Saturday, July 25, 2009

Scientific American goes nuclear on Ritalin

Edmund Higgins, a clinical associate professor [1], has written a blistering attack on Ritalin, and gotten it published in Scientific American – a magazine that’s presumably sharing the industry’s revenue problems.

Dr. Higgins compares Ritalin (methylphenidate) to methamphetamine. This is the rhetorical equivalent of comparing a human to Hitler; it’s chemically correct but it’s the mark of a crank. It’s a Godwin’s Law violation.

On the other hand, as someone who’s child has been on Ritalin and other ADHD meds for years, I’ve long had the same sort of concerns. Ritalin has an astounding safety record, but we’re messing with the neurochemistry of a rapidly evolving brain over a period of years and decades. I personally wouldn’t use this, or any other, long-term psychiatric medication medication in my child unless all other options had been exhausted and the disability and risks of non-treatment were severe. I’ve previously made the comparison to treating cancer. Nobody should expose a child to life threatening chemicals with severe long term effects– unless the alternative is worse.

Another point in Higgins favor is his interest in animal models. Given the immense difficulty of studying psychiatric medications in children, animal models are pretty much all we’ve got. So let’s see what he says about the animal models, stripping out some inflammatory rhetoric and considering only studies of meds used to treat ADHD. Note that much of this research is more recent that a 2006 review of mine that was pretty reassuring, but that means it won’t have been validated by other researchers …

Do ADHD Drugs Take a Toll on the Brain?: Scientific American

Edmund S. Higgins is clinical associate professor of family medicine and psychiatry at the Medical University of South Carolina and co-author, with Mark S. George, of The Neuroscience of Clinical Psychiatry (Lippincott Williams & Wilkins, 2007) and Brain Stimulation Therapies for Clinicians (American Psychiatric Publishing, 2009).

… In an experiment published in 2003 psychiatrist Eric Nestler of the University of Texas Southwestern Medical Center and his colleagues injected juvenile rats twice a day with a low dose of methylphenidate similar to that prescribed for children with ADHD. When the rats became adults, the scientists observed the rodents’ responses to various emotional stimuli. The rodents that had received methylphenidate were significantly less responsive to natural rewards such as sugar, sex, and fun, novel environments than were untreated rats, suggesting that the drug-exposed animals find such stimuli less pleasurable. In addition, the stimulants apparently made the rats more sensitive to stressful situations such as being forced to swim inside a large tube. Similarly, in the same year psychiatrist William Carlezon of Harvard Medical School and his colleagues reported that methylphenidate-treated preadolescent rats displayed a muted response to a cocaine reward as adults as well as unusual apathy in a forced-swim test, a sign of depression.

In 2008 psychopharmacologist Leandro F. Vendruscolo and his co-workers at Federal University of Santa Catarina in Brazil echoed these results using spontaneously hypertensive rats, which—like children with ADHD—sometimes show attention deficits, hyperactivity and motor impulsiveness. The researchers injected these young rats with methylphenidate for 16 days at doses approximating those used to treat ADHD in young people. Four weeks later, when the rats were young adults, those that had been exposed to methylphenidate were unusually anxious: they avoided traversing the central area of an open, novel space more so than did rats not exposed to methylphenidate. Adverse effects of this stimulant, the authors speculate, could contribute to the high rates of anxiety disorders among ADHD patients…

… In February 2009 neuroscientists Yong Kim and Paul Greengard … injected … mice with either methylphenidate or cocaine daily for two weeks. Both treatments increased the density of tiny extensions called spines at the ends of neurons bearing dopamine receptors in the rodent nucleus accumbens. Compared with cocaine, methylphenidate had a somewhat more localized influence; it also had more power over longer spines and less effect on shorter ones…

Furthermore, the scientists found that methylphenidate boosted the amount of a protein called ΔFosB, which turns genes on and off, even more than cocaine did…

So when I strip out everything else, the bulk of Higgins’ article is coming from 3 animal studies in 2003, 2008, and 2009. All of the studies involved injecting methylphenidate, which is not how it’s used in humans. Injecting Ritalin is a mark of abuse with pretty different pharmacology from oral use.

The most interesting of these articles is Nestler et al in 2003 [2], an article with a rather strange title (emphases mine – incidentally, Nesler is the last listed author, so why did Higgins credit the study to him?) …

Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood.

Bolaños CA, Barrot M, Berton O, Wallace-Black D, Nestler EJ.
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Biol Psychiatry. 2003 Dec 15;54(12):1317-29.

BACKGROUND: Methylphenidate (MPH) is a psychomotor stimulant medication widely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Given the extent of prescribed use of MPH, and because MPH interacts with the same brain pathways activated by drugs of abuse, most research has focused on assessing MPH's potential to alter an individual's risk for adult drug addiction. Data examining other potential long-term behavioral consequences of early MPH administration are lacking, however. METHODS: We investigated the long-term behavioral consequences of chronic administration of MPH (2.0 mg/kg) during pre- and periadolescent development in adult rats by assessing their behavioral reactivity to a variety of emotional stimuli.
RESULTS: The MPH-treated animals were significantly less responsive to natural rewards such as sucrose, novelty-induced activity, and sex compared with vehicle-treated control animals. In contrast, MPH-treated animals were significantly more sensitive to stressful situations, showed increased anxiety-like behaviors, and had enhanced plasma levels of corticosterone.
CONCLUSIONS: Chronic exposure to MPH during development leads to decreased sensitivity to rewarding stimuli and results in enhanced responsivity to aversive situations. These results highlight the need for further research to improve understanding of the effects of stimulants on the developing nervous system and the potential enduring effects resulting from early-life drug exposure.

Why did I say that was a “strange title”? Because an article on rats in a journal called Biol Pyschiatry would normally contain the word rats in the title.

If we simply scaled the dose to humans, but the way, this would be 80 mg (twice daily?!) by injection – which would be a whopping abuse dose in humans. The article has gotten very little attention in the past six years, being cited only four times of which two appear to be reviews.

A related articles query produced a very large number of similar rat studies, including one that, surprisingly, found no effects (surprisingly, because these look like “fishing expedition” studies, when you include publication bias they almost always show some effect.) These are boom times for rat studies of methylphenidate, probably reflecting new NIH funding.

On review I’m left with several only mildly related conclusions …

  1. I’m happy the animal studies are being done. I’d like to see fewer fishing expeditions, and more replication of results. For example, repeat the Bolanos study with a larger group, maybe a different clonal line, and see if the same results appear. These need to be registered studies, so we don’t get messed up by publication bias (which is a huge problem in the low cost animal studies domain). I would really like to see more studies of tolerance effects in rats.
  2. Higgins may turn out to be correct (lots of people are suspicious that stimulants can be used so long, including me) but I think he’s got a crank agenda. His article is more inflammatory than the evidence supports. A more sober article would have been welcome.
  3. You shouldn’t put children on psychoactive medications without a very good reason. Of course that was always true.
  4. Don’t assume any other medications are in any way safer – Ritalin has been studied far more than, say, Stratera.
  5. Scientific American is running out of money. We’ll know they’ve hit rock bottom when they do an article on the scientific evidence for Creationism. They should have known better than to publish this article in its current form.

[1] I have a similar sort of title today, and have had similar roles in the past. In the hierarchy of academia, this title carries less glory than research assistant.

[2] Parenthetically, why does PubMed make it so very hard to find the link to a citation? It’s like they’re trying to hide things.


Anonymous said...

WhI feel ritalin is far more emotionally harmful to kids than adderall and also less efficient. However... the 19 deaths reported in all these years from ritalin to me says its EXTREMELY safe... 19 deaths out of like 20 MILLION people whove used it all the time....

Anonymous said...

Update: the Nestler paper has been cited 92 times in the 7 years since publication and is on pace to get an incredible 200+ citations total.

Also, the author is certainly smart enough to know that rats are different from humans. Direct comparison of doses across species is beyond useless. For example, mice generally need double the dose a rat needs to get comparable results. Rats take higher doses than humans. Metabolism rates, body fat ratio, blood volume and a dozen other factors make these comparisons meaningless.