In the past, we have investigated several different ADHD genes, or genes that are believed to play some type of role in the disorder of ADHD. A recent article, titled CREM mutations and ADHD symptoms suggests that another specific gene, called CREM (short for Cyclic Adenosine Monophosphate Responsive Element Modulator), may actually play an integral role in the onset of ADHD and its symptoms as well.
Before we go any further, we must bear in mind that the journal in which this article is located is titled Medical Hypotheses. As the name suggests, we should be careful not to confuse hypothesis with thoroughly-investigated scientific data. However, the arguments are typically well laid out, and many of these hypotheses are in fact well-grounded based on a number of well-researched facts which point in their directions. In other words, a number of scientific studies or findings are often preceded by publications of these hypotheses, so we could very well be at the cusp of a new scientific discovery.
A second point worth mentioning is that the CREM mutation article is actually based on the mouse model. This in itself is not unusual, as numerous other studies on ADHD have used analogous murine models, such as the spontaneously hypertensive rat (SHR) model. Numerous comparison studies have supported the validity of SHR as a relevant and accurate model of ADHD in humans (although a few studies have disagreed, these disagreement studies are relatively small in number, however). Furthermore, based on the high degree of similarity between the DNA sequences in the human and mouse CREM genes, there is also a potentially high degree of functional overlap between the two. As a result, it is highly possible that CREM gene findings in the mouse may carry over well into CREM gene studies in humans. Additionally, mice with mutations in the CREM gene have been shown to exhibit ADHD-like behaviors.
Location of the CREM gene:
If you are not familiar with human genetics, the human genome typically has 23 different chromosomes (which come in pairs, so 46 chromosomes total), which are numbered 1 through 23. Scattered out through these 23 different chromosomes are some 30,000 to 50, 000 total different genes (the number is constantly in debate, but this is typically a good estimate), which means that the average chromosome will typically carry between 1,000 to 2,000 different genes on it. Further numbering and lettering schemes denote more specific locations of these genes on the chromosomes. In humans the CREM gene is located on the 10th chromosome. For a more detailed look at the specific location of the CREM gene, please click here.
The association between CREM function and ADHD:
The CREM gene is believed to play a significant role in regulating the secretion of the hormone melatonin throughout the day. Melatonin, which is chemically similar to another key hormonal and neuro-signaling agent serotonin (serotonin actually converts to melatonin in the body), plays a number of roles, such as the regulation of sleep patterns. Melatonin is typically secreted by a specific gland called the pineal gland. For most individuals, lower levels of melatonin are produced during daylight, while higher levels are produced during darkness, which leads to the feeling of sleepiness. Furthermore, emotional states such as chronic stress can also effect melatonin production and secretion.
The CREM gene is believed to exhibit a controlling mechanism on the melatonin secretion patterns throughout the daily process. However, mutations or deletions (i.e. removal) of the CREM gene can result in a number of changes, such as different melatonin secretion patterns and excessive movement (locomotion) and activity at night. In other words, day/night differentiation is typically reduced if mutant or lower-functioning forms of the CREM gene are present.
The connection to ADHD:
Numerous findings suggest that individuals with ADHD are prone to differences in genes which regulate key chemicals in the neurosignaling process (as well as their receptors, or biological targets to which they bind). These include serotonin, dopamine and norepinephrine. Melatonin levels are also typically different in individuals with ADHD, and these ADHD individuals are more prone to daytime sleepiness due to oversecretion of melatonin. Furthermore, several studies indicate that individuals with ADHD are more prone to sleep disorders and abnormal sleep patterns in general, although a number of other studies have indicated conflicting results to this assertion. As a result, the melatonin regulating activities of CREM may be at work as underlying factors to these melatonin-related sleep disorders.
The role of ADHD medications on regulating melatonin levels:
Abnormal melatonin levels (caused by CREM mutations or other factors) may be able to be offset by common ADHD medications. For example, methylphenidate (Ritalin, Concerta, Daytrana), has been implicated as a potential agent in correcting sleep disorders in children with ADHD. This is somewhat interesting, because it contradicts numerous other findings in which stimulant medications have been shown to interfere with sleep.
**Blogger's note: While there are a number of studies regarding impaired sleep quality due to ADHD stimulant medication, we must remember that strategic timing and lower dosing of stimulant medications can significantly reduce the number of sleep-impairments. Most of the sleep problems, at least in my opinion based on personal experiences, are due to the administration of medication doses which are too high and given too late in the day. Although outnumbered with regards to the current number of publications for or against it, I personally side with the assessment that methylphenidate, when administered at the proper dose and the proper time for real ADHD cases, is actually beneficial for promoting and regulating sleep patterns. Again, I want to reiterate that this is simply my opinion based on personal observations and research.
The CREM mutations and ADHD symptoms authors referred to a small study they did on the effects of methylphenidate on lowering melatonin levels. Based on these (extremely limited) findings, it is possible that melatonin regulation via methylphenidate treatment may be a contributing factor to the drug's effect on sleep performance. However, we should be careful not to put too much stock into this finding, since melatonin levels are highly variable among individuals (i.e. comparison of absolute melatonin concentrations between individuals is often ineffective, and intra-individual fluctuation of melatonin levels occur throughout the day anyway).
While the hypothesis that the CREM gene (which, as mentioned, is located on the 10th chromosome in humans) may play a significant factor in regulating melatonin levels and affecting ADHD behavior is predominantly theoretical at this point, I personally believe that this possible connection is at least worth mentioning. Additionally, potential gene/medication interaction studies may emerge, such as studies involving different methylphenidate dosage requirements based on the different CREM gene mutations. We have discussed analogous gene/medication interaction studies in previous posts such as the one entitled ADHD Genes Influence Medication Dosage . We should remain on the lookout for future studies on the possible connections among these different areas.
Friday, February 27, 2009
In the past, we have investigated several different ADHD genes, or genes that are believed to play some type of role in the disorder of ADHD. A recent article, titled CREM mutations and ADHD symptoms suggests that another specific gene, called CREM (short for Cyclic Adenosine Monophosphate Responsive Element Modulator), may actually play an integral role in the onset of ADHD and its symptoms as well.
Friday, February 20, 2009
We have spoken extensively on some of the related or comorbid disorders associated with ADHD ("Comorbid" here refers to an accompanying disorder that frequently occurs alongside ADHD. These may include disorders such as depression, Tourette's Syndrome, allergies, substance abuse problems and the like). The topic of this post is to investigate whether there is a pronounced gender effect on these comorbid disorders; in other words, whether boys and girls are more prone to a particular disorder comorbid to ADHD based on their gender. As we will see later, age and ADHD subtype effects are also important factors with regards to comorbid disorders.
Much of this info was taken from an article titled Gender Differences in ADHD Subtype Comorbidity by Levy and coworkers. Here is a summary of some of the main points in the study:
- Approximately half to over three quarters of ADHD children carry some type of comorbid behavior disorder. These include oppositional defiant and conduct disorders, learning disabilities and communication disorders (including speech and reading difficulties). Additionally, many exhibit anxiety disorders such as generalized anxiety disorders or separation anxiety disorders.
- Additionally, ADHD has traditionally been separated into three different forms or subtypes: inattentive, hyperactive/impulsive, or combined (a combination of the other two subtypes). All three subtypes are heavily skewed towards the boys, which outnumber girls from anywhere around 2:1 to 5:1 (some studies skew this gender difference even higher, up around 10:1). Based on the study by Levy and coworkers, here is an approximate distribution (numbers indicate overall percentages among the study population, which includes non-ADHD individuals) among the prevalence of the three subtypes for both genders:
- Of the three subtypes listed above, it appears that the subtype (again, perhaps not surprisingly) most associated with comorbid disorders (listed in the first point) is the combined subtype.
- There appears to be a discrepancy between the genders as far as internal/external symptoms of ADHD and related disorders. Some studies have suggested a general trend in which many of the symptoms or problems of girls with ADHD and related disorders are more internalized (i.e., they do not outwardly manifest themselves as readily as boys), which may contribute to the skewed gender differences mentioned above. On the contrary, the same study suggests that external or outward symptoms are more apparent in boys, which may compound this effect.
- Reading disabilities are, perhaps not surprisingly, more common in children with ADHD. It appears that reading disabilities correlate more to "internal" symptoms in girls and "external" symptoms in boys with ADHD, however, reading disorders appear to have very little overlap with conduct or oppositional behaviors such as aggression or delinquent behavior. Furthermore, reading difficulties appear to be more related to the inattentive side of the disorder of ADHD than the hyperactive/impulsive side of the disorder. In other words, the inattentive and combined ADHD subtypes are significantly more likely to have problems with reading than the exclusive hyperactive/impulsive subtype for both genders. It appears that reading difficulties and inattentive behavior may have an even stronger correlation in girls.
- Furthermore, with regards to reading and speech disabilities, there is a strong gender difference for non-ADHD individuals. However, once the disorder of ADHD is introduced, the gender difference becomes less of a factor (this holds for all three ADHD subtypes). This may at least suggest, that ADHD symptoms may override or overpower what appears to be more subtle gender differences with regards to speech and reading disorders.
- There is a significant association between generalized anxiety disorders and ADHD for both genders. Gender differences for the combined ADHD subtype were especially pronounced, with rates among females with the combined ADHD subtype being significantly higher than the combined subtype males. In addition, the combined subtype was more associated with generalized anxiety for both genders (when compared to the inattentive subtype), which suggests that hyperactivity/impulsivity may play some sort of role in generalized anxiety for both genders.
- With regards to separation anxiety disorders (such as from parents or loved ones), it also appears that there is a higher correlation to girls with ADHD, especially with regards to the inattentive ADHD subtype. For boys, the separation anxiety disorders were highest for the combined ADHD subtype. The study suggested that separation anxiety disorders may be a sign of immaturity for both genders, and may be indicative of later "internalizing" problems in girls. Furthermore, this assertion is in agreement with several studies which associate ADHD with a delay in maturity.
- Based on the two findings above, in which girls with the inattentive ADHD subtype had higher rates of separation anxiety disorders and girls with the combined subtype having increased rates of generalized anxiety disorders (both of which are considered more "internal" symptoms) than their male peers, it may be suggest that screening for ADHD in girls who exhibit anxiety disorders may be beneficial, in that it may reveal underlying comorbid ADHD and offset some of the skew among gender differences and ADHD.
- Finally, age has been shown to be an important factor with regards to symptoms and severity of ADHD comorbid disorders. In this study, comparisons were done between the younger (ages and and under) and older (ages 11 and older) children in the study population. For males, the prevalence of most of the comorbid disorders (speech and reading difficulties, oppositional defiance, generalized and separation anxieties) decreased with age, with the notable exception being conduct disorders, which increased with age. For females, age was less of a factor for all of the comorbid disorders listed above with the exception of Separation Anxiety Disorders, which decreased with age (supporting the earlier assertion that this disorder is tied to maturity levels and would naturally decrease as a child gets older). In addition, inattentive symptoms associated with ADHD actually increased with age for the female population of the study. This was the exception to the overall trend of decreasing ADHD symptoms with age, which was seen in the other two subtypes for females and all three subtypes for males.
In addition, it appears that girls may have a higher prevalence of the more "internal" comorbid disorders such as anxiety, which are often more difficult to detect than the more outward comorbid disorders of oppositional defiance and conduct disorders. This may play a major part in the gender discrepancy of ADHD diagnosis, which may leave a number of girls with ADHD undiagnosed and untreated.
Additionally, the more "internalized" nature of female cases may also lead to a lack of diagnosis and treatment for comorbid disorders associated with ADHD as well. The Levy study pointed this out, citing the discrepancy between referrals for ADHD-related reading disabilities. Reading disorders for boys were more likely to be associated with some of these outward characteristics, while girls with reading disorders exhibited more of the aforementioned "inward" traits. As a result, the rates of referral for boys with reading disabilities (based on their overall representation in the population) was almost twice that of girls.
Furthermore, this study by Levy, as well as several others, indicate that there are several (sometimes unusual or counter intuitive) associations between gender, and ADHD subtype and the expression of symptoms of specific comorbid disorders. For example, attributing an increase in Separation Anxiety disorders to younger females with the Inattentive ADHD subtype or Conduct Disorders to the Combined ADHD subtype in males may give us some possible insight as to which subpopulations of ADHD children are most "at risk" for developing some of the aforementioned comorbid disorders.
Since several of these comorbid disorders carry their own lines of medication and other treatments, the subclassification of ADHD children based on age, gender and subtype may be especially beneficial with regards to developing successful individualized treatment plans. I firmly believe that by separating out and subcategorizing ADHD and its comorbid disorders based on factors such as age, gender and subtype whenever possible could lead to a new a wealth of information for diagnosing and treating ADHD and its associated comorbid disorders.
Thursday, February 19, 2009
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.
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.
Monday, February 16, 2009
There is a relatively strong connection between ADHD and drug abuse, with nicotine being one of the most common types of "self-medication". It is believed that ADHD and nicotine addiction share similar neural pathways, although there still remains a fair amount of debate as to the exact underlying mechanisms at work between the two conditions.
One topic of equal intrigue may be the relative effects of withdrawal from nicotine in ADHD vs. non-ADHD individuals. If smoking and ADHD do share overlapping neural pathways, then we might expect that cessation of smoking may have different effects between people with and without ADHD. According to a recent study by Kollins and coworkers on ADHD and smoking abstinence, individuals with ADHD have a much wider array of behaviors with regards to reaction times to specific stimuli and cognitive processing. In other words, smokers with ADHD who temporarily give up nicotine have a greater variety (and hence less predictability) with regards to concentration-related tasks than do non-ADHD smokers. A more detailed explanation of this study follows:
- Giving up cigarettes and other forms of nicotine has a wide range of negative effects such as working memory, attention, and the ability to control or inhibit ones' responses. However, these effect typically subside when one resumes original smoking behaviors. As a result, based on the negative side effects due to decreased cognitive function, quitting smoking can result in a number of disadvantages with regards to brain function.
- Many previous studies have shown that individuals with ADHD are more prone to some of these disadvantages, especially with regards to slower reaction times to external stimuli when abstaining from smoking. This may be one of many reasons why smoking is more popular among individuals with ADHD than within the general population.
- For example, using a special computerized test called Conners Continuous Performance Test, to test for reaction time, comparison studies were done between ADHD and non-ADHD smokers under conditions where they were allowed to smoke and conditions where they were required to abstain from smoking (typically starting the previous night before the morning Continuous Performance Test. Briefly, the test consists of pressing a specific key on a computer keyboard when any letter (except for "X") flashes on the computer screen continuously for a period of approximately 15 minutes. If the letter "X" were to appear on the screen, the test subjects were instructed not to press any keys on the keyboard. Reaction times and accuracies were based on these behaviors.
- However, based on the study by Kollins and coworkers on smoking abstinence and ADHD, there is a relatively significant amount of evidence that the above point may not entirely be true. Based on the results of their study, Kollins and coworkers suggest that the average impairment with regards to reaction times during smoking cessation may actually be less for most ADHD smokers when compared to non-ADHD smokers. For example, when deprived of smoking, the reaction time of highest frequency for ADHD smokers was somewhere around 0.3 seconds, while the non-ADHD group was slightly slower (but still significant and measurable), hovering around 0.35 seconds. However, the ADHD group is also more likely to have a few individuals who are prone to lengthy delays in reaction times (as in multiple seconds). Kollins instead attributes this to attention lapses in which the individuals concentration was broken. In other words, it appears that while the majority of individuals with ADHD smokers may actually have faster reaction times than non-ADHD smokers, ADHD smokers have more extreme cases of reaction time delays due to attentional lapses, especially when deprived of nicotine. Therefore, by separating out the "common" cases from the more "extreme" cases in their study, Kollins and coworkers may have uncovered this underlying trend.
- There are several possible causes for these potential attentional lapses due to smoking withdrawal. One may stem from a brain region called the cingulate gyrus, whose approximate location is shown below (region #7, for orignal file source, click here) on the diagram.
The actual area is a specific subsection of this region, but we will not go into the detail here. This region, the cingulate gyrus (#7), is in some ways analogous to a gear shifter in a car. If this brain region is underactive (think of a loose gear shifter), then an individual often bounces around from one thought, idea or focus to the next, which is a common characteristic of ADHD. Lapses in attention have been attributed to subsections of this cingulate region. On the other hand, generalized overactivity in this brain region often leads to excessive fixation on a particular topic, idea or behavior (think of it as pushing too hard on a gear shift and getting stuck in a gear). This latter condition is often seen in dysfunctions such as obsessive compulsive disorder (OCD). With regards to our topic of discussion, Kollins suggests that this brain region may be the culprit for increased attentional lapses in ADHD smokers.
- Kollins and coworkers also found that when the smokers are "satiated" (i.e. allowed to smoke their desired amounts leading up to the reaction-time test), the ADHD smoking group also had relatively faster reaction times when compared to the non-ADHD smoking group. The ADHD smoking group also had a greater variability in reaction times (i.e. more "extreme cases" or extra-long response times) during satiated conditions, but the differences in variation between these "extreme" cases of ADHD and non-ADHD groups' reaction times were less pronounced than during the nicotine abstinence trials.
- Finally, it may seem strange that the majority of ADHD smokers appeared to have faster reaction times both with and without smoking. What is even more interesting is that in the nicotine-deprived state, most of the ADHD smokers actually showed a slightly faster reaction time than in the nicotine-satiated state (although the extreme cases of multi-second attention lapses were also greater). One potential explanation of this may be due to the increase in impulsive behaviors, where the individuals attempted to "guess" or predict when the designated letter flashed on the screen (see the previous point about the nature of the Conners Continuous Performance Test). This would be in agreement with fact that nicotine, which is a stimulant and a common form of "self-medication", may help curb impulsive behaviors in ADHD individuals.
- A final take-home message from this study is that it highlights a relatively common and important trend which we must often consider when dealing with ADHD: studies of ADHD groups which deal with response or reaction times have shown data which is more skewed with a higher variability (and hence a lower predictability) than comparative non-ADHD groups. If study sample numbers are small, these highly variable measurements can sometimes throw off the data and lead researchers to the wrong conclusions. In other words, when doing comparative studies between ADHD and non-ADHD individuals, we must be careful to consider these higher degrees of variability and unpredictability in the ADHD groups and factor these in to our calculations and conclusions accordingly. I will be touching on other cases where we see this significantly greater levels of variability and unpredictability in ADHD in future posts.
Saturday, February 14, 2009
Due to a high degree of overlap in symptoms with other disorders, finding accurate ways of differentiating ADHD is of utmost importance. Based on a recent study by Romanos and coworkers, it appears that individuals with ADHD may be able to "sniff out" their disorder. In a publication on Improved Odor Sensitivity in ADHD, Romanos and others found that children with ADHD had significantly better sensitivity for particular odors when compared to their non-ADHD peers. In other words, children with ADHD may be able to better detect minute or trace levels of certain smells when compared to other children. As an interesting aside, the study noted that boys actually had a slight advantage as far as odor detection when compared to girls (which goes against many other study findings which indicate that females have better senses of smell).
Friday, February 13, 2009
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:
- 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.
- 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.
- 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).
- 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.
- 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).
- 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.
- 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).
Thursday, February 12, 2009
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:
- Their impact on brain development, especially in young children (a topic in which there is still relatively little conclusive data available).
- How dopamine level changes due to these medications may alter the dopamine system, including the levels of dopamine transporter proteins (DAT proteins).
- 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.
Tuesday, February 10, 2009
In the past, we have investigated the role of the COMT gene and its effects on the onset and severity of ADHD cases. Now it appears that this gene may play a role not only in the ADHD itself, but conduct or behavior disorders which often occur alongside (or are comorbid to) of ADHD.
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.
Monday, February 9, 2009
Since the economy seems to be on everyone's mind these days, I wanted to shift gears for a couple of posts and briefly discuss some of the economic impacts of ADHD. In this post, we will begin by reviewing some articles on the approximate cost that untreated ADHD bears on society. In the next one, we will review a paper on what (in general) are the most cost-effective treatment options for ADHD.
Direct and indirect costs associated with ADHD. There was an excellent review done by Bernfort and colleagues on ADHD from a socio-economic perspective, which investigated the effects of costs such as increased educational expenses, costs of addressing drug and substance abuse (which is higher in ADHD individuals than the general population), increased traffic accidents, employment costs (such as loss of productivity), health care costs (which cover both prescription drugs as well as therapy, as well as increased medical costs from high-risk behavior, which is also more common in individuals with ADHD), as well as a few others. The importance of this study was to shed light on some of the far-reaching implications of the ADHD and the surmounting costs associated with them.
Another review article by Pelham and coworkers attempted to put a price tag on these different factors and behaviors. The review, which investigates costs associated with pediatric and adolescent ADHD, and factors in issues such as education (and special educational needs), loss of work to parents of ADHD children, impacts on the juvenile justice system as well as health-care costs, placed the overall cost per individual with ADHD to be almost $15,000 annually! While I personally view this number as being a bit high, I believe that the sheer magnitude of this number is extremely telling, and an important indicator for the need for proper treatment for children and young adults with the disorder.
We have spent a number of pages investigating the high heritability of the disorder by investigating the genetic components of ADHD. Given this fact, family studies and the economic impact of the disorder of ADHD on families should be especially relevant. From a study (note that this was done by Eli Lilly, so please consider the source) on medical claims found a 2 to 3-fold higher cost of claims and payouts to family members of ADHD. These number suggest the significant burdens that can be placed on both family members and their health care providers surrounding their relationship with ADHD individuals. Keep in mind that the genetic component of ADHD is often believed to be somewhere around 75% (and some studies place it as high as 90%), so the likelihood of multiple cases of ADHD in a single family is also high. Not surprisingly, the financial burden is another facet of the disorder which can act as another source of stress on parents and other family members of ADHD children, especially during more difficult economic times.
Finally, claims data from individuals with ADHD and their family members was obtained from a single large company in the US, and an attempt was made to extrapolate the data to the American population as a whole (which is a big if, but may be at least indicative of the whole population, if the makeup of this company is even close to being representative of the US population as a whole). Taking into account factors such as health care and work loss costs involved with the individuals with ADHD and their families, this study estimated a total excess (meaning above the average non-ADHD person) cost to be over 30 billion dollars a year. Breaking this down amongst the individuals with the disorder (which, using a relatively conservative estimate of 5% of the US population, which would put around 15 million individuals as having the disorder), this would amount to around $2,000 per person. This falls somewhere in between the numbers tossed around by some of the other studies.
Again, keep in mind that this data is extrapolated from a small portion of the American population, which, statistically, is often a dangerous thing to do. However, just the sheer magnitude of these numbers, especially when we begin to see some degree of numerical overlap between economic estimates from different studies on the costs associated with treating or dealing with the disorder of ADHD should be eye-opening, even if there is still a fair amount of ambiguity involved among some of these figures. Since most of these studies place the direct and indirect economic impacts of the disorder to be in the thousands (and in some cases 10 thousands) per person, we can see the importance of treating the disorder and its potential economic impacts on society as a whole. In the next post, we will investigate the cost-effectiveness of different measures in treating ADHD (along with some of the common comorbid or co-existing disorders).