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

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

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

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

• Prevalence of Enuresis in ADHD: Enuresis refers to urinary incontinence which is limited to the night-time. Additionally, the term is typically limited to individuals over the age of 5 (i.e. a 3-year-old child who frequently pees in their pants would not be considered as suffering from enuresis, at least in the context of this study). The article cites other studies in which the rate of bedwetting (enuresis) in ADHD is as high as 30%, although other studies have it down around 10-20%. Still, compared to the general population, (factoring in things such as the age of the child, of course)the high rate of bed wetting in ADHD is especially noteworthy. There is some evidence from other studies that ADHD and enuresis may be more intricately linked than previously imagined. For example, one particular study has shown that treating urinary incontinence has a higher rates of failure in children with ADHD vs. non-ADHD children.
  
  
• The role of Oppositional Defiant Disorder (ODD) on Bed wetting: The study examine several different psychiatric disorders which frequently occur alongside of (or are comorbid to) ADHD. These include depression, anxiety disorders, obsessive compulsive disorders, tic disorders, nail biting, bruxism (teeth grinding), conduct disorders and oppositional defiant disorders. However, out of all of these different disorders which often appear alongside ADHD, the only one which exhibited a statistically significant correlation to increases in bedwetting was oppositional defiant disorder. Interestingly, oppositional defiant disorders have been associated with bedwetting in other ADHD studies.
  
  As its name suggests, Oppositional Defiant Disorder is a disorder in which a child exhibits disobedience, irritability and hostility towards authority figures beyond the range of normal age-appropriate behaviors. Of course there is a significant gray area with regards to what is age appropriate, especially when the child's environment is considered. Nevertheless, Oppositional Defiant Disorder (or ODD) is much more than just routine temper tantrums. Oppositional Defiant Disorders may also be associated with auditory processing issues and ADHD. It is somewhat interesting that anxiety disorders, which have also been correlated to oppositional behaviors, did not elicit a significant positive correlation to bed wetting.
  
  
• The autonomic nervous system as a potential underlying cause of ADHD, bedwetting and Oppositional Defiant Disorders: The autonomic nervous system is the part of the nervous system responsible for involuntary muscle actions such as digestive processes, blood vessel contraction, etc. It is subdivided into the sympathetic and parasympathetic nervous systems, which often act in a sort of "push-pull" opposition to each other. For example, the sympathetic nervous system does things such as boosting heart rate and constricting blood vessels, while the parasympathetic nervous system is in charge of activities such as reducing heart rates and relaxing sphincter muscles (which plays a role in bladder control).
  
  Typically, the sympathetic and parasympathetic components of the nervous system are kept in balance, but this balance may be thrown out of whack and result in numerous disorders. For example, it is believed that the parasympathetic nervous system is over dominant in cases of Oppositional Defiant Disorders (ODD). The study found that for ADHD and Oppositional Defiant Disordered children, functions such as heart rate were controlled excessively (if not almost exclusively) by the parasympathetic portion of the nervous system (while non-ODD and non-ADHD children had both sympathetic and parasympathetic controls operating on their heart rates. This suggests a common underlying imbalance among the different components of the nervous system which is common to ADHD and ODD individuals and often separates them from the non-ADHD'ers. Interestingly, other studies have indicated that bedwetting or generalized incontinence problems may also be caused by an overactive parasympathetic nervous system, which suggests that ADHD, ODD and night-time bedwetting may all share some underlying causes within the nervous system.

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

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

Excessive Talking as a Potential Methylphenidate Side Effect

Methylphenidate (Ritalin, Concerta, Daytrana) is one of the most common stimulant medications prescribed for ADHD. However, there have been several questions as to its side effects. Studies have been conducted on the effects of methylphenidate which include excessive talking, cardiac abnormalities, hallucinations, bruxism (teeth grinding), movement disorders, psychotic and manic-like symptoms, appetite suppression, and temporary weight and growth reduction.


Please note, however, that this list above is not meant to scare anyone off of this medication. While some side effects appear to be relatively common and well-grounded (such as appetite suppression and temporary growth impairment), many of these side effects are relatively rare, and the results are often based on isolated studies with poor reproducibility. To be fair, methylphenidate has been subject to a number of tests, with the vast majority supporting the claim that it is a relatively safe medication (provided one uses it appropriately as prescribed).

Furthermore, previous entries of this blog have dismissed the notion that methylphenidate carries an addiction potential on the level of cocaine or illegal amphetamines (a claim often erroneously made by many of the anti-medication crowd. Keep in mind that I personally do share many of the same concerns of these groups, but likening a controlled prescription drug with multiple addiction-reducing features to illegal street drugs is both irresponsible and does the overall argument on ADHD medication concerns a disservice in my opinion). Nevertheless, some of the above associations, while limited in scope and supporting data, do seem intriguing. For this post, I would like to briefly assess the results of the first unusual side effect of methylphenidate on the list, the surprising link between methylphenidate and excessive talking.


Before we proceed, we must bear in mind that this association is based on a single case report, and not a controlled clinical study. For those unfamiliar with the differences between the two, a case report is essentially a report of one (or a few) individuals, who exhibit particular symptoms, often in response to a particular medication or treatment strategy. While these reports lack the statistical power and overall scientific magnitude when compared to tightly-controlled clinical studies involving large sample sizes, we should not be quick to dismiss these findings. Individual anomalies, while often statistically small, do offer insight into some of the idiosyncrasies of medication and other forms of treatment, and involve real individuals (who are often in a more "natural" setting than those in clinical trials).

Given the recent advances in genetic studies and innovations in imaging and computational power, we appear to be at the dawn of a medical revolution, in which medication and treatment plans are becoming increasingly tailored towards individuals rather than groups or the general population. I personally believe that because of this general trend, individual case studies will begin to carry more weight and validity among the medical community than they have previously.

While not my intention to digress from the topic of today's post on methylphenidate and excessive talking, I did want to state some of the potential implications of the data accumulated from one particular individual. With regards to the study, here were some of the key findings and observations:

• The case involves a 5-year old Iranian boy who was prescribed methylphenidate (10 mg per day) for extreme hyperactivity and impulsive behavior, two key symptoms of ADHD. Treatment with this dose of methylphenidate produced significant improvements in both impulsivity and hyperactivity.


• Approximately 45 minutes after taking the medication, both parents and teacher reported a sharp increase in excessive talking. These results continued for 3-4 hours, which approximates the duration of effectiveness of methylphenidate (immediate release formula).


• Most interestingly, perhaps, was the apparently direct association between methylphenidate intake and hyper-talkative behavior. The study reported that methylphenidate treatment stopped and was reintroduced on over 20 different occasions within a 7 month period. In all 20 plus cases, the hyper-talkative behavior resumed when methylphenidate treatment was reintroduced. The magnitude of the difference, between talking behavior on and off the medication, while subjective, was significantly pronounced. On a 1-10 scale (done by parents and teachers, with 10 being the highest), the child's talking was around a 2-3 when off the medication and a 7-9 while on it. This extremely high frequency of association and pronounced behavioral differences between methylphenidate and excessive talking strongly attributes the abnormal behavior to the medication.


• The study gives several potential explanations for this association between behavior and medication. For example, methylphenidate, which regulates free dopamine levels and dopamine-related neural function, was shown to regulate word production in individuals with schizophrenia.


• Additionally, methylphenidate has been used to restore talking in patients treated with anesthesia.


• Finally, methylphenidate has been shown to effect the striatal region of the brain (see below, original file source here), which has a regulatory effect on cognitive motor functions, including talking patterns.

The striatum region of the brain (shown in green in the figure above), which has been shown to have a response to methylpenidate, and may be an underlying reason for the connection between methylphenidate and excessive talking.

As mentioned above, we should obviously not put too much stock into one case study on the potential connection between the unusual side effect of excessive talking in response to methylphenidate. However, based on the severity and consistency of the association for the individual and the underlying theoretical basis of the association based on the results of other studies, we should not overlook the observations of this particular study. Furthermore, given the effectiveness of methylphenidate for reducing hyperactive and impulsive ADHD symptoms for this particular child, the fact that excessive talking behaviors (which can be a sign of ADHD-based impulse control problems) suggest the possibility that the methylphenidate treatment may have an effect on shifting the outward expression of symptoms of an underlying ADHD condition such as impulsivity. As a result, a number of questions should be raised on the basis of this study.

Increasing Concerta Medication Dosage: Benefits and Risks

In the last post, we introduced the concept of dosage windows for ADHD medications. In other words, we see that the dosage level of an ADHD medication can be of equal importance to the type of medication used. For more info on this topic, please check out the blog site of Dr. Charles Parker called CorePsychBlog. It is extremely well-organized, concise, and easy to follow, in my humble opinion. This is where I was first introduced to the "window" concept of medications, the term which I have borrowed for the last couple of posts.

This post is meant to expound on the dosage principle in the context of on of the more popular ADHD stimulant medications currently on the market, Concerta (slow-release methylphenidate). We will be drawing information from a few key articles, including one from the 2003 Journal of Pediatrics by Mark A. Stein and coworkers. A copy of the original online journal containing a summary of this article can be found here.

If you do not have time to read all of this post, feel free to skip to the last paragraph at the bottom of the page to get the overall message of this blog entry. If you are looking for more detail, I have addressed the key points made in this article in the major points below:

• The drug Concerta releases the active methylphenidate ingredient into the system at slowly increasing levels over roughly a 12-hour period. The overall effect is similar to that of the traditional tri-daily methylphenidate medication.

• The article studied the positive and negative effects of this medication in 5 to 16 year-old children under three different common prescription doses, 18, 36 and 54 milligram doses. These children were of average or above-average IQ, with about 1/3 being diagnosed as Learning Disabled. About two-thirds of the children had never taken any type of stimulant medication for ADHD before the study.

• Noticeable differences were seen between different ADHD subtypes. For the Inattentive subtype, lower levels doses were optimal, while for the Combined subtype (inattention plus impulsive behavior plus hyperactivity), higher amounts were typically optimal. When the effects of co-occuring disorders such as oppositional defiance (ODD) and learning disabilities were factored out to focus in the ADHD itself, the subtype differences were even greater. This underscores the need for proper subtype diagnosis as opposed to just labeling an individual ADHD.

• For the Primarily Inattentive (PI) subtype of ADHD, the inattention difficulties improved most dramatically with the first 18 mg of medication. Beyond this dosage, only slight effects were seen. This is in agreement with another earlier study which analyzed different doses of another form of methylphenidate for treating ADHD. For the accompanying hyperactivity and impulsive behavioral symptoms (which are often present in the inattentive subtype, just not at the same elevated level of the Combined subtype) were most effectively reduced with the first 18 mg of the medication. While the effectiveness of higher doses leveled off, slight but noticeable improvements were also seen as medication dosage was increased from 18 to 36 mg. At 54 mg, however, improvements stopped or even regressed. This suggests that the "sweet spot" for the Inattentive Subtype of ADHD is somewhere around 18 mg (or slightly higher). Note that Concerta is also available in the 27 mg level, a dosage which was not tested in the study.

• In contrast to the Inattentive Subtype, where the greatest gains were seen from 0 to 18 mg of Concerta, for the Combined Subtype of ADHD, the greatest overall boost in effectivness was seen between 36 to 54 mg. Based on the trends of the graphs in the paper, as well as data from other studies, it appears that doses beyond 54 mg may still be of benefit for several individuals with the combined subtype. In other words, treatment of individuals with the Combined ADHD Subtype typically requires at least 18 mg more medication than those of the Inattentive Subtype (see note at end of the post for an important caveat and exception to this).

• Negative side effects of the medication were minimal at low (18 mg) to middle (36 mg) doses. However, beyond 36 mg, these negative side effects became more pronounced.

• Sleep problems (such as insomnia) began at the 36 mg dosage for Concerta, with the most pronounced effects seen in younger and smaller children.

• Noticeable appetite suppression was seen even at low doses (from 0 to 18 mg), especially for younger and smaller children. However, the overall severity of this was limited. However, the percentage of children who experienced "severe" appetite suppression dramatically increased between 36 to 54 mg treatments of Concerta.

• At 36 mg, the presence of or increase in tics (see related post on ADHD and tics) was seen, and a further increase was seen for some children at the 54 mg dosage.

• None of the dosage levels corresponded to blood pressure increases, and only minimal increases in pulse rates were seen. Compare this to another post on the cardiovascular risks of ADHD stimulant medications.

• A much earlier study on the ADHD medication methylphenidate (an earlier non-Concerta form) suggested that while hyperactive behavior continued to improve at higher doses, the ability to perform cognitive tasks decreased at higher levels of medication. While these effects were difficult to duplicate in future studies, it does suggest an upper limit for certain medications in which going above may lead to a reduction in improvement. We have seen similar effects in previous posts (see the "upside down U curve" in point #6 for tyrosine and clozapine treatment for ADHD here as an example).

A caveat and final blogger's note: Based on the conclusions of the study, it appears that going above the 54 mg limit may be beneficial for certain individuals of the Combined Subtype. While the data of the study may support this, it is important to note that the study only lasted 3 weeks. As a result, long-term effects of high doses of medication were unable to be observed. Additionally, we saw in one of the points above that negative side effects began to creep in at the 36-54 mg level. Based on other blog posts with regards to risk factors of certain ADHD medications as well as potential medication side effects, I urge you to err on the side of caution, especially on issues concerning young and small children (who are at much greater risk for developing severe side effects). In the above study, the highest dosage (54 mg of Concerta) was omitted for the smallest study participant as a precautionary measure.

A quick overall summary of this post: It is imperative that we take ADHD subtype seriously. The take-home message of this blog post should be that lower doses of methylphenidate are often optimal individuals with the Inattentive subtype for ADHD, while those of the Hyperactive-Impulsive (not studied in the above journal article) and Combined subtypes of ADHD typically require significantly higher levels of medication.

ADHD Medication Dosage Windows

Blogger's note: I was first introduced to the concept of a "window" in the blog of Dr. Charles Parker. I highly recommend it. A link to his site, CorePsychBlog, can be found here. I would like to borrow his "window" analogy, as I think it is a very relevant description for what is going on here.

We have spent quite a bit of time discussing the different medications for treating ADHD. Recent attention has been given to methylphenidate (Ritalin, Concerta, Daytrana) treatment. While the choice of drug is extremely important for treating ADHD, there is often a less discussed, but equally important, factor for medication treatments: the actual dosages used. Of related interest is the timing effect of ADHD medications. If you are interested in the need for proper timing for ADHD medications, please visit the site here.

In treatment areas such as homeopathic medicine, we see that specific volumes and concentrations of the desired compounds are essential for the effectiveness of the agent used. In these treatments, treatment effectiveness depends on extremely low concentrations of the treatment agent being used.

While there are stark differences between standard ADHD medications and homeopathic remedies, it is important to realize one common overlapping factor the two treatments often share is overdosage is countereffective and often harmful. While this seems inherently obvious, it is important to note that "overdosage" here can refer to even a slight excess of medication, and is not limited just to exceedingly high amounts.

Going one step further, we even see that specific ADHD medications actually have completely different modes of action and completely different effects when taken at different dosage levels. For example, a 15 mg dose of Ritalin may not only be "overkill" for a patient who should be taking the 5 mg dose, but the extra 10 mg may actually offset or even counteract the benefits derived from the first 5 mg. We have seen similar effects in previous posts such as the one on tyrosine and clozapine. With regards to the medication and amino acid combination treatment, we see that tyrosine supplementation boosts the effectiveness of clozapine to a certain point, but beyond this point, excess tyrosine is counterproductive. Essentially, tyrosine supplementation follows an upside down "U" curve (see bullet point #6 in this post).

This same effect can also be seen in medications, especially when minimizing negative side effects is a concern. In other words, the ADHD medication dosage window is often extremely small. Given the fact that multiple other factors including diet, sleep patterns, other medications, co-existing conditions and health of the patient, etc. can all interfere with medication effects, it is no wonder that even at the right prescription doses individuals frequently shift between "on" or "off" days for medication-controlled treatments. In the next post, we will be examining the effects of different doses of the ADHD medication methylphenidate (Concerta).

Do ADHD Medications Cause Birth Defects?

ADHD Medications and Pregnancy

Do ADHD Medications Cause Birth Defects?

Due to the impulsive tendencies of adults with ADHD (currently thought to be as high as 4% of the general adult population), one would expect higher rates of unplanned pregnancies among this subgroup of the adult population. This is, in fact, often the case. As a result, it is worth investigating whether women with ADHD, who are often on medications are posing hazardous risks to their babies by taking these drugs during pregnancy. Although this area of ADHD medications and birth defects has not been studied extensively, here are some following observations and guidelines to go by:

Since some of the most common primary forms of ADHD medications are amphetamine-based stimulant drugs (such as Adderall), it is necessary to mention the fact that amphetamine usage during pregnancy has been shown to correlate with a reduction in birth weights of these children. However, other factors of growth, such as head size or birth length were unchanged, and the birth weight reduction amounts were often significantly less than a pound compared to newborns of non-users of amphetamines (or less than a 5% difference on average). Another relatively large study done primarily on the stimulant dextroamphetamine (Dexedrine), showed no significant difference in birth weights or the prevalence of birth defects.

For medications such as methylphenidate (Ritalin, Concerta), which is not an amphetamine but rather and amphetamine-like stimulant, no significant evidence has shown any connection to birth defects or lower birth weights. However, one study in which the mothers had taken methylphenidate alongside alcohol, cigarettes and other drugs showed higher rates of birth defects, mental impairments and reductions in birth sizes. However, this study had no adequate group of controls, so the effects of the ADHD drug itself could not be determined. Nevertheless, we must leave room for the possibility that this type of stimulant may worsen birth defects triggered by other maternal patterns of substance abuse.

Some other ADHD medications have not been explored in depth in human mothers, but have been investigated in other mammals. For example, in a study done on the non-stimulant ADHD medication Atomoxetine (Strattera) in pregnant rats, it was shown that weight reduction, impaired bone development, and lower offspring survival rates were tied to high levels of this drug. Of course, this was done on a different mammalian system at doses up to 30 times higher than the recommended optimal levels for humans (on a pound-for-pound basis). An even higher relative dose done on rabbits was shown to interfere with development of the circulatory system with the offspring. However, these levels were shown to be significantly over the relative toxic level of the drug in humans.

As a quick side note, I should mention that a small fraction of the population carries an uncommon form of the genetic region CYP 2D6, which, among other things, is connected to the metabolism or breakdown of the Atomoxetine drug. Individuals with this rare form (which can be determined by genetic screens), may be somewhat more at risk than their counterparts. However, individuals with this genetic form would often exhibit adverse effects to the medication early on, and would likely be placed on a different medicated treatment option.

Based on the overall dearth of information involving ADHD medications and pregnancy, we cannot arrive at any definite conclusions about their relative safety in pregnant or nursing mothers. However, if the connection between these medications and birth defects was significant, the results of some of the aforementioned studies would likely have been much more foreboding. As a result, the use of controlled and prescribed medications at appropriate doses are unlikely to pose any sort of major threat in pregnant or nursing mothers. Nevertheless, certain drugs, although much less common as primary modes of treatment for ADHD can be utilized if potential pregnancy or birth defects are a concern.

Medications such as Bupropion (Wellbutrin), have been shown to be useful in treating some forms of ADHD and may be especially effective for individuals who also suffer from depression or those who want to quit smoking. Unfortunately, one of the negative side effects of this medication is that it can increase the risk of seizures (for more information on ADHD and seizures, please check out this earlier post). Nevertheless, aside from some of these potential risks, it appears that Bupropion poses a noticeably smaller role than most stimulants in triggering birth defects.

Additionally, the drug Clonidine, which has shown to be effective in treating ADHD in several cases (especially those cases in which an ADHD comorbid disorder such as Tourette's Syndrome), is also less likely to cause birth defects than stimulants. Clonidine, which also goes by the brand names Catapres and Dixarit, is also used as a treatment for hypertension and can also be used in conjunction with stimulant medications to treat ADHD individuals. This is often done because of the sedative effects of the drug, which, when administered strategically before bedtime, can help calm things down a bit by offsetting the stimulant effects of other ADHD medications. One major caveat with Clonidine, however, is that sudden withdrawal or discontinuation of the drug can cause a rapid and dangerous spike in blood pressure. If Clonidine is to be discontinued, the individual must be gradually weaned off the drug to avoid these negative and harmful side effects.

It is my hope that some of this information will serve as good news to pregnant or soon-to-be pregnant individuals with ADHD. While the information contained here should never be a substitute for personal medical advice, I want you to leave with the fact that, at least as of now, the overall risks of birth defects or complications remain relatively low for most ADHD drugs. This is especially true when other non-prescribed chemical substances are avoided.

ADHD medications and Pregnancy