHD some of the benefits to nutrient supplementation.
Acetyl-carnitine may offer the brain an alternative energy source during glucose shortages: Multiple studies have found glucose deficiencies in key specific brain regions in ADHD patients. A study found that glucose can actually inhibit the uptake of acetyl-carnitine into the brain, indicating a similar metabolic pathway. This conclusion of acetyl-carnitine as an alternative energy source was reached by the authors, however, it has been backed up by a body of research from numerous other studies. This seems to indicate that carnitine and its various forms may offer a viable means of alternative energy for glucose-starved ADHD brains.
Carnitine plays a role in acetylcholine (and possibly dopamine) synthesis: Acetylcholine is an important neuro-transmitter in the brain. While it often takes a back seat to more well-known ADHD-related neuro-signaling agents such as dopamine and norepinephrine, several stimulant drugs which alleviate ADHD symptoms may target acetylcholine-dependent pathways (interestingly, nicotine appears to have a high degree of interaction with the acetylcholine receptors, and is often a popular drug of choice in ADHD individuals, often as a means to "self-medicate").

It appears that carnitine can help offset acetylcholine deficiencies in the brain, especially with regards to neuro-degenerative diseases. These effects can be even more pronounced if carnitine is co-administered with other key nutrients such as S-Adenosylmethionine (SAMe) and N-Acetylcysteine (NAc). To do these other two nutrients justice with regards to their effects on ADHD and related disorders or illness, they will need to be covered in their own separate posts. Finally, it appears that carnitine also affects dopamine-related pathways as well, which has numerous potential implications for ADHD, given that dopamine shortages and metabolic differences in key brain regions are often associated with the disorder.
Improved circulation via administration of carnitine (and vitamin E?): There is a mounting body of evidence that supports the assertion that individuals with ADHD have reduced bloodflow to key regions of the brain necessary for maintaining focus, eliminating distractions and maintaining attention to specific tasks. Certain ADHD medications, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana), can actually alter patterns of cerebral bloodflow in ADHD patients. It appears that carnitine can also improve blood flow to brain tissue (the study refers to the term "ischemia", which is simply a reduction of blood supply via blood vessels). These effects may possibly be increased even further, when combined with vitamin E, as highlighted in the same study. Carnitine can also help reduce ischemia to the spinal cord.
Carnitine helps maintain cell membrane integrity: Numerous diseases and disorders are the result of damages to (or "leaky") cell membranes. These membranes are comprised mainly of fats, with several different proteins interspersed among the fatty acids. Ample omega-3 fatty acids play a critical role in maintaining a structure to the cell membranes, which is one of the reasons why adequate carnitine levels are so beneficial. However, fatty acids are prone to oxidation (think of a damage similar to rusting or corrosion, but within the body), so adequate antioxidant levels are needed to maintain these key components of cell structure and overall health.

In addition to its numerous other roles, carnitine is considered to be an antioxidant. Dietary deficiencies, as well as environmental stresses can leave these membranes prone to damage, resulting in a whole slew of potential diseases and disorders, such as increased risks of viral infections, allergies, buildup of cellular toxins, impairment of blood flow (this is actually related to our previous point on carnitine and ischemia) etc. In addition, cells contain inner membranes, whose structure and function can also be dependent on carnitine.

How much carnitine should we be taking, especially for ADHD?
This is a good question, which, unfortunately, does not carry a straight answer. There is no official "RDA" for carnitine at the moment. One group studying carnitine metabolism suggested a recommended daily dose of carnitine to be 200 mg/day. The Dutch study used a dose that was proportional to the patient's body weight, 100 mg of carnitine/kg body weight to be precise. This corresponded to a maximum of 4 grams of carnitine (note that this study was done in children) for the study. Dosage at this level corresponded to about a doubling in plasma carnitine concentration. With regards to side effects, there were relatively few, although one individual discontinued the study due to onset of a strange odor emanating from his skin. It was believed that this may be due to a buildup of a compound known as trimethylamine, which has a characteristic fishy, ammonia-like smell.

However, some of the effects in other studies were seen at only a fraction of these doses, such as some reporting effects such as significant improvements in attention at only 25 mg carnitine/kg body weight. 50 mg/kilogram body weight was the dosage used in a study that found carnitine to be effective in combating hyperactivity. These studies are simply rough estimates for amounts needed to suppress inattentive and hyperactive/impulsive behaviors associated with ADHD. As far as safety and toxicity issues are concerned, there are few published reports about dangerously high levels of carnitine. For a one-year study on the effects of carnitine for ADHD boys, a daily dose of 1 gram per day was found to be safe. This study recommended 20-50 mg carnitine per kg of body weight, which is roughly one fifth to one half of the levels used in the Dutch study.

Regional/Geographic effects on carnitine supplementation for ADHD: A mult-site study on the effects of carnitine on ADHD by Arnold and co-workers made an interesting observation. They studied the effects of carnitine on ADHD symptoms in children in 10 different sites across the United States, and found that significantly more pronounced effects were seen in 3 sites in Ohio and northern Kentucky. All of these sites were about 150 miles northwest of the Allegheny Mountains. The other parameters (age range, demographics, ethnicity, ADHD symptom scores, doses of carnitine, etc.) were similar to the other sites, and the researchers in the study offered no explanation for the findings and suggested the difference to be merely coincidental. While this is obviously a possibility, this blogger offers a possible explanation: the potential effects of interaction between carnitine and minerals or heavy metals.

One possibility may have to do with magnesium deficiency in this particular region. Some studies note that the soil in the Allegheny region is deficient in magnesium due to erosion or poor soil management. It is possible that this magnesium depletion in the soil may result in a higher prevalance to dietary magnesium deficiency in these geographic regions. We have demonstrated the effects of magnesium deficiency in ADHD in several previous posts, such as one on Magnesium Deficiency and Childhood ADHD. However, we have also seen that magnesium can often work in conjunction with other vitamins, minerals and antioxidants in treating ADHD as well. These highlights can be found in an earlier post on magnesium combination treatments and ADHD.

Some research has found that magnesium can boost the activity of the enzyme Acetyl-CoA carboxylase, which plays a significant role in fatty acid biosynethesis. A fatty derivative of carnitine can also push this same enzyme along. It is possible, therefore, that carnitine supplementation may take over some of the roles of the depleted magnesium, thereby freeing up magnesium for some of the other ADHD-fighting fuctions as previously noted. Of course this is just a personal hypothesis, but this blogger earnestly believes that there are a number of carnitine-mineral interactions that have not been studied extensively that warrant further investigation.

Carnitine does not act in isolation:
If you get nothing else out of this post or any of the other posts in this blog dealing with nutrition strategies for ADHD, please remember this: nutrient therapies often do not work because not all the pieces are in place. In other words, the different nutrients are highly interdependent, and a missing piece or two can sabotage the whole system. I personally believe that this is why a number of ADHD supplementation strategies do not work to their full potentials, because they are often missing key ingredients. Instead, for ADHD combination treatments to be effective, it is vital that we begin to understand all of the individual steps of nutrient metabolism and their affiliation with the disorder.

Just from this post alone, we have seen that carnitine has potential interactions with:

Omega-3 fatty acids
Vitamin E and other antioxidants
S-Adenosylmethionine (SAMe)
N-Acetylcysteine (NAc)
Magnesium
Glucose
Coenzyme Q10
Valproic acid (and other medications often used to ADHD or disorders which often show up alongside of it)

The point is, is that the various ADHD medications and treatment alternatives do not exist in a vacuum. One of the goals of this blog is to further elucidate the many interactions and factors at work in the different treatment strategies for ADHD. We need to consider all possible food-food, drug-drug, food-drug, food-supplement, drug-supplement and supplement-supplement interactions in order to tailor an effective treatment method for any individual. It is my belief that only then will we be truly able to see consistently effective individual treatments for ADHD and related disorders.

10 Ways Zinc can Combat ADHD

2009-04-12T20:57:00.008-04:00

Here are 10 reasons why zinc may be an effective treatment method for ADHD and related disorders:

Protection against oxidative damage of omega-3 fatty acids: We've previously discussed the role of omega-3's and their use as a treatment option for ADHD. However, the downside to this is that these fats (along with many others) are prone to oxidation. As a result, dietary antioxidants are needed to preserve these effects. According to a work by Villet and coworkers, zinc may be beneficial in retarding this omega-3 fatty acid oxidation process. As a result, zinc may be a good supplement to go alongside omega-3 treatment for ADHD.
Conversion of Vitamin B6 to its active form: We have mentioned the role of vitamin B6 and its role in the treatment of ADHD, including how B6 can work alongside another key nutrient, magnesium. Zinc is needed to convert the inactive form of the vitamin B6, pyridoxine, to the active form pyridoxal phosphate. Thus, zinc is needed in vitamin B6 metabolism.
Production of melatonin: Melatonin is a hormone we have also discussed earlier with regards to its effects on ADHD in an earlier post titled CREM gene, melatonin and ADHD. It appears that melatonin deficiencies may be attributed to a shortage of zinc. In short, melatonin plays a role in regulating the important neuro-chemical signaling agent dopamine, which is a key neurotransmitter involved in the symptoms and treatment strategies for ADHD.
Zinc can modulate or affect thyroid function, especially when melatonin is a factor: We have also discussed how thyroid dysfunction may closely mimic ADHD symptoms, and highlighted the importance of iodine to combat this . Now it appears that imbalanced melatonin levels may disrupt the thyroid. However, zinc may combat the negative effects of excessive melatonin on thyroid function. Combining this point with the previous one, we now see that zinc may be needed not only for the production of melatonin, but can actually be used to reel in this hormone when excessive melatonin levels lead to unwanted side effects such as thyroid dysfunction. Thus, it appears that zinc may play a role of double duty with regards to regulating melatonin production and curbing the negative effects of its excess.
Production of serotonin: This piggy-backs on the vitamin B6 role highlighted in point number 2 above. ADHD is often considered a disorder associated with the neurochemicals dopamine and norepinephrine. However, serotonin may also play a role in this disorder. For individuals who exhibit anxiety and depressive symptoms alongside their ADHD (which is surprisingly common), a serotonin deficiency is often partly to blame. Serotonin is synthesized in the body from the amino acid tryptophan. However, for this conversion process to go through, sufficient and functional vitamin B6 is required for serotonin to be formed by the tryptophan conversion process via a special type of enzyme known as aromatic amino acid decarboxylase. As previously mentioned, zinc is needed for functional vitamin B6, and therefore plays an indirect role in the synthesis of serotonin. Thus, zinc may be extremely important in individuals with ADHD and comorbid (co-occurring) depression or depressive-like symptoms.
Reduction of hyperactivty, impulsivity and antisocial behavioral symptoms: For direct treatment of ADHD, it appears that zinc may be more effective in treating the hyperactive/impulsive aspects of the disorder than the inattentive portion of the disorder. This study also noted the effectiveness of zinc for older children and children with a higher body mass index, which at least suggests that the effectiveness of zinc as a treatment for children with ADHD may increase as the child ages and grows.
Zinc may also play a role in the process of brain waves associated with ADHD as well as other disorders: We have already investigated differences and discrepancies in the brain wave patterns of ADHD children, including how these may actually be tied to an individual's genes. Information processing, which is often impaired in ADHD individuals, is believed to be tied to a brain pattern known as N2 (which is short for second negative wave, no need to concern ourselves with the exact details of this process here). Some research suggests that N2 mediated information processing may be negatively affected by zinc deficiency. This relates to unwanted attentional shifting (i.e. distraction) to irrelevant stimuli. In other words, N2 is related to the "novelty effect" of a specific stimulus or change in stimuli. As an interesting aside, N2 brain patterns are thought to be affected by serotonin, which, as mentioned in point #5, is indirectly tied to zinc levels. Based on this, it is at least plausible that zinc may play an integral role in this mechanism of distraction.
Boosting the effectiveness of ADHD medications: While we have reported on this in an earlier post on zinc and Ritalin, I believe it is worth repeating here. Multiple studies suggest that zinc can boost the effectiveness of methylphenidate for treating ADHD and related disorders. This may be of importance with regards to reducing some of the negative side effects associated with the drug. Many of these negative side effects often don't set in at the lower doses of the various forms of the drug, but instead, begin to appear with greater frequencies at higher doses. Taking this into account, it seems reasonable (at least in this blogger's opinion) that concurrent treatment with zinc may be enough to hold some of these methylphenidate dosages below the threshold of some of these negative symptoms, thereby increasing the tolerability of this common ADHD drug.
Zinc Inhibition of the Dopamine Transporter Protein: This may offer a further explanation as to why zinc is effective in boosting the effectiveness of methylphenidate. We have spoken extensively about the dopamine transporter (DAT) protein and its effects on dopamine levels and ADHD. Several ADHD medications, especially of the stimulant variety (such as methylphenidate), work by inhibiting or blocking DAT. It appears zinc may also act as a natural DAT inhibitor, thereby mimicking the effects of some of the more commonly used drugs.

In my previous post on zinc and its amplification of Ritalin's effectiveness, I wondered aloud as to whether zinc could be used as an outright substitute for the medication methylphenidate. While still a personal hypothesis, I still believe that for low level doses, zinc may be an ample natural alternative, but, this hypothesis obviously needs to be tested at a clinical level. Nevertheless, I personally believe it to be worthy of investigation.
Zinc as a possible treatment option for juvenile growth impairments: It is suggested that children with ADHD exhibit a delay in the overall growth process. We actually discussed this very topic in an earlier post titled: Do ADHD stimulant drugs stunt growth? Now it appears that zinc may possibly play a role in this. Using a primate model of zinc deficiency, Golub and coworkers found that zinc deficient monkeys showed a slowing of the growth process during what would normally be a period of growth spurt. If this translates into humans, then it is possible that underlying growth and attentional impairments, as well as abnormalities in activity levels (which is sometimes evident in children with ADHD, often more alongside those with the inattentive subtype of the disorder), may actually be due to zinc deficiencies.

Perhaps on an even more interesting note, the study found that "attention performance was also impaired before the onset of growth retardation". In other words, an attentional deficit may serve as a proverbial canary in the coal mine that a child may suffer from a subsequent delinquency in growth in the upcoming years. As a result, this blogger personally believes that some of these "attentional deficits" may not simply indicate an isolated case of ADHD, but rather serve as a warning of a much larger underlying problem that may be tied to a nutritional deficiency. Furthermore, it is at least possible that the underlying problem of attentional deficits and growth impairments in children with ADHD may be remedied by an intervention strategy that involves adequate dietary zinc or treatment via zinc supplementation.

This list of zinc levels and the direct or indirect relationships to ADHD is by no means extensive. Further connections, such as the relationship between zinc deficiencies and digestive disorders such as Crohn's disease, should also be noted. On an interesting note, a very recent publication came out evaluating the effectiveness of various nutrition supplementation strategies for treatment of ADHD listed zinc as the nutrient of most promise.

Given that zinc deficiencies are common in both Western countries such as the U.K., as well as developing countries such as China it seems evident that ADHD symptoms may be part of a larger picture, a proverbial cry for help due to a widespread nutritional deficiency. In addition to ADHD, other disorders dealing with cognitive development may be susceptible to zinc deficiencies. Of course, a great deal of further study is needed to back up this assertion, but it leads us to wonder exactly how often a case of ADHD is actually due to something as simple as a deficiency in zinc or another common nutrient. We will have further discussions regarding this important mineral in future posts.