Why the Menstrual Cycle may affect ADHD Medication Dosing Levels

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.

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Strattera (Atomoxetine) response may be affected by SLC6A2 gene

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:

1. An individual will even respond to particular drug (such as Strattera for ADHD), and
2. 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.

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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.

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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.

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Methylphenidate vs. Atomoxetine ADHD Medications: Effects on Sleep

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

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

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

Methylphenidate:

Adult ADHD studies on methylphenidate and sleep quality:

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

ADHD, Methylphenidate and Sleep Quality in Children:

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

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

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

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

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

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

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

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

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

Methylphenidate vs. Atomoxetine: Comparative Effects on Sleep

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

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

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

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

Why the pronounced difference between the two ADHD medications?

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

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

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

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

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

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

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

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

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2 Key Brain Regions Which Are Smaller in ADHD Individuals

We have previously held several different discussions about brain regions and ADHD. Some have hinted at reduced activity, often measured by lower bloodflow patterns either during resting states or mental challenge, while others have examined different patterns in brain waves and food allergy-induced changes in brain electrical activity. Still others have pointed towards gene-based lowering of chemical signals in key brain regions of ADHD individuals. Additionally, we have looked at articles dealing with alcoholism and the relative size of specific brain regions with regards to ADHD.

Adding to this growing body of evidence on the differences between brains of ADHD'ers and non-ADHD individuals is recent article by Ellison-Wright and coworkers on structural brain differences in ADHD individuals. We will be extracting some of the key findings of this meta-analysis (a review which combines and analyzes bodies of data amassed from a number of previous findings and publications and compiling it into a larger set of data to look for underlying trends and relationships). Here are 10 key points to take home from Ellison-Wright's findings (as well as from some of the other articles he cites in the analysis study):

1. An overall reduction in gray matter in the right putamen (shown in red) and globus pallidus (shown in blue) regions of the brain has observed in ADHD patients compared to controls. This is an underlying theme among multiple previous studies. The image below is of the human brain with the approximate regions of the putamen and right portion of the globus pallidus regions (the view is from the top down on a subject with the front part of the brain at the top and the back part of the brain at the bottom of the image).
   
   




2. Brain volume changes in two other regions, the frontal lobe and the caudate nucleus have been associated with genes related to processes of the key neurotransmitter dopamine. Please note that the frontal lobe has often been tied to ADHD, both through a decrease in size (in the prefrontal cortex region part of the frontal lobe, see below for details). Additionally, the caudate nucleus, actually combines with the putamen and globus pallidus to form a larger brain region called the corpus striatum (see diagram below). The approximate locations of the prefrontal cortex (brown), globus pallidus (blue), caudate nucleus (green) and right putamen (red) are shown in the image below. As in the image above, we are looking from the top down on an individual who is facing forward towards the top of this page.
   
   



3. Adding to this discussion, the article refers to a process in which the globus pallidus acts like a type of highway (the article uses the term "circuitry", but a highway or series of highways may be easier to visualize) between other brain regions, including the caudate and putamen regions. Therefore, the size and shape of this globus pallidus may play an even more crucial role with regards to ADHD and other related disorders, as multiple other brain regions can be critically dependent on it.
   
   
4. Many previous publications frequently study brain regions which are easier to study (i.e., ones that are less complex and easier to map and analyze than the smaller and more elaborately dense brain regions), often out of necessity. However, this selection process for sake of convenience can leave out several critical brain regions and sub regions which may actually play a critical role in the brain volume/ attentional disorders connection. At this point, it appears that we are just scratching the surface with regards to studies involving these key brain regions and ADHD.
   
   
5. ADHD seems to be more correlated brain volume imbalances due to decreases of specific brain regions, namely the putamen and globus pallidus (see diagram above), rather than relative increases in other brain regions. In other words, ADHD appears to be more of a "brain volume decrease-based" type of disorder, at least at the moment.
   
   
6. Further adding to the idea that the striatum region of the brain as a whole is another study done by Bush and coworkers, which have pinpointed this brain region as one bearing a significant role on the disorder of ADHD. The striatum is comprised of the putamen and caudate nucleus (on both left and right halves of the brain), and is shown in green in the diagram below:
   
   




7. Studies involving brain damage (such as those caused by impact or injuries to the brain) found a strong association between ADHD symptoms and lesions for both the right and back parts of the putamen region of the brain. It appears that reductions in these sub regions either due to lack of size or damage can elicit similar results which include an increase in ADHD or ADHD-like behaviors.
   
   
8. The basal ganglia (the odd "snail-shaped" region in the diagram below, which includes the aforementioned putamen, globus pallidus and caudate nucleus, as well as a few other sub regions we haven't yet discussed) is another key brain region which is believed to be involved in ADHD and other related disorders. The basal ganglia region of the brain essentially determine how fast a person's brain "idles". This region has often been found to be underactive in ADHD and similar disorders and overactive in obsessive compulsive or anxiety-related disorders. Thus the basal ganglia function can have some far-reaching implications. Not surprisingly, then, is the fact that mis-development in the "wiring process" of the basal ganglia (such as seen in the formative years), may play a crucial role on the onset of ADHD both directly, and indirectly (via interaction with other key "ADHD" brain regions).
   
   
   


9. Returning to the two main brain regions of investigation (the globus pallidus and the right putamen) for a moment, we see that these brain regions may also play a key role in governing the response to and effectiveness of potential ADHD medications.
   
   For example, a positive response to the ADHD stimulant methylphenidate (Ritalin, Concerta, Daytrana) may be influenced, at least in part, to the function of the right putamen region of the brain. According to this study, a higher level of bloodflow to the right putamen region (among a few others listed in the study), was significantly correlated to a positive response to the methylphenidate medication. In other words, a functionally active right putamen brain region may increase the odds of a child being able to tolerate their Concerta, while children with reductions or abnormally slow developments of the right putamen might be prone to less success with this type of medication. As of now, it is unclear if this brain region exhibits the same effects on other ADHD stimulants as well.
   
   
10. It is also likely that metabolic differences in the globus pallidus play a role in ADHD. A metabolic study involving the ratio of two types of "fuel" (creatine and N-acetylaspartate or NAA), which is often a good indicator of neuronal health in several key brain regions, found that individuals with ADHD had an abnormally low ratio of NAA to creatine. Taking this one step further is the topic of supplementation. Creatine supplements, often used by exercise enthusiasts, have been shown to boost levels of this nutrient to the brain as well, which can decrease the NAA to Creatine ratio (i.e., more creatine and less NAA). This brings up the hypothetical question as to whether creatine supplementation can actually exacerbate some of negative effects of ADHD by tampering with this desired ratio. We will actually be exploring the topic of creatine supplementation and its effects on the brain in another blog post in the near future.

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Do ADHD Stimulant Drugs Stunt Growth?

Here are seven questions or factors we need to address to assess the validity of studies on ADHD stimulant medications and their effects on growth:

1. Is there a history of prior stimulant medication use? Surprisingly, a number of studies on the inhibitory effects of ADHD stimulant medications either neglect or downplay the fact that children in their studies had a previous history of stimulant medication usage for their conditions. This can seriously confound effects, for if a child was taking a stimulant medication previously, he or she may still be on track for a lower baseline growth rate. Furthermore, if a child was taken off stimulant medications recently, there remains the possibility that his or her system is beginning to play "catch-up" by displaying a greater-than-normal increase in growth following a medication "holiday". In either case, baseline readings are skewed, and these effects muddy the accuracy of current stimulant medication studies on growth effects. Poulton and Nanan make this observation in their article on prior treatments with stimulant medication and growth in children with ADHD. They go on to say that growth is an accurate indicator of prior treatment with stimulant medication.
   
   
2. Beware of the pretreatment bias with regards to effectiveness of stimulant medications: Poulton and Nanan also warned about the natural bias of individuals with a previous treatment history of stimulants in that they have already proven to have a greater tolerance to potential side effects (otherwise they would have likely discontinued earlier stimulant treatments) and an overall higher levels of compliance and positive response to stimulant medications. This too, can give a potential "false positive" with regards to evaluating the effectiveness of current stimulant medication treatments for ADHD.
   
   
3. Do untreated children and adolescents with ADHD have different growth patterns than non-affected children? This is also a much-neglected consideration. Spencer and coworkers performed a study in which they saw a slower growth rate in the earlier years for children with ADHD, which was followed by a significantly later "catch" up period. In other words, compared to non-ADHD children, individuals with ADHD may be more predisposed to being "late bloomers", even when they are unmedicated. This potential difference in growth patterns between ADHD'ers and non-ADHD'ers, while still highly debatable, should at least raise the question as to whether delays in growth patterns for medicated individuals with ADHD can actually be attributed to the medications or to the nature of the disorder itself (or a combination of both).
   
   
4. Do "drug holidays" work? This is actually comprised of several questions and considerations. It is not uncommon for parents or prescribing physicians to allow for "drug holidays" for unmedicated ADHD children. These holidays can vary from a few days to longer periods such as an entire summer vacation. If the period of these drug holidays is long enough, such as in a summer-long study by Gittleman-Klein and coworkers on methylphenidate and growth, significant changes may be seen. This study saw a relative increase in weight but not in height following a summer off of medication of the stimulant methylphenidate (Ritalin). Of potential interest was the observation that following a second holiday from medication the following summer, a relative increase in height but not in weight was observed. It is entirely possible that the duration and frequency of drug holidays may effect the two parameters (height and weight) in slightly different fashions. Another article by Poulton suggests the possibility that height gains may take longer to remedy because gains in weight may drive subsequent growth in height.
   
   
5. Does the type of stimulant medication make a difference? In a preliminary sense, it appears that the answer would be "yes". For example, it appears that the stimulant drug dexamphetamine (d-amphetamine, also called by common name Dexedrine) has a greater inhibitory effect on growth during the first year of treatment than does methylphenidate (Ritalin, Concerta, Daytrana).
   
   
6. What is the typical extent of growth impairments due to stimulant medications? We need to be careful on this one, especially with regards to some of the earlier factors and considerations mentioned above. Nevertheless, a review of the literature seems to indicate a relative deficit in growth of around 1 cm per year for up to about 3 years which can be attributed to stimulant medication treatment. Furthermore, it appears that weight may be even more affected than height due to stimulant medication treatment, although it also appears that weight differences are easier to remediate than height differences and therefore pose less of a concern.
   
   
7. Are the growth changes due to stimulant medication temporary or permanent? Although hotly debatable, it appears that growth impairments due to prescribed stimulant medication usage is more of a short-term effect. A follow-up study of medicated ADHD children into adulthood indicated that even at moderately-high doses of the stimulant medication methylphenidate (45 mg/day average), medicated children with ADHD eventually reached normal final heights when compared to controls. It is worth mentioning, however, that these children eventually discontinued their medications. It is unclear as to what the effects may have been had they continued on with the methylphenidate usage into adulthood (especially since there has been a sharp trend towards continuing stimulant medication treatment into adulthood for adult ADHD).

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Ritalin vs. Cocaine: Addiction Potential of Methylphenidate

If you were to read the opening couple of pages of most natural or alternative treatment books on ADHD, you would likely find some version of the following argument: "Ritalin is chemically similar to cocaine and amphetamines and studies have shown it has a high addiction potential". There actually is a fair amount of truth to that statement, but the latter half leaves out some equally important information concerning the nature of these studies.

This post is not meant to be a pro-stimulant drug message, I certainly do see some apparent risks for many ADHD medications, especially concerning young children and their developing nervous systems. However, I also feel that we should carefully examine the nature of many of these "anti-methylphenidate" studies and evaluate the relevancy of their findings. To facilitate this discussion, I have taken data from a serious of research articles on the topic of habit-forming potentials of methylphenidate (Ritalin, Concerta, Daytrana, etc.) and have attempted to box together some of the overlapping information with relevant conclusions that are, to the best of my ability, as unbiased as possible. Here are some key points worth noting:

• Chemical similarity to cocaine and amphetamines. The chemical structure of methylphenidate is given below. As a comparison, the structure of methamphetamine is also given. I realize that the majority of readers here are not organic chemists, so I have highlighted the similar regions of the two molecules (which is a relatively big overlap as far as chemical structure and function is concerned). The purple/red regions below highlight chemically similar regions between the two drugs, while the green/blue areas show chemical differences. For brevity and simplicity, I have not included the structure of cocaine, because there are fewer obvious similarities between the chemical structures of methylphenidate and cocaine. Just realize that there are chemical and functional similarities between the two drugs.

• A huge factor in a drug's addiction potential rests on how fast the drug can both enter and leave the brain. In short, the faster the entry and the faster the clearance of the drug from the brain, the greater the "high" and the greater the addiction potential. We have seen this before in earlier posts, such as the one on Vyvanse for ADHD treatment. The chart below summarizes some of the key comparisons between methylphenidate and cocaine (most of the data comes from studies by Volkow and coworkers on brain entry and clearance times of cocaine vs. methylphenidate:

We can see from the chart above that cocaine and methylphenidate show similarly quick routes of entry into the brain when administered intravenously (note that this is not the typical route for taking methylphenidate for ADHD patients). However, note that the clearance time from the brain is significantly longer for methylphenidate than cocaine (half-life is a common measuring tool, which refers to the amount of time it takes for half the drug to clear the system). Also note that when methylphenidate is taken in the appropriate manner (orally), the time to arrive at a peak concentration (based on a mammalian model) is significantly longer as well. Both the longer clearance time and times to peak concentrations play a crucial role in reducing the involved "high" and addiction potential for methylphenidate, when compared to drugs such as methamphetamines and cocaine.

• The type of methylphenidate administered may also play a role in the addiction potential. There is a general trend towards prescribing longer-lasting sustained release versions of methylphenidate over the original immediate-release version (although cost is also a factor, with the longer-release versions typically carrying a higher price tag). At the 20 and 40 mg levels, one study showed that the immediate-release version of methylphenidate produced a higher degree of addictive level effects than the longer-release version, although this was based on more qualitative subjective measurements than hard, concrete numerical data.

• On somewhat of an interesting note, it appears that the reinforcing effects of methylphenidate may be much more pronounced in the case of sleep deprivation. One study indicated that methylphenidate only produced reinforcing effects when study participants were limited to 4 hours of sleep the previous night. Given the fact that sleep problems and disturbances are remarkably common in individuals with ADHD, this may actually lend a fair amount of support to potential for abuse among ADHD individuals. However, I personally believe that, based on the other points regarding individuals with ADHD, this population is still relatively "safe" from stimulant medication abuse when the medication is administered and taken in a proper manner.

• We have spoken extensively on the role of Dopamine Transporter (DAT) proteins and their role on governing levels of dopamine, a key neuro-signaling agent which is thought to be critically involved with regards to the onset and symptoms of ADHD. In short, DAT proteins are responsible for shuttling dopamine into and out of neuronal cells and maintaining an overall balance of this important chemical. Individuals with ADHD are thought to have more of these DAT proteins in their brain systems, which results in lower levels of dopamine in the areas between nerve cells, a phenomena which is commonly seen in cases of ADHD and related disorders. DAT proteins are therefore common targets of many ADHD stimulant drugs, which typically act by binding to these DAT proteins and reduce their shuttling effects, which, in turn, helps restore higher dopamine levels in these key regions between nerve cells. It is hypothesized that drugs, even at low doses (such as 20 mg methylphenidate) which bind to and saturate these DAT proteins may contribute to some of the "high" associated with these drugs. However, other findings have contradicted this, with regards to the role of the DAT proteins on "highs" associated with stimulant medications such as methylphenidate.

• Finally, in what may be the most important piece of the puzzle with regards to addictions and ADHD stimulant medications, there was a review done by Kollins which examined the nature of pre-existing studies on the abuse potential of methylphenidate. Kollins noted that a large number of the studies which suggested high addiction potentials for methylphenidate and related subjects gathered their data from non-ADHD individuals. This is important to note, especially considering some of the aforementioned differences between ADHD individuals and non-ADHD individuals with regards to chemical balances (such as the dopamine levels) and hard-wiring issues (such as a higher density of Dopamine Transporter Proteins or DAT's in individuals with ADHD). While this should not be grounds for immediate dismissal of these findings, the lack of studies on actual ADHD patients should raise some serious questions as to whether methylphenidate deserves its "guilty" label with regards to addiction potential. Of course, these studies provide ample evidence to support the assertion that ADHD medications such as methylphenidate can be abused if they are taken by the wrong individuals (non-ADHD patients, such as healthy individuals with few to no signs of ADHD as well as generalized drug abusers), but there appears to be an overall lack of evidence to support the claim that needy patients who do suffer from ADHD will turn into stimulant abusers if they begin to take methylphenidate at prescription-based levels.

• Kollins does conclude with some more relevant (at least in this blogger's opinion) concerns surrounding the use of methylphenidate for ADHD. He questions the impact of methylphenidate and related drugs with regards to:

1. Their impact on brain development, especially in young children (a topic in which there is still relatively little conclusive data available).
2. How dopamine level changes due to these medications may alter the dopamine system, including the levels of dopamine transporter proteins (DAT proteins).
3. The role of early stimulant exposure on latter stimulant abuse (although Kollins notes that early treatment with appropriate stimulants may actually have a protective effect against latter stimulant abuse).

For the most part, I am in agreement with this line of thinking. It is my opinion that we should shift our focus away from the fears of addiction potentials with regards to stimulant medications taken via appropriate doses and methods for ADHD and related disorders, and instead shift our attentions to the effects of these substances on the developing nervous systems of young children. We have seen that methylphenidate has several built-in safety measures with regards to reducing its abuse potential. Furthermore, I personally believe that there are much greater potential risks of stimulant medications with regards to their effects on the critical early neural developmental stages (such as those in the first 5 years of life) than to overall addiction potentials of these substances, and that our research focuses with regards to overall safety of these medications should shift in this direction.

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Cost Effectiveness of ADHD Treatments

In the previous post on the economic impact of ADHD, we examined some of the eye-opening numbers attached to the disorder of ADHD and its impact on society. We reviewed 4-5 publications on the subject, most of which attached an annual price tag of several thousand dollars to the direct and indirect costs of the disorder on individuals with ADHD and their families. These factors included loss of productivity at work (which can be up to almost a full month of the year less than non-ADHD counterparts), medical expenses from the disorder itself, as well as from the increase in risk-taking behaviors of ADHD patients, additional educational expenses, loss of work time for family members, and the increased cost of treatment for substance abuse (which is also much higher in ADHD individuals).

It is important to take these numbers and figures with a grain of salt, and see them more as projections as opposed to actual hard, concrete figures. However, they should begin to give us at least a ballpark estimate of the economic impact that ADHD has on our society. The natural question which should flow from this information is: what is the actual cost of treating ADHD? While the treatment options for ADHD vary immensely from individual to individual and treatment to treatment, a study by Jensen and coworkers has sought to investigate the approximate cost-effectiveness of different ADHD treatments. A summary of this study can be found here. I will highlight some of the key points from the article:

• Cost-effectiveness for ADHD treatment was studied in four different areas: medication treatment, behavioral management treatment, a combined medication/behavioral treatment, and community care-based treatment (this last one would include things like juvenile justice programs, community mental health services, etc) . These data were based off of an original 1999 study on children with ADHD called the MTA Cooperative Group.
• Treatment "effectiveness" was determined by the ability of a particular treatment to bring a child's behavior to a "normal" level. An outcome of "normal" was determined by using a cutoff score determined by a special psychological scale called the SNAP scale, which assigns numbers to behavioral improvements in multiple categories, and is determined by parents, teachers and clinicians. Although somewhat subjective in nature, this scale has been a good indicator of tracking improvements with regards to the disorder of ADHD.
• Different scenarios of ADHD with regards to comorbid (co-existing) disorders were also analyzed. These included both internalizing comorbid disorders (anxiety and depression), externalizing comorbid disorders (which include conduct disorders or oppositional behaviors), as well as a combination of both types of comorbid disorders.
• Costs were determined by average consulting fees of psychiatrists, psychologists and behavioral therapists from the American Medical Association Socioeconomic monitoring system surveys, the approximate costs of prescription drugs based on wholesale prices and common markup values (often around 40%), and wages of behavioral support staffs.
• Out of the different treatment methods available, medication alone provided the most bang for the buck, as far as the most cost-effective measures go. Behavioral therapy was found to be exceedingly costly in terms of its relative effectiveness, and in some cases, actually limited some of the improvements in the overall symptoms. Thus, from a strictly economic standpoint, medication treatment appears to win out as the most cost-effective treatment for ADHD.
• Interestingly, it appears that for children with more internalizing ADHD comorbid symptoms (anxiety and depression), the behavioral treatments were not only more costly, but reduced the overall effectiveness of the medication treatment option, when compared to the medication option alone. This was a bit surprising, and suggests, that behavioral therapy should be considered more for externalizing symptoms (such as oppositional behavior or conduct problems) than for internalizing ones.
• This report was not meant to knock the effectiveness of behavioral treatment for ADHD, it just sought to investigate the cost-effectiveness (or lack thereof) of this type of treatment. However, if cost is not a factor, a combined medication/behavioral treatment program led to much higher rates of "normalizing" childhood behaviors, especially in children who exhibited both internalizing and externalizing comorbid disorders. In other words, for children who have ADHD, anxiety or depression, as well as some type of oppositional behavior, combining medication with therapy can be much more effective than treatment via either medications or therapy alone. However, based on a cost-effectiveness model, for those on a tight budget or with limited resources, the medication treatment option still wins hands-down.
• It is also important to note that community-based care programs, while largely inexpensive, often, unfortunately, have little effectiveness in treating ADHD with or without these side disorders, even though medication managements and behavioral measures are often utilized. This suggests the importance of specialization of professionals outside of basic community resources for dealing with and treating these disorders, which, unfortunately, often carries a heftier price tag. However, the approximate increase in costs of medication management alone (including the cost of a qualified diagnosing professional outside of the typical "community" environment), was relatively small in comparison to the community care model. This again, supports the evidence of the cost-effectiveness of a predominantly medication-based treatment.
• The ineffectiveness of community-based care was explained in part by the relatively lower levels of dosing for medications as well as less follow up (community care physicians often followed up only twice per year in the study, while the individuals on the non-community care based medication treatment plan often got monthly visits).

I realize that some of these findings are confusing to interpret. There were sections of the paper which were difficult to follow at times, but I would just like to hammer home a few personal points with regards to my thoughts on the article:

• Given the pinch most of us are feeling with the economic situation, we want to seek out the best treatments possible for the dollar. Based on this study, it appears that treatment with medication is by far the most cost-effective option.
• If money (or insurance) is less of a problem, there are advantages to utilizing behavioral treatment methods for ADHD. However, based on the findings of the above study, it appears that behavioral treatment on its own is still largely cost-ineffective.
• The one exception to the above point is if a child exhibits both internalizing (anxiety, depression) symptoms and externalizing symptoms (oppositional behaviors or conduct issues) along with his or her ADHD symptoms. It appears that, based on the results of the study listed above, that a combined medication and therapy treatment may be advantageous, although the price still jumps once behavioral management treatments are introduced.
• I realize that the idea of "drugging" our children is inherently wrong in the minds of most individuals. While I personally have a natural bias against this treatment method, I have written extensively about the relative safety and lack of risk factors for most ADHD medications out there today. Given the fact that many of us are feeling the pinch economically, medication treatment is often the only cost-effective option to most people, and this study indicates how cost-effective this treatment method really is.
• By no means is this post meant to downplay the vital role of community-based programs and treatment options out there, for a number of individuals, these programs have been extremely beneficial. Additionally, I know that a number of children exhibit wonderful behvioral changes with regards to their ADHD and related disorders. Nevertheless, the purpose of this review was to simply investigate the cost-effectiveness of these treatment options, and, on the whole, these resources often provide less bang-for-the-buck than medication treatments.
• Finally, I acknowledge that this is just one major study, and that to attach an unquestionable certainty to these findings would be irresponsible. However, we should note that, from the previous post, that the cost of untreated ADHD poses as an enormous economic threat to our society. As a result, all of the measures addressed in the passage above offer at least some degree of advantage over leaving ADHD and its comorbid disorders untreated.

If I can find enough quality studies on the topic, I may post further discussions on the cost effectiveness of different specific medications for ADHD in the near future. In the meantime, we will be returning to more hard-science based articles for the next several posts.

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Reboxetine for ADHD Treatment

In previous blog posts, I have mentioned some unconventional and lesser-known medications used to treat ADHD. Many are either new to the market or have primary uses not designated as ADHD drugs, such as anti-depressants, mood-stabilizers, anti-convulsants, etc. Unfortunately, these results are often obscured or hidden from the general public. The medical community (somewhat understandably) often initially shies away from these studies because they are often done on a small scale, have less-rigorous built-in-controls, are not done by big-name researchers, are studied in foreign countries, and are published in less-prominent journals. What is often surprising is that the results of treatment with these less-publicized medication choices, is that, although small and somewhat isolated in nature, a number these studies have displayed eye-opening levels of success, and should warrant further investigation.

The beauty of being a blog-writer, as opposed to a highly-publicized journalist, is that one can take more of a "chance" by reporting some of these findings, without feeling pressured to stick to the more "mainstream" findings.

Without further ado, the drug of topic for today is Reboxetine.

Like many ADHD drugs, Reboxetine (also marketed under labels such as Solvex, Prolex, Vestra, Davedax, Edronax or Norebox). It's main line of treatment is for depressive and panic disorders, but has also shown solvency in the treatment of ADHD on a small-scale. Like many other ADHD medications, Reboxetine exists as a mixture of two compounds, which are mirror-images (also called enantiomers), of each other. It is used in a number of European countries, but is yet to be approved in the United States.

Functionally, and to a lesser-degree, chemically, Reboxetine resembles another common ADHD medication, Strattera (Atomoxetine). Unlike many types of anti-depressant medications, which often target the key neuro-signaling agent serotonin, Reboxetine's primary target is another major signaling compound known as norepinephrine. Norepinephrine, a chemical "cousin" to adrenaline, is often found to be at lower-than-normal levels in the surrounding environment outside neuronal cells in individuals with attentional and depressive (in addition to other related) disorders. Essentially, there is an imbalance in the amount norepinephrine inside and outside the cells on the nervous system. Reboxetine functions as a "blocker" of the process of taking norepinephrine up into neuron cells, which helps restore the balance of this neurotransmitting agent inside and outside cells in the nervous system.

This selective restoration of balance concerning levels of norepinephrine serves other benefits as well. For example, disorders such as fibromyalgia and chronic pain are associated with norepinephrine level imbalances. Based on multiple case studies, it appears that reboxetine can help alleviate at least some of these pain-related symptoms. Attentional deficits are often (perhaps, not surprisingly) a secondary symptom of pain-related disorders, so this is of some therapeutic value already. Additionally, migraine headache pain is also a common comorbid symptom of ADHD. However, there is more...

One of the most difficult issues surrounding drug design is specificity. We naturally want the drug to reach its desired target in the body. However, it is often difficult for a drug to reach only its specific target and avoid all other undesired ones. Unfortunately, this is not always possible, and one of the main consequences of a drug's lack of selectivity is unwanted side effects. In the case of Reboxetine, however, it appears that its overall degree of affinity for unwanted targets (often referred to as receptors in biological terms) is less than many other comparable medications. In other words, Reboxetine is less "promiscuous"; it has minimal interaction with target receptors for other neurotrasmitters such as acetylcholine (which can lead to digestive dysfunction, and is partly responsible for the dry-mouth and constipation symptoms found in many drugs) and serotonin (which can lead to drowsiness and other sedative effects).

Returning to the specific topic of ADHD, however, Reboxetine has shown to have some other advantages over other ADHD medications.

• Reboxetine is long-lasting. Reboxetine's plasma half-life is around 13 hours (that is, it takes around 13 hours for half of the drug to be cleared and eliminated in the body). In comparison, atomoxetine (Strattera) has a plasma half-life of around 4 hours.

• It serves as a good "back-up" treatment for ADHD as a medication. While stimulants remain the drug class of choice for ADHD, roughly 30% of children with ADHD show little response to stimulant medications. Based on findings from a recent study, children with previous adverse effects to methylphenidate were able to handle Reboxetine. In addition, based on a side-by-side comparison study of Reboxetine and methylphenidate, the Reboxetine performed equally well with its counterpart as far as reducing ADHD symptoms.

• While some medications have shown to be effective in treating the predominantly inattentive symptoms of ADHD or the hyperactive-impulsive symptoms of the disorder, Reboxetine appears to improve symptoms of both. Based on a study of boys ages 6-16 of the Combined subtype (that is, they show significant levels of inattentive as well as hyperactive and impulsive symptoms), treatment with Reboxetine showed significant improvements based on parent ratings in as little as 2 weeks.

• In addition, Reboxetine has shown some success in treating conduct disorders, which are often comorbid to (or occur alongside of) ADHD. In this case, the disorder was called hyperkinetic conduct disorder, which is very similar to ADHD, but with more severe behavioral issues and a greater probable genetic component.

• While specificity in choice of biological targets appears to be an advantage of Reboxetine, it also appears that Reboxetine can also boost free dopamine levels in the prefrontal cortex region of the brain (which is a region thought to be highly-connected to ADHD). Dopamine is another highly important agent used in signaling throughout the nervous system and its cells, and is intricately connected with ADHD in the prefrontal cortex region of the brain (which is located behind the forehead). Reduced levels of dopamine in between nerve cells in this important region of the brain (like the lower levels of norepinephrine described above), typically results in an increased onset of negative ADHD symptoms. These effects are thought to be more indirect, as norepinephrine carriers can also transport and clear dopamine from the areas in between neuron cells. However, if these carriers are tied down or "busy" handling the Reboxetine, then these carriers are less available to shuttle away the free levels of dopamine in this critical brain region. As a result, a gradual build-up to more "normal" levels of dopamine are seen, which often results in a reduction of ADHD symptoms.

Other interesting points of note regarding Reboxetine:

• As mentioned above, Reboxetine was rejected by the FDA in the United States, although it has been used widely in over 50 other countries. The reasons for its rejection by the FDA have not been disclosed in full to the general public.

• While the study mentioned above cited the effectiveness of Reboxetine treatment for some children who had experienced adverse side effects with methylphenidate, around half of the children in the study who showed negative side effects to methylphenidate also saw similar effects to Reboxetine (although many were more mild than for methylphenidate).

• While Reboxetine does not target serotonin receptors like many other antidepressant medications (which can cause sedative effects), drowsiness is still one of the more common side effects of the drug. Additionally, treatment with Reboxetine can also lead to appetite suppression, which is a common side effect of stimulant medications used to treat ADHD.
  

• While dopamine is the main agent of concern in the prefrontal cortex region of the brain with regards to the disorder ADHD, norepinephrine levels in this brain region are thought to be connected to oppositional behavior. While this study used atomoxetine for treating these symptoms (albeit in a rat model), it leaves the door open for investigation of treatment with atomoxetine or reboxetine for both ADHD along with comorbid conduct disorders such as Oppositional Defiant Disorder (ODD, which is actually quite common in ADHD individuals).
  

• Reboxetine is metabolized mainly in the liver, using an enzyme called CYP3A4. Several other drugs and food compounds also utilize this enzyme system. This is important because when two or more drugs or food-substances share a similar pathway, there is a much greater potential for these substances to interfere with each other. The result is often impairments or drug-drug interactions. For a comprehensive list of other types of drugs and compounds which also use this enzyme system, please click here. Although not emphasized in the previous link, I personally found it interesting that the compound quercetin was a strong inhibitor of this enzyme system. Quercetin is found in high concentrations in foods such as onions, teas, apples, and berries, many of which are touted for their numerous health benefits such as cardiovascular health and antioxidant properties. While no significant studies (at least to the best of this writer's knowledge), have been done on the effects of quercetin and the drug Reboxetine, there is a strong possibility that high levels of consumption of these healthy antioxidant-rich foods may actually interfere with the metabolism of Reboxetine and potentially alter its effectiveness in treating ADHD or related disorders.

In spite of a number of positive findings surrounding the drug, there is still a shroud of mystery (much of which is due to the FDA rejection of the drug in the U.S.) over the effectiveness of Reboxetine for treating ADHD on a large scale. Given the fact that its main function is that of an antidepressant, it would appear that functionally, Reboxetine would be useful for treating individuals with ADHD and comorbid depression (in a way somewhat analogous to drugs such as Wellbutrin).

Nevertheless, some of the promising results surrounding the drug suggest a potential for treatment of comorbid conduct disorders. This may serve as a potential all-in-one approach, as opposed to being prescribed multiple drugs for multiple co-existing symptoms. The versatility of this drug is intriguing, especially when we consider the relative specificity that Reboxetine has almost exclusively for the signaling agent norepinephrine.

Given the fact that this class of antidepressants appears to bypass the serotonin-dependent pathways, it is possible that this drug could be used in conjunction with other anti-depressant drugs as well, with a reduced potential for negative drug-drug interference.

Finally, due to its comparatively long half-life, and potential interference from foodstuffs such as quercetin, there is an increased risk of unwanted buildup and possible side effects associated with toxicity issues surrounding the drug. Nevertheless, there is room for further exploration, especially in the context of approaching ADHD treatment from a different angle than most stimulant medications. This is definitely a drug to keep on the radar for the near future.

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