Immaturity Officially a Disease: You Saw It Here First

The kid in red is in the same grade and classroom as the other four

In my post of September 20, 2010, Immaturity in YoungChildren: Officially a Disease, I described two studies published in a very obscure journal, the Journal of Health Economics, that both found nearly identical data about the diagnosis of ADHD in school children.  In the these articles, two different research groups (Evans, Morrill, &Parente, 29, 2010 657–673; Elder, 29 2010, 641–656) using four different data sets in different states came to the same conclusion. 

In one, roughly 8.4 percent of children born in the month prior to their state’s cutoff date for kindergarten eligibility – who typically become the youngest and most developmentally immature children within a grade – were diagnosed with ADHD, compared to 5.1 percent of children born in the month immediately afterward. The study also found that the youngest children in fifth and eighth grades were nearly twice as likely as their older classmates to regularly use stimulants prescribed to treat ADHD!  The results of the second study were quite similar.

Translated into numbers nationwide, as Steindór summarized in his comment on my blog, this would mean that  between 900 thousand (Elder) and 1.1 million (Evans et al. 2010) of those children under age 18 in the US diagnosed with ADHD (at least 4.5 million) are misdiagnosed.  

Now, a year and a half later, another study, published in a more widely read journal and reported widely in the news, came up with the exact same conclusion.  (“Influence of relative age on diagnosis and treatment of attention-deficit/hyperactivity disorder in children” by Richard L. Morrow, et. al., Canadian Medical Association Journal, published on line March 5, 2012). 

In a cohort study (a study of a group of individuals with something in common followed over time) of more than 900,000 Canadian children, researchers found that boys born in the month of December (the cutoff birth date for entry to school in British Columbia) were 30% more likely to be diagnosed with ADHD than boys in their grade who were born the previous January.

This number was even more dramatic in the girls, with those born in December 70% more likely to be diagnosed with ADHD than girls born in January.

In addition, both boys and girls were at a significantly higher risk of being prescribed an ADHD treatment medication if they were born in the later month than in the earlier one.

 "It could be that a lack of maturity in the youngest kids in the class is being misinterpreted as symptoms of a behavioral disorder," said lead author Richard L. Morrow.  


Could be?  About about “is?”

Some of these behaviors could include not being able to sit still, not being able to focus and listen to the teacher, or not following through on a task, he added.


"You wouldn't expect a 6- and 9-year-old to behave the same way, but we're often putting a 6- and 7-year-old in the same class. And we're learning that you can't expect the same behaviors from them," he added. "We would like to avoid medicalizing a normal range of childhood behaviors."  No sh*t!

This problem has been complicated recently by the fad of "redshirting" children for kindergarten: overachieving parents purposely starting them at age six rather than five in order to give them a competitive advantage academically over their classmates.  Now children in the same class may be as much as two years apart in age.

The study authors went on to  note that potential harms of overtreatment in children include increased risk for cardiovascular events, as well as effects on growth, sleep, and appetite.  There was no mention of the harm of making this diagnosis and using these potentially toxic medication instead of investigating and addressing possible psychosocial reasons for “hyperactivity” such as a chaotic family environment or abusive and/or inconsistent parenting practices.

This brings up the issue of the risk to the heart and the rest of the cardiovascular system posed by stimulant use.  There have been several studies recently published that have been reported in both the medical and lay media that claim that this risk is minimal.  


This is in an interesting contrast to the publicity about an article, published this week in BMJ Open (the online version of the British Medical Journal)  that purported to show that the use of sleeping pills increases the risk of dying from all causes by a factor of 4 over just two and a half years.  Sleeping pills are generally regarded as far less dangerous and less likely to be abused than stimulants.  The FDA categorizes benzos as "Schedule IV" (lower likelihood of abuse) and stimulants as "Schedule II" (most likely to be abused short of the illegal "Schedule I" drugs).

That study about sleeping pills seemed to me to be a bit hard to believe, especially since epidemiological studies are notoriously unreliable.  But even if the numbers are valid, the fact that the risk of death from all causes increases most likely means that there is  some other characteristic, or a bunch more characteristics, of the population of people who are prescribed sleepers that are not characteristic of other populations. Those additional factors might explain the findings.

As for stimulants, in the February, 2012 issue of the American Journal of Psychiatry, there is an article on methylphenidate (Ritalin and its variations) and risk of heart problems in adults. Using a large medication database, researchers matched about 44000 methylphenidate (MPH) users and about 176,000 controls. 


They looked at main the incidence of a cardiac event defined as a myocardial infarction, stroke, ventricular arrhythmia, or sudden death. They found a 117% increased risk - or over double the risk – in the Ritalin group. After adjustment for some potential confounding factors, the risk was still 84% higher.

The news stories about the study on the benzo’s seemed to be meant to scare people out of using them, while the stories about increased risk in stimulant users seemed to be meant to reassure people about using them.  Of course, both of these studies described relative risk and not absolute risk (See my post Stats.com from November 2, 2011).   


This means that  “double the risk” means the risk might go from, say, a tenth of a percent to two tenths of percent.  Double a very small risk is still a very small risk.  The absolute risk in this example would have gone up just one tenth of one percent.  Still, if millions of people are getting the prescriptions, this increased risk can still turn out to apply to a sizeable number of people.

Physicians will not be able to see the increased risk in their clinical experience.  As Nassir Ghaemi says, “They don't happen in 10-20% of patients in our practice; they happen in 1-2% (or 0.1-0.2%), and so, the average clinician, faced with a welter of patients, doesn't make the causal connection.”

The question should be, what are the risks versus the benefits from taking the medication.  For sleeping pills, for instance, one might want to know if there is a much larger increased risk of death for people who are sleep deprived.  For example, before the practice was stopped, medical interns would routinely work 36 hour shifts.  Fatal accidents on the car trip from the hospital back home were not all that unusual.

Then there is the whole question of other, non-pharmacological treatments, which is relevant for both the use of sedatives and stimulants.  Of course, they do not work for everyone either.

An editorial in the same issue of the American Journal of Psychiatry as the study of Ritalin in adults sounded reassuring about stimulant use.  Based on that study, I’m not so reassured.  

Assuming Facts Not in Evidence II - Sleeping Medications

As I described in my post of January 31:

One marketing technique used by big Pharma to mislead physicians is the engineering of a journey of ideas that have never been proven into the clinical lore as if they were established facts.  So-called experts who are paid off by drug companies make presentations at continuing medical education conferences or write "review" articles for medical newspapers or throwaway journals in which they mention these so-called "facts."

In these situations, conditional phrases are said or written as a quick aside in order to leave the speakers and writers a loophole just in case a member of the audience challenges them about overstating their case. Should this happen, the speakers are then able to point to the conditional language they used and “remind” the audience that their use of this language indicates that they are not making spurious claims.  


Most of the time, however, no one in the audience will make such a challenge. The audience is left with a dangling implication that the statement is an established fact. The non-discerning physician comes away with the “take home lesson” that the assertion is true.  Research has shown that most people only remember one or two salient points from a paper or an oral presentation anyway.

I have also written about how I suspect (but cannot prove), that drug companies begin to actively spread negative information and even disinformation about drugs as soon as most brand-named drugs in a certain class become available generically.  As I wrote in my post of October 19, 2011:

Pharma-inspired or paid-off writers denigrate highly-effective drugs (antidepressants and benzodiazepines) that just happen to have gone generic, in hopes that doctors will prescribe more expensive, potentially more toxic, and less effective brand-named drugs (particularly atypical antipsychotics). 

It amazes me how drug companies have only now been releasing negative information (that had apparently been held back from the public previously) about SSRI anti-depressants -since they have been available since the mid-1980’s.

I had seen this sort of thing done before to a class of drugs called benzodiazepines, which are demonized as being far more addictive than they actually are.  Interestingly, this demonization of the drugs started anew with the introduction of three new sleeping medications (Ambien, Lunesta, and Sonata) that, although slightly different in chemical structure than benzodiazepines, do exactly the same thing in the brain.  (Ambien has gone generic, but Pharma sells a delayed-release version that is still brand named.  As we shall see shortly, this type of formulation directly undermines one of their claims - that the new drugs are safer than the old ones).

Benzodiazepines include such popular drugs as Valium, Librium, Klonopin, Ativan, Xanax, Dalmane, and Restoril.  Ambien, Lunesta, and Sonata  are technically not benzodiazepines, but they might as well be.  They are called non-benzodiazepine benzodiazepine receptor agonists.  Loosely translated, this means that they affect the same nerve cells in exactly the same way as benzodiazepine benzodiazepine receptor agonists.   

They offer no advantage in terms of addictive potential, side effects, or efficacy.  In fact, they offer some real disadvantages.  They are far more likely than the old benzo’s to cause people to do things in their sleep that they do not remember the next day, including cooking large meals and even driving significant distances!  Also, if you take Ambien and force yourself to stay awake, you get really high.

As an aside, most of the public, and many physicians who should know better, believe that some benzodiazepines are tranquilizers, while others are sleeping pills.  An old joke asks, “What is the difference between a tranquilizer and a sleeping pill?”  The answer: marketing. 

Most outrageously, the drug companies successfully lobbied the government to have benzodiazepines excluded from the Medicare drug benefit program – the only major class of drug so excluded – while not excluding the new, more expensive brand named sleepers!  This law has finally been changed to allow for the old drugs, but that change will not take place for some time.

Pharma shills have fanned out to convince everyone that the new drugs are both safer and more effective than the old ones.  With success. I frequently see physicians who seem to think that benzodiazepines are the scourge of the earth due to their addictive potential prescribing the new drugs with abandon (not to mention prescribing much more serious drugs of abuse such as stimulants).

Now, that the new drugs are better and safer is one of the widely-disseminated “established facts” that are not really facts at all.  Again, I am going to pick on an article in the psychiatrist newspaper, the Psychiatric Times.  I do so reluctantly because this publication often prints more balanced articles, but lately it has been just feeding me blatant examples of points I’m trying to make in this blog.

The article in question appeared in the January 2012 edition of the paper and was entitled, “Treatment of Insomnia in Anxiety Disorders.”  It was written by Gregory Asnis, Elishka Caneva, and Margaret Henderson.

In discussing pharmacological treatment of insomnia, they say, and I quote, “Not only are the non-benzodiazepines effective [that part is true], but there is a notion that they are safer than benzodiazepines.”  They give two reference here I will discuss shortly.

A notion?  Notice they are not actually saying here that the drugs are safer.  As I mentioned above, they do try to leave themselves an out.  However, the authors go on to make a stronger statement: “Although head to head studies comparing these classes of hypnotics have been minimal [If that’s true, than how can they draw conclusions], a recent metanalysis supports the findings of reduced adverse effects for the non-benzodiazepines.”  They give a third reference.

They explain that the new drugs have a shorter half-life, and therefore cause less residual daytime sedation, and “other  [unnamed] adverse effects."

Without even looking at the reference, they are already spouting complete bullsh*t here that strongly suggests that the new drugs are better.  So what about half-lives of the drug?  Half life is the number of hours it takes for the body to excrete 50% of an ingested drug from the body.  In truth, the different old benzodiazepines on the market have a wide variety of different half lives. 

Some of them such as Xanax have a very short or even shorter half life than the new drugs.   Some have a mid-range half life such as Tranxene. Some have a very long half life like Klonopin and Valium.  If daytime sedation is a problem, the doctor can either reduce the dose, or prescribe a shorter acting drug!  There is no need for the more expensive alternative.  If you take a delayed release preparation so you sleep through the night, then you would face just as much daytime sedation as if you took a benzo with a longer half life!

Not only that, but the shorter the half life of a sedative, the more addictive it is.  Furthermore, the shorter the half-life, the more the drugs are likely to cause “rebound” insomnia if suddenly discontinued. So, if the authors of this article are touting the importance of short half lives, perhaps they should also mention these facts, which are well known among addictionologists.  Funny that they did not, isn’t it?

So what about the meta-analysis?   I’m glad you asked, since I found it and read it.  It says quite clearly that, in the studies they are pooling, the drugs were analyzed irrespective of their differences in half life, potency (how the drugs compare in strength milligram to milligram) or dosages.  

There were no indications in direct comparisons indicating that the new drugs were safer.  There were some “indirect comparisons” (whatever those are) that were made that seemed to indicate that the new drugs were slightly safer, but again, since half life, potency and dosage were not considered, what the hell does that even mean?

Also noteworthy is that the studies meta-analyzed were in people who did not also have an anxiety disorder.

As for the other two “references,” one of them clearly attributes the results of studies that showed fewer side effects in the new drugs to their shorter half-lives.  The other never really clearly states that the new drugs are preferable to the old benzodiazepines at all, although it also discussed issues concerning drug half lives.

Let the buyer beware, baby.