Tuesday, July 22, 2008

ADHD treatment: Placebo versus….placebo?

JAMA just published a study of St. John’s wort for ADHD. Pubmed18544723.

This made a lot of headlines. For example,
“Herbal Remedy No Better Than Placebo in Treating ADHD” [Psychiatric News]
“St. John's Wort No Help for ADHD” [TIME magazine]
“ATTENTION-DEFICIT HYPERACTIVITY DISORDER: St. John's wort may not affect symptoms” [Washington Post]

I spotted this article as I was looking at the recent publishing activities of Dr. Joseph Biederman, who has been investigated lately for either poor memory, or not really knowing how to fill out forms for his employer, Harvard.

http://www.nytimes.com/2008/06/08/us/08conflict.html?fta=y

This poor performance in filling out forms has drawn the attention of a senate investigating committee, and press in the New York Times, and none-too-soon. We can’t have Harvard researchers out there failing to properly fill out routine forms. It has been quite noble of Dr. Biederman to acknowledge that there were some problems filling out forms, and note that this should all be straightened out tout-suite. His employer has been supportive.

I can understand all of this. Dr. Biederman publishes well over ten peer-reviewed articles per year, and has maintained this steady rate for over a decade. Much of this has focused on ADHD, AKA “hyperactivity” and ADD.

It seems that some people have suspected that an herbal remedy, St. John’s wort, may be useful in treating ADHD. So, Dr. Biederman being a leading authority in ADHD diagnosis and treatment, along with his colleagues, ought to evaluate whether this herbal remedy actually does provide some relief.

Not to mentioned Dr. Biederman’s other interest in ADHD: he profits greatly from his involvement with the pharmaceutical companies who sell the FDA-approved drugs for ADHD. Specifically, ALZA corporation makes Concerta, a sustained-release Ritalin that is under patent for a few more years. ALZA supports Dr. Biederman, per the disclosures at the end of this article on St. John’s wort and ADHD.

OK – segue back to the article: Well, I had not heard of St. John’s wort as a possible treatment for ADHD. So I decided to look at this article.

A bunch of kids were screened for ADHD – not difficult to find nowadays since everyone has ADHD – you just need to exclude the kids that also have bipolar and autism. Then, randomized to receive either “treatment” or “placebo.” “Treatment” was hypericum, a component of St. John’s wort that is believed to be the active ingredient, or at least one of the active ingredients, in St. John’s wort.

So, the kids receive ADHD measurements at “baseline,” then every couple of weeks up to eight weeks. Ideally, if the herb has some effect, average ADHD scores will be lower for the hypericum group compared to the placebo group.

Well, Dr. Biederman, your financial status is safe. Hypericum did no better than placebo. Actually, the placebo group did a bit better than the hypericum group. The herbalists will not be replacing the pharmacists anytime soon.

OK, so I am done looking at the picture that tells me the main result, and I am on to the Discussion. Almost done gathering this bit of knowledge.

Wait. What is that in the discussion?

I have to quote this directly. This literary passage is too good to not share.

“Hyperforin is a very unstable constituent that quickly oxidizes and then becomes inactive, which is likely what happened to the product used in this clinical trial.”

Inactive?

Haven’t I heard that before?

Oh, yes: in the definition of “placebo.” A placebo is an inactive formulation, per Wikipedia and as per the rest of the knowledgeable world.

So, JAMA publishes a study that declares that St. John’s wort is not effective for ADHD, but the active arm of the randomized study received a formulation that was inactive, just as the inactive arm did?

What would the result be if the study was repeated with hypericum which had not gone stale?

We don’t know. The hypothesis is still totally untested.

However, the drug reps that are out there for ALZA are now able to declare, when it is worth mentioning, that “St. John’s wort was not any better than placebo, in a recent JAMA study.”

I am gonna wrap up this part with a couple comments: I believe there is such a thing as ADHD. I belive it exists at a much lower prevalence that Dr. Biederman might believe. But I believe it exists. I also believe that there are medications that can be helpful. I also believe that any child who has ADHD will need top-notch parenting, and will need skilled teachers. ADHD may make a kid distractible, leading to poor school performance, etc. A pill can help some of this. But a kid with ADHD still needs to learn all of the things that any other kid has to learn. To follow through. To figure out how to understand and complete assignments. To cooperate with others. Et cetera. ADHD interferes with the acquisition of these qualities. These learned qualities cannot be delivered by pill. They can only be delivered by people and the right circumstances. Usually, family and school teachers. School teachers get training and experience dealing with this sort of thing. But any given parent does not have some special place to learn how to be a top-notch parent for a kid with a demanding challenge. Whether an herb or some other pill works, it will be the social dimensions of response that will help get the kids with ADHD ready for the real world. The parents will need some training - perhaps from a therapist.

OK: You can return to your regular web-browsing.

If you want to read a bit further, I am gonna throw in a couple more thoughts and observations.

Would it have been that much more difficult to recruit another 60 kids, and run it all again with ACTIVE ingredient?

At least the authors note that the hypericum can easily become inactive. It gets stale, basically. Moisture from the air leads to processes that result in the breakdown of this molecule. They get credit for noting this. Nonetheless, it is sad that a leading medical journal chose to run this story as is. That means that the peer reviewers were OK with this (or that some editor over-rode the objections of peer reviewers).

Another acknowledged weakness is the sample size. Each group had 27 participants. Considering the heterogeneity of ADHD, the variability in ADHD scores generally, and the use of multiple tests (two subscales of RDS and two of CBCL = 4 tests), this study probably was under-powered. If you don’t understand all of that, don’t worry. Bottom line is they probably did not include enough study subjects to detect a clinically significant effect for St. John’s wort if, hypothetically, it actually works (which would apparently require using fresh, not stale, St. John’s wort).

One odd thing I noticed that was not acknowledged was the odd pattern of results on CBCL. The Child Behavior Checklist is a checklist of a bunch of problem behaviors that kids might perform. This is a widely recognized instrument for measuring child behavior, and a decent general measure of ADHD problems, although it is not specific to ADHD.

While the study may have been underpowered to have a real-world meaningful difference also show up as a statistically meaningful difference, the pattern of results on the CBCL show that the placebo worked better than the St. John’s wort. How could that be?

The CBCL scores are “standard scores:” a score is translated into a standard scale that is more easily interpreted and understood: this is the same as saying that the Farenheit scale can be translated in to a standard scale of Celcius, with freezing at zero and boiling at 100. It is just more interpretable. For the CBCL, the standard deviation is 15. The placebo group had their scores, on average, drop about 15 points, or one standard deviation, on both the “internalizing” and the “externalizing” scales of the CBCL, while the scores of the St. John’s wort group dropped only 4 points on each of these two parts of the CBCL.

Why would the placebo group have a consistently decent, even admirable, therapeutic response to placebo, but the herb group does not? The herb group should be benefitting from any placebo effect to about the same degree as the placebo group. The placebo group scores on the ADHD symptom scale also followed this pattern, with the placebo group experiencing lower scores, thus more improvement, than the herb group, although the actual differences are probably far from being at clinically meaningful difference.

Frankly, that pattern makes it plausible that something else was going on.

Here is my guess: as the authors note, the kids were randomized, but the randomization did not succeed, as it typically does, in spreading various factors out equally between the two groups. The authors go no further. However, my eye gets caught on the assignment of gender: for the placebo group, half were males, while for the herb group, three-fourths were males. So, maybe females happened to have more response just to the burst of clinical attention compared to guys. Or maybe females have more sensitivity to hypericum, possibly through some sex-based difference in metabolism. The authors note that they controlled for sex statistically, but this is really a difference that can only be controlled by a greater sample size: first, the study certainly was not powered to determine if my pet hypothesis is supported: that the treatment, whether placebo or herb, had a greater effect on females than males, and second, with a greater sample size, the assignment would increasingly get closer to an even match of boys and girls in each of the two groups.

Again, as I have said already: JAMA published this? The leading medical journal?

Hmmm. Pharmedout reports that a third of JAMA pages are advertisements.
http://pharmedout.org/bingofunwithpharmads.pdf

JAMA has been heavy on publishing studies noting the influence of direct-to-consumer drug advertising upon prescribing habits. Maybe it is time that JAMA evaluate the influence of drug advertising in JAMA upon editorial decision-making. Cuz a ‘conflict-of-interest’ type explanation would sure fit this pattern of results.

Saturday, July 19, 2008

License, Please. –or- What Happened to the Third Arm?

“Escitalopram and Problem-Solving Therapy for Prevention of Post-Stroke Depression.” JAMA May 2008.

OK, so I recently got around to looking over a recent JAMA study. Right up my alley. Meds versus therapy. I am so curious! Did therapy prevail? Should the health care system be directing patients to counselors, versus to the pharmacy, for yet another clinical problem?

Well, the short answer seems to be “No.”

Darn. Meds wins this one. But maybe I can call, “FOUL!” So I begin a careful reading. Especially alert for the subtle-yet-profound influence of Big Pharma.

The issue: Given that the prevalence of depressive episodes post-stroke is fairly high, can preventive / prophylactic depression intervention prevent some of this depression incidence? If so, does medication or therapy, or both, work? Better than placebo? If both medication and therapy work, which works better?

The article is Pubmed ID 18505948.

The article tells that this study recruited people who had recently had a stroke, and randomly assigned them to one of three treatment groups, each with a different, competing treatment for prevention of depression in a follow-up treatment surveillance period of one year. Some cases of depression should be expected in each group. The degree that either the medication or therapy group would have a lower portion of depressive episodes compared to the placebo group would be the degree that the intervention worked – that it prevented depression.

Well, it worked. Both meds and therapy worked. Fro the group receiving placebo, 22% had a depressive episode. That can be seen as a base rate. For the group receiving escitalopram, 9% had a depressive episode. For the group receiving therapy, 12% had a depressive episode. So, preventive depression treatment worked to prevent depression, both meds and therapy. And meds worked a bit better than therapy.

That is good news for Forest pharmaceuticals, who sell escitalopram as Lexapro, still under patent. Forest can seek the FDA to approve escitalopram for post-stroke prophylaxis of depression, thus creating a whole new market for this antidepressant – anyone who has had a stroke.

Darn. Meds beat therapy in this one. But let’s dig a little deeper.

For many reasons, it is a challenge to run a therapy study. Therapy is always individualized to some degree, despite efforts to have it be standardized. Also, with a pill, you know the specific dose received. But if a therapy client doesn’t really ‘work’ at therapy, and doesn’t happen to get as much out of therapy, then the dose can really differ. For one person, eight hours of therapy might be life-changing, while for another person, it might just be tedious. In contrast, if you give someone a pill, and they take it, you know they got one dose of the pill.

So, I looked over the training and standardization of the delivery of therapy. Pretty good. Problem-Solving Therapy may not be the most intimate, life-changing brand of psychotherapy, but it can be effective for depression. In this study, it was trained and supervised to be orthodox. Good.

One thing that is missing, however, is information on the therapists. Were they licensed? Were they graduate students? Were they master’s level? Doctoral level? Were they psychiatrists?

No info.

Hmmm.

Well, I search and finally find some information. Not in the article. But tucked in the back between the study and the references, is a set of notes. Including a note thanking two people for administering the therapy. One of these people has a bachelor’s degree noted after their name, and the other has a master of arts degree.

What?

180 patients receiving therapy, and some received therapy from a master’s level person, and some from a bachelor’s level person? Are you kidding me? Is there anyone out there looking to pay $100 an hour for psychotherapy from a person with a bachelor’s degree? This was funded by NIH? No info about license on either.

So, medsvstherapy, and meds won. But there is no evidence that therapy was even provided by a counselor or therapist. What if this were a physical therapy intervention, but the person doing the physical therapy was not a physical therapist? What if this was yoga versus surgery for back pain, but the yoga instructor was not a yoga instructor? What if this was a comparison of two surgery techniques, but the person performing the surgery was not a surgeon?

The person with the bachelor’s degree clearly is not in the game. There is some outside chance that they could legitimately be legit to do therapy – if they were a seasoned, trained minister, for example. But that would be some rare kind of exception. So, let’s just figure that at least one therapist is not a therapist. What about the second noted therapist, with the MA?

This could be a master’s level counseling degree, and the person could be credentialed as a master’s level counselor. Or it could be a master’s degree in some other area. The study just does not say.

So, with a few minutes, I decided to figure out if I could find evidence of licensure. Other published literature establish this person as a colleague at Iowa’s psych research shop for years, sometimes as co-author, sometimes as research assistant. Thus, the most likely jurisdiction of licensure would be Iowa.

Iowa has a listing of all licensed professional occupations here:
http://www.iowaworkforce.org/lmi/publications/licocc/index.html

You can see who is licensed here:
https://eservices.iowa.gov/ibpl/

Well, this person is not a licensed marital / family therapist. Not a Mental Health Counselor. Not a Health Service Provider in Psychology. Not a Psychologist.

It is possible that this person, who provided this therapy, was a licensed counselor of some kind. But the topic is avoided in the study, and there is no indication of licensure in Iowa, despite some hunting on the web I was able to do.

In some U of Iowa document on the web, I did find this person listed as a “Research Assistant II” for 2006 – within the time span of recruitment, 2002 – 2007. Doesn’t sound very likely that this person is a counselor or therapist.

So, meds versus therapy, but not therapy provided by an actual counselor. Were they afraid that therapy might win if it were delivered by an actual counselor?

Maybe the original proposal would say. The proposal submitted to NIH for funding. Well, I don’t have the original proposal. However, the article does have the NIH grant number, allowing the original study abstract to be pulled up on the government’s website listing all research grants: CRISP. Just google CRISP and you will find this.

So, I enter the lead author’s name, and quickly locate the study’s abstract from when it was submitted for funding. NIH R01 grant 65134. I discover the grant. And I discover a couple things that don’t quite match up with the publication.

First, the proposal reported that citalopram, not escitalopram, would be used in one arm, and problem-solving therapy in a second arm. But there was also supposed to be a third arm: a group receiving another antidepressant, nortriptyline. Commercial name Pamelor.

What happened to the nortriptyline?
What happened to the citalopram?

First: What happened to the nortriptyline?
Was the nortriptyline given, per the NIH grant? Did it win? Why would it be excluded? Hmmm.

I have a theory. A suspicion. Nortriptyline is no longer under patent, unlike escitalopram, so discovery of a new use for nortriptyline would not be a gold mine of a new clinical population. Maybe the authors chose not to report the nortriptyline arm of the study, so that escitalopram, under patent, could be promoted, without the data out there in the published realm concerning the generic?

Second: What happened to the citalopram?
It turns out that citalopram was about to go generic as this proposal was submitted to NIH. However, at the same time, the developers of citalopram were just developing a similar drug, escitalopram, to replace citalopram as a money-maker. Right around the time when this study proposal was funded. So, escitalopram being very similar to citalapram, the researchers may have switched to the newly developed, newly available drug which would be under patent for a while, thus potentially generating more revenue if the drug worked as suspected for preventing post-stroke depression.

So, after this little review, these are my thoughts:
First: problem-solving therapy conducted by therapists might have had similar or better results, compared with escitalopram, for preventing depression post-stroke.
Second: if the nortriptyline arm of the study was conducted, nortriptyline may have had a similar efficacy when compared with escitalopram, but the strategy of not reporting this would leave open the possibility of spreading the knowledge regarding the under-patent medication, not the now-generic medication. The benefit of this, for the pharmaceutical company, would be: a new market consisting of the post-stroke population in general, barring any contraindications.

Now, I am gonna consider how to follow up on this. Cuz in the battle of meds versus therapy, therapy really might have won this one, if only it had a chance.

Monday, July 14, 2008

Meds Versus Therapy: Opening Salvo

Hello. This is my first blog. So, please excuse the blog-quality while I learn.
However, I know my content. Meds versus therapy. Specifically, in mental health / psychology / counseling / psychiatry, the heavy promotion of medications when psychotherapy, and other therapeutic interventions, may be preferred. I plan to also address the topic of non-medication interventions for other health care problems when there are decent interventions to be considered, and even preferred, over medications.

I am going to review research as it emerges to illuminate how Big Pharma works the marketing campaign to get research developed, executed, shaped, and dispersed to favor increased sales, whether helpful or not. And how psychiatry in general is involved in the ride.

Many people are blogging on this and similar issues. I believe I can contribute to this emerging discussion. Someone has to. The over-promotion of medications, and the pathologizing of phenomena that should not be pathologized, has gone to such an extreme that some sort of counter is needed. So, what occurred to me is the counter: therapy, versus meds.

Sure, there are lots of problems where medications help. And where medications are needed. Are life-saving. Are the best things going, although they may not be optimal. Yes, I believe mental illnesses exist. And should be treated with pharmacotherapy when indicated.

However, Big Pharma, along with the practice of medicine in general, psychiatry in specific, and also medical research as well as other parties, have really gone too far. They have gone too far.

Time after time, medication is provided, is heavily promoted, as the answer, when the answer ought to be therapy. Talk therapy. Psychotherapy. Counseling. Personal Effctiveness Training. Personal Financial Management. Parent Effectiveness Training. Stress Management. Relaxation Skills. Problem-Solving. Assertiveness. There are currently many problems where the evidence is there to indicate that decent therapy is about equal to medication. Yet, in practice, medication is promoted as the first-line treatment, with often no mention of talk therapy as a preferred intervention, a viable alternative, etc. There are circumstances where therapy should be prescribed along with medication. But therapy is never mentioned.

Why? Well, that is what I plan to blog about. I will probably get to sound like a broken record. Heavy marketing by Big Pharma. Pharma's well-planned manipulation of physicians and the educational media to which physicians are exposed. Our society's general desire to have a pill, versus hard work, to cure our problems. The lack of the field of psychology to make psychotherapy understood the way it should be. The misguided belief by people in general and by physicians specifically that physicians are scientists, and thus know how to consume science. The role of third-party payers in health care. The influence of Big Pharma money upon psychiatric research. Shifty, sneaky, misleading research. Lies, Darn Lies, and Statistics. Did I mention Big Pharma? OK. But Big Pharma has not been able to achieve their stunning success alone. Other stakeholders have been complicit.

Well, it comes down to this: sometimes, it is simply meds versus therapy, and sometimes the evidence says therapy wins, even though in practice meds wins. To me, that doesn't sound right. So I am gonna blog about it.