10 Ways Zinc can Combat ADHD

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

1. 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.
   
   
2. 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.
   
   
3. 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.
   
   
4. 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.
   
   
5. 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.
   
   
6. 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.
   
   
7. 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.
   
   
8. 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.
   
   
9. 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.
   
   
10. 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.

Ritalin and Cocaine: Similarities and Differences

We have previously investigated some of the similarities between the chemistry and modes of action of Ritalin and cocaine. In this past post, however, we looked more at the rates of uptake and metabolism of the two drugs and investigated a side-by-side structural comparison.

I was originally planning on continuing with posts on Daytrana, which is very similar to the more common ADHD medications Ritalin and Concerta (it is actually comprised of the same chemical agent, methylphenidate. However, I recently saw an interesting article on the topic of methylphenidate, cocaine and nicotine, and the mechanism of interaction between these different stimulants. As a result, in lieu of the Daytrana postings, I would like to discuss these findings in the next couple of posts.

Here are seven key points to be aware of regarding the similarities and differences between methylphenidate and cocaine:

1. SIMILARITY: Uptake patterns into the brain: Both methylphenidate and cocaine enter the brain at similar rates and target similar specific regions of the brain. When injected, around 7.5% of the injected compound makes it into the brain tissue for each compound at similar rates (peak uptake only takes around 2 to 8 minutes for cocaine and 4 to 10 minutes for methylphenidate in the injected form, oral administration, which will be discussed later, is significantly longer, especially for methylphenidate). The most favored target region of the brain is the striatum for both cocaine and methylphenidate (see brain diagram below). In fact, several studies have indicated that the two drugs share a number of target binding sites within the brain, to the point where the ADHD medication methylphenidate has actually been used as a treatment option for cocaine abuse.
   
   
2. Brain Regions Targeted by each drug: In addition to similar uptake patterns in the brain between the two drugs, there is a relatively large degree of overlap for particular brain regions targeted. However, there is at least one notable exception, which bears relevance to our discussion. On an interesting note, the method of delivery not only affects the speed of uptake of a drug (injected is almost always faster than snorted, which is almost always faster than ingested), but also the actual brain regions targeted by the drug. For example, another brain region, called the Nucleus Accumbens (see image below for approximate location) is targeted by cocaine and injected methylphenidate. However, when methylphenidate, such as Ritalin, Concerta or Metadate is taken orally, this nucleus accumbens region is not targeted (at least not anywhere near the level of injection).
   
   The nucleus accumbens is believed to play an important role in the addiction potential of a number of drugs, including many stimulant medications. Thus, proper use of the methylphenidate medication actually bypasses a key brain region believed to be critically involved in the "high" or addiction process of a stimulant drug. This highlights a major difference in the pharmacology between Ritalin and cocaine.
   
3. Key Difference between methylphenidate and cocaine: Rate of clearance from the striatum region of the brain: As mentioned in an earlier post, the addiction potential of a drug is typically correlated to the rate of exit or clearance from the brain. In other words, drugs that linger in the brain's receptors for extended periods of time are often much less addicting than ones which exhibit a short and rapid spike in their brain levels and then a quick drop-off in their concentration in the brain. In the striatum, the rate of clearance takes about 90 minutes for methylphenidate, and only 20 minutes for cocaine. If we go by peak concentration duration (i.e. the amount of time the highest concentration typically lasts in the brain before going back down), we see that methylphenidate's peak lasts around 15 to 20 minutes, while cocaine's is a fleeting 2 to 4 minutes. In both cases, the higher dissipation of the drug from high levels in the brain is much more pronounced in cocaine, giving this drug a much more addiction-worthy effect over methylphenidate (even when methylphenidate is abuses and either snorted or injected, it still cannot match the rates of clearance of cocaine).
   
   
4. Potency of the two drugs: The following may seem surprising at first. With regards to specific brain targets, methylphenidate is almost twice as potent as cocaine. We have discussed at length the role of the dopamine transporter protein (DAT), and its role in ADHD and related disorders. Essentially, this DAT protein is responsible for retaining a proper balance of the important brain chemical dopamine in and out of nerve cells. For individuals with ADHD, this balance is often skewed, typically with too much dopamine being taken up into the neuron cells and not enough in the gaps between the cells. Many stimulant medications remedy this problem by essentially binding to and plugging up the dopamine transporter proteins in the nervous system, which inhibits their abilities to shuttle dopamine into the cells. As a result of this medication-effected correction, dopamine balance can be somewhat restored. As a frame of reference, based on some of the current literature, it takes often takes at least a 60% saturation of these dopamine transporters with a drug to elicit the "high" (of course, there is a significant degree of variation between individuals).
   
   With regards to potency, we see that both cocaine and methylphenidate love to bind to these dopamine transporter proteins. To shut down the function of these dopamine transporter proteins to 50% of their original function (a common way of measuring the potency of a drug in pharmaceutical and laboratory testing), a 640 nanomolar concentration was needed for cocaine, while only a 390 nanomolar concentration was needed for methylphenidate to do the trick. If you're not familiar with these units of concentration, don't worry. These numbers work out to very small amounts (around the neighborhood of only 0.001 grams of drug per liter of fluid). I just put the numbers out there to show that only about half the amount of methylphenidate was needed to share the same effects with cocaine (i.e. the methylphenidate is approximately twice as potent for this particular process).
   
   
5. Difference between Ritalin and Cocaine: DAT saturation levels and perceived high: The relative saturation of these dopamine transporters are also believed to play a role in the "high" of stimulant drugs such as methylphenidate and cocaine. However, research by Volkow and coworkers found that while the level of saturation of the dopamine transporters with cocaine correlated with the "high" associated with this drug, the methylphenidate drug tells a different story. As mentioned previously, the reinforcing effects of a drug including the "high" typically correlate with the rate of clearance from the brain.
   
   We have also seen that methylphenidate clears much more slowly than cocaine. However, in the case of methylphenidate, the diminished effects of the the high occurred long before the drug had fully cleared from the dopamine transporter. In other words, there appears to be a relatively strong connection between the binding of cocaine to the dopamine transporter proteins and the perceived "high" but the effects are much less pronounced with methylphenidate. This highlights a major difference between methylphenidate and cocaine and at least suggests the possibility of a difference in mechanisms between the two stimulants.
   
   
6. Divergence in metabolic patterns between methylphenidate and cocaine: Furthering this issue a bit more, there is some evidence that the pathway of the two drugs is almost identical for the first part of the journey into the system, but their modes of action split off at some point when it comes to dopamine transporter occupancy and the corresponding reinforcement effects (see sketch below).
   
   
   
7. Difference between methylphenidate and cocaine: Drug lingering and tolerance: The persistence of methylphenidate on the dopamine transporter proteins may result in more than its reduction of abuse potential. It also appears that this "lingering" of the drug on these dopamine transporter proteins may also play a significant role in the phenomena of tolerance to methylphenidate.
   
   Acute tolerance to methylphenidate is nothing new. Newer formulations of the drug (Concerta, Metadate) were designed in part to address the problem of the reappearance of ADHD symptoms by ramping up and releasing increased levels of the drug throughout the day. This is important, because, the effects of methylphenidate appear to be best felt when its levels are climbing or building up, and not stabilizing (i.e. you do not want a constant level of methylphenidate throughout the day, but rather a constantly increasing one to maintain the same effects). Essentially, this is "micro-tolerance" to methylphenidate and is seen on a daily level. The ideal dosing strategy for methylphenidate typically entails a morning dosage which is approximately 50% of an evening dosage, i.e. a "ramping" effect of the drug throughout the day is often needed to maintain the desired results.
   
   It is suggested that this tolerance to methylphenidate may be due, at least in part to its continued presence and relatively slow clearance in specific areas, such as on the dopamine transporter proteins. Other faster-clearing drugs, such as cocaine, do not exhibit this property. However, given the fact that cocaine tolerance is also common, it is unlikely that the whole "dopamine transporter saturation" theory can fully address the issue of tolerance for stimulant drugs. Volkow and coworkers explored this role of blocking dopamine transporters with methylphenidate and the perceived high in greater detail. Nevertheless, at least in this blogger's personal opinion, the lingering effect of methylphenidate still plays some degree of significance to the process of tolerance to the drug, and the need for ramping its dosage to treat disorders such as ADHD.

Daytrana Absorption and Metabolism Patterns Compared to Ritalin and Concerta

In the previous post, we introduced the relatively new ADHD medication Daytrana. Composed of the same chemical compound as Ritalin and Concerta (methylphenidate), Daytrana offers the distinct advantage of existing in the patch form, which is typically worn on the hip. At the present moment, this medication is used exclusively for children with ADHD and related disorders, although it can also be used off-label for adults with the disorder.

Given the entirely different delivery system of the patch form of Daytrana vs. the conventional pill form of Ritalin and Concerta, the question arises on how the rates and patterns of drug delivery compare between the two forms of the medication. A copy of a table from the previous post, titled Daytrana Dosing Equivalents to Ritalin and Concerta is given below:

Patch size refers to the size of the Daytrana patch worn by the individual. The total content of drug per Daytrana patch (in milligrams methylphenidate) and rate of delivery (per hour) of the different patch sizes are also listed above. The standard wear-time for the patch is 9 hours, so a comparison in total drug dosage for a 9-hour period is also listed. Finally, equivalents to Ritalin (Immediate release, abbreviated "MPH-IR", the dosage listed is given 3 times per day, in milligrams), as well as Concerta (given once per day, also in milligrams) are also listed.

As far as total methylphenidate content delivered, the three methods of comparison are all similar. However there are some differences in rates of delivery, drug absorption patterns, and drug metabolism between the three different methods. A comparison, based on a report from Pierce and coworkers on the pharmacokinetics of the methylphenidate transdermal system (a technical term for Daytrana) is highlighted below. Please note that some of the data are supplemented from other similar studies on children with ADHD, so don't take these numbers as absolute. There is still a large amount of variation between the different studies. Nevertheless, these values are, to the best of this blogger's knowledge and current research, a good representation of values typically found in the literature (sometimes numerical ranges are given in lieu of exact numbers to reflect this). In other words, look at the numbers for comparative purposes instead of absolute values. The important thing to note below are some of the trends and comparative differences between the different forms of methylphenidate.

About the table above:

The columns going across include Immediate Release methylphenidate ("MPH-IR", similar to short-acting Ritalin and the like), Osmotically released methylphenidate (MPH-OROS, which is the drug form used by Concerta) and the four different patch sizes of Daytrana currently available ("DT" 10, 15, 20 and 30, which reflect the amount of methylphenidate delivered in milligrams to the body over the standard 9 hour patch-wear time of the 4 different patch sizes, listed in our first table).

For the first column, Max Concentration reflects the highest concentrations of the drug methylphenidate which are typically seen (again, don't scrutinize the exact numbers too closely, just look for trends across the chart). The next entry, Time to Reach Cmax, reflects the approximate amount of time after first taking the methylphenidate capsule or putting on the Daytrana patch for this maximal concentration to occur (in hours, again, an approximation).

Effectiveness is a more relative term, but it is based on how long the desired effects typically last (in hours) of each drug formulation. Again, experts and studies disagree, so just use these as relative guidelines. Finally, the term half-life is used as a measuring tool for how fast the drug is eliminated or cleared from the body. For example, a drug with a half life of 3 hours means that every three hours, the amount of drug remaining in the system is cut in half (used in a similar matter to how radioactive decay is measured).

4 important trends to note from the table:

For convenience, the same table is listed again below.

1. Higher drug concentrations from the patch form: Note that much higher plasma concentrations are typically seen with the Daytrana patch form of the drug than the other delivery system. This is likely due to the route of administration which bypasses several enzymes and other metabolic factors in the digestive system reserved for oral delivery routes. As a result, higher plasma concentrations can more easily occur. This is especially apparent in the two largest Daytrana patch sizes, where maximum plasma concentrations are close to double the levels attained via the traditional oral delivery methylphenidate medications for ADHD.
   


2. Greater time to reach high concentrations: The time to reach these high concentrations is greater as well. This is often an advantage, given the fact that stimulant medications which exhibit the greatest abuse potential typically enter the bloodstream (and, subsequently the brain), extremely quickly (often in 15 minutes or less), and then leave the brain and body quickly. As a result, while this more drawn out process (relatively similar to that of Concerta, but slightly longer), is good news for lower abuse potentials. However, the relatively long time to reach maximum concentration can be difficult for seeing the desired effects shortly after medication. However, given the higher apparent "ceiling" for these patch-style delivery systems, adequate drug concentrations are typically seen within 2 hours (data not shown). In other words, medication effects can be felt long before these high maximal concentrations occur.
   


3. Longer duration of effectiveness: The pharmacokinetics study of the methylphenidate patch for ADHD noted that detectable levels of the drug, when given in the patch form, were still seen in the blood the next day, up to 15 hours after the patch was removed (although only around 5% of the maximum concentration). Nevertheless, this 9-hour patch delivery method may prove useful in maintaining a constant presence of the medication throughout the day, and may extend the drug's effectiveness beyond even some of the longest-lasting oral methylphenidate forms. This may prove useful for individuals who still need to control for lack of focus and hyperactivity, such as a child with a big homework project. Of course, the flipside to this could be a greater potential for long term side effects, due to the constant persistence of the drug (keep in mind that this Daytrana system is only 2-3 years old, so long-term evaluations are still not available to any sufficient extent).
   


4. Similar rates of clearance: Perhaps the most consistent parameter across the board, it appears that the clearance rates of the patch and oral systems of methylphenidate all seem to hover around the three hour mark. This suggests that once the drug is actually delivered (albeit by a different delivery system), the rest of the metabolic processes are pretty much the same for the different forms of methylphenidate.
   
   
   

The enantiomer effect of Daytrana:
Before going, I just wanted to mention another peculiarity of the transdermal (patch-based) form of the methylphenidate delivery system:

Most methylphenidate medications are actually a mixture of two compounds of the same formula that exist as mirror images of each other. These mirror images are called enantiomers. While they have the same chemical formula and structure, the two different mirror image forms of the drug can behave entirely differently. In some extreme cases, getting the wrong enantiomer or mirror image of a drug can even produce disastrous side effects. For example, for the drug thalidominde, which was prescribed for morning sickness in pregnant mothers was actually found to have one safe enantiomer, but the other enantiomer, or mirror image resulted in severe birth defects. As we can see, this one minor change in drug shape can have huge repercussions if we're not careful.

In the case of methylphenidate, however, the effects of the differnt mirror images of the drug are much less pronounced. However, one of the two enantiomers (called the "d form") of the drug is much more potent or active than the other form. As a result, new formulations containing only the more "active" form of the drug began to develop. The drug Focalin (dexmethylphenidate) is an example of this. It has been demonstrated that Focalin can produce similar effects to regular methylphenidate at half of the methylphenidate dosage. We will save further discussion on this topic for later posts.

The reason I mention this enantiomer effect is that the two mirror images of the methylphenidate are metabolized and cleared at different rates. What is interesting is that the actual form of delivery for the drug (i.e. the patch for Daytrana, or the oral form for Ritalin or Concerta) actually affects the ratio or balance of the two mirror images of the drug after short periods of time.

To illustrate, consider the following:

• For Methylphenidate Immediate Release (Ritalin-IR), the "L" form (the less active form) is almost non-existent shortly after dosage is administered. That is, the "D" form (the more active form, or the mirror image which exists exclusively for Focalin), is the overwhelmingly predominant form of the drug remaining within a period of 1-2 hours.

• For Concerta (a slower releasing form of the drug compared to the immediate release Ritalin form of methylphenidate), the ratio is still skewed shortly after administration of the drug, with the "D" form: "L" form exhibiting a ratio of around 40:1 (after a few hours). Once again, the more potent form of the drug predominates shortly after the drug is given, and the less active form is more quickly cleared.

• However, with Daytrana, the "D" to "L" mirror image ratio of the drug is still in favor, but not by nearly the amount of the two oral delivery forms (Ritalin and Concerta). In the case of Daytrana, the "L" form stays around longer, sitting at about 55-60% of the more active "D" form of the drug. It is still unclear at the moment as to why this is, but some possibilities include the difference in enzymes and enzyme systems used to break down the drug between the skin and the digestive forms of delivery. Nevertheless, this blogger would not be surprised to see another patch form of delivery comprised exclusively of the more potent "D" form of the drug (as in a patch form of Focalin) on the horizon as an even more effective treatment for ADHD.

To summarize, Daytrana appears to be an effective alternative form of delivering methylphenidate for children with ADHD. Given the fact that the individual can now control two variables (patch size and wear time), it appears that this form of the medication may be easier to tailor to the individual than the oral form of methylphenidate.


We will continue our discussion about some of the other pluses and minuses of the Daytrana form of methylphenidate and how they relate to strategies of ADHD treatment in the next few posts.

Daytrana Dosing Equivalents to Ritalin and Concerta

Methylphenidate remains one of the most popular choices of medications for individuals with ADHD. However, the combination of dosing difficulties and negative side effects connected with oral administration left room for an alternate form of delivery: the methylphenidate transdermal delivery system, more commonly known as Daytrana. Currently, this medication is prescribed for children with ADHD and not adults, although it is sometimes prescribed off-label for adults with ADHD and related disorders.

If you are not familiar with Daytrana as a method of treatment for ADHD, you are not alone. It is a relatively new medication, introduced in 2006. It consists of the drug methylphenidate, the same chemical compound used in the more common ADHD medications Ritalin and Concerta. It is currently the only ADHD medication available in the patch form.

We will begin a series of posts exploring this new player in the world of ADHD, but I would like to start off with just providing a table of approximate dosing equivalents between Daytrana and the more common forms of methylphenidate, Ritalin and Concerta. A rough comparison, obtained from an article by Arnold and coworkers in the journal Pediatrics titled Treating Attention-Deficit/Hyperactivity Disorder with a Stimulant Transdermal Patch: The Clinical Art.

Please note that there are four different patch sizes of Daytrana currently available, which, based on the pharmacokinetics of a 6-12 year old child, correspond to four different doses of both the immediate release methylphenidate (note this 2nd-to last column corresponds to a Ritalin immediate release dose that given 3 times/day) and an osmotic-based release form of methylphenidate (Concerta). The patch is typically placed on the relatively inconspicuous location of the child's hip, and should be administered to the same site on a daily basis for consistency (different locations can actually affect the releasing dosage patterns of the patch)

Typical wear is for 9 hours, which is why the 9-hour dosing equivalents are given. However, the theoretical maximum dose per patch (which is the delivery rate times a 24-hour period) is also given. However, anything beyond a 9-hour dose is typically considered "off-label" use for Daytrana. These delivery rates of dosing for the different patch sizes are slower than the other forms of methylphenidate, as we will see in future posts. Nevertheless, I have included them to illustrate the patch size/dosing rate relationship for Daytrana. Note that the patch area and delivery rate follow a linear relationship, which is indicative of a uniform distribution of the drug across the surface of the patch which provides approximately 2.2 mg of methylphenidate content per square centimeter of patch area (over a 24 hour period).

We will be going into much more detail about the modes of action and functional differences of the Daytrana form of the drug methylphenidate (especially the differences between this patch form and the conventional "pill" form) as well as highlight some of the advantages and disadvantages of this new form of treatment for ADHD in the next few posts. Topics addressing the difficulties of an oral delivery system (we have hinted at some of the problems of food or drug metabolism and the ensuing consequences due to digestive issues such as celiac disease and ADHD symptoms) will also be discussed in the very-near future. In the meantime, a good overview of Daytrana, as evaluated by the FDA can be found here.

Methylphenidate vs. Atomoxetine ADHD Medications: Effects on Sleep

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

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

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

Methylphenidate:

Adult ADHD studies on methylphenidate and sleep quality:

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

ADHD, Methylphenidate and Sleep Quality in Children:

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

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

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

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

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

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

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

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

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

Methylphenidate vs. Atomoxetine: Comparative Effects on Sleep

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

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

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

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

Why the pronounced difference between the two ADHD medications?

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

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

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

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

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

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

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

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