Friday, May 14, 2010

Eli Lilly: Our Drug Failed, So it Has Serious Potential

ResearchBlogging.org
These folks at Lilly must think we are exceptionally stupid. As in can't tie our own shoes. A study in the Journal of Psychiatric Research recently found that their experimental antidepressant LY2216684 was no better than placebo. Here are a couple of quotes from the abstract:
LY2216684 did not show statistically significant improvement from baseline compared to placebo in the primary analysis of the Hamilton depression rating scale (HAM-D17) total score. Escitalopram demonstrated significant improvement compared to placebo on the HAM-D17 total score, suggesting adequate assay sensitivity.
On the primary outcome measure, the experimental drug failed whereas Lexapro worked to some extent. I know what you're thinking - "the sample size was probably too small to find a significant effect." Um, you're wrong. How about 269 people on the Lilly drug, 138 on placebo, and 62 on Lexapro.

But wait, here comes the good news...
Both LY2216684 and escitalopram showed statistically significant improvement from baseline on the patient-rated QIDS-SR total score compared to placebo... The results of this initial investigation of LY2216684’s efficacy suggest that it may have antidepressant potential.
The good news for Lilly is that most people who claim to "read journal articles" really just browse the abstract without actually looking at the full text of the paper. For the select few who have nothing better to do than read Lilly propaganda, take a look at Table 2. A total of 12 secondary outcome measures are listed. The Lilly drug beat placebo on... ONE of them. Lilly doesn't say much about how much better their drug was than placebo on the QIDS-SR measure beside throwing around that often meaningless term of "statistically significant." People on the drug improved by 10.2 points whereas placebo patients improved 8.3 points. So about a 20% difference. If you bother to calculate an effect size, it is d = .24, which is quite small and clinically insignificant. So on the ONE measure where the drug was better than placebo, it was by a small margin, and it missed the mark on 11 other secondary measures as well as on the primary outcome measure. But "it may have antidepressant potential." Hell yes, I've never been so exited about a new drug.

By the way, Lilly is apparently trying this wonder drug out in at least five trials. The journal in which this article appeared has published other dubious Eli Lilly research in the past. The editorial review process is clearly working wonders over at the Journal of Psychiatric Research. Sad, really. The journal publishes some really good work, but then runs this kind of junk as well.

Depression Self-Report Sidebar: The self-reported measure on which the drug had an advantage, the Quick Inventory of Depressive Symptoms (QIDS) - it's really awesome, according to Lilly. Remember, it's the only measure on which their experimental failure drug had an advantage over placebo. So the authors wrote "Self-reported depression symptoms, such as those obtained by the QIDS-SR, may be more sensitive than clinician-administered scales for signal detection in clinical studies of depression."

What does Bristol-Myers Squibb think? In three trials of Abilify for depression, self-reports of depression were unfavorable. So the publications for these studies made sure to downplay these depression self-reports by saying that these measures were not sensitive, that they weren't picking up improvements in depression.

So if a self-report provided positive results, then BAM, it's an awesome measure of depression. But if it provided negative results, then it's a horrendously inaccurate measure and should never have been used in the first place.

Citation below. Yes, one of the authors' last names is Kielbasa.

Dubé, S., Dellva, M., Jones, M., Kielbasa, W., Padich, R., Saha, A., & Rao, P. (2010). A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression Journal of Psychiatric Research, 44 (6), 356-363 DOI: 10.1016/j.jpsychires.2009.09.013

13 comments:

Radagast said...

Ah, yes, but if one goes to one's quack for a prescription, placebo is not an option, apparently because it's not ethical to prescribe placebos (can't remember where I read that pearl, but it was somewhere reasonably official!). So, while you and I both know that one could buy a pack of M&Ms from a sweetshop, and be entitled to expect roughly the same level of relief from our depression, most people don't, as you suggest.

Matt

Joseph Arpaia, MD said...

@Radagast

Liked your comment. However, sugar is actually a decent mood enhancer. Works for me anyway. Possibly because of the release of beta-endorphin. So the M&M's would actually be better than the pills.

--Joe

The Cave of the Dead said...

I'm pretty new to interpreting articles. So this is a strong reminder of the need to be sceptical of peer-reviewed papers, and also a demonstration of the kinds of shenanigans that can be employed.

I think it's particularly important that you called the journal on its endorsement of dodgy science through publication. Bravo for that. It seems to me as a novice, that a combination of genuine peer-review - as enhanced by this blog, and routine evaluation by an experienced statistician, can only be to the benefit of science, and the detriment of charlatanry.

Bernard Carroll said...

Good stuff, CP. We know that Alan Schatzberg, the US editor in chief of this journal, has long had a big time consulting relationship with Lilly. Despite some searching, I was unable to locate any statement of disclosure by the editors on the journal website today.

Journal of Psychiatric Research used to be a fine journal under the leadership of its founder Seymour Kety, and then Joe Schildkraut and Merton Sandler. The current editors appear to treat it as a house journal. A lot of Eli Lilly pabulum shows up on the US side and, in general, a lot of what looks like self dealing, cronyism, and academic nepotism can be found in the pages of JPR nowadays. The expression race to the bottom comes to mind.

Radagast said...

Joseph Arpaia, MD wrote:
"Liked your comment... So the M&M's would actually be better than the pills."

Thanks. Yes, I should be more precise: placebos are not recognized to have any clinical value. And then, of course if one's placebo was a chocolate M&M, there's all sorts of interesting stuff in the chocolate, apart from the sugar!..

But, for me, it's the passive nature of taking a pill - a patient with depression believes that they can do nothing about it, but a drug will do the trick. One of the consequences of this is that it allows people to believe that they must take a drug for evermore, in order to stave off their depression (or whatever). Why don't people allow themselves to consider the possibility that they've at least contributed to their own recovery?

Matt

Anonymous said...

Hey CP:
Nice post, as usual. What's your take on the current Archives of General Psychiatry study regarding rTMS? Any thoughts? Is this a scam or what???

Anonymous said...

Anon: here's a post on the rTMS article: http://chekhovsgun.blogspot.com/2010/05/transcranial-magnetic-stimulation-does.html

Neuroskeptic said...

The HAMD is generally regarded as more sensitive to change than self-report scales...

Also don't forget the side effects:
"Headache, nausea, constipation, dry mouth, and insomnia were the most frequently reported adverse events in the LY2216684 group. A 3-6 beats per minute mean increase from baseline in pulse rate was observed in the LY2216684 group"

All in all it sounds like the new reboxetine - officially the worst antidepressant according to the Lancet super fancy meta analysis.

Anonymous said...

Hope you plan to keep posting CP.

Been missing your stuff.

Vorobiev said...

I too think that the placebo effect has a lot to do with bettering on one's depression.

Our minds can auto-hypnotize ourselves into believing that a pill is making us better.

Anonymous said...

Is this blog still active? What are some other good blogs mixing psychology and psychiatry?

thanks

Fat Bastard said...

When are you charlatans actually going to cure something?

Kellen said...

Ohhh, thank you. Is there anything better than a healthy dose of science AND a good, hearty laugh?

Dr. Kielbasa, huh? Better than a Dr. Toten I once visited (toten being the German word for death).