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Monday, April 17, 2017

Methylphenidate Anxiety and ADHD How do they fit together

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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 OBrien 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 individuals 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 brains 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 its 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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