You Read It Here First

By Neuroskeptic | August 26, 2010 9:00 am

Remember the paper from 2009 about combining two different drugs in the treatment of depression?

It was about a clinical trial in which patients were randomly assigned to get just one antidepressant, fluoxetine, or two – mirtazapine & fluoxetine, mirtazapine & venlafaxine, or mirtazapine & buproprion. The people who got two antidepressants did better.

But as I said at the time, in a comment beneath my post about it…

All the first 6 weeks shows is that mirtazapine is better than placebo. Everyone in the study got a non-mirtazapine antidepressant, so any improvement in the non-mirtazapine group (i.e. the fluoxetine alone group) could have been placebo, regression to the mean etc. The only placebo-controlled aspect was that some people got placebo mirtazapine and some people got real mirtazapine.

Now Dr’s El-Mallakh, Kaur and Lippmann have written in a Letter to The Editor of the American Journal of Psychiatry (where the original paper appeared) that

There was no mirtazapine plus placebo study group. This comparison arm is necessary in order to be confident that the observed effect by the three combined treatments could not have been accomplished by mirtazapine as a single drug. The observation that mirtazapine alone was equivalent to fluoxetine or paroxetine alone in a previous study does not negate the need for a control in the Blier et al. study. Without such a control, one cannot assume that two antidepressant medications are more effective than mirtazapine alone.

What I said – on 18th December 2009. The new Letter was “accepted for publication” in May 2010, and it’s only just appeared.

Am I just blowing my own trumpet? No. Well, a bit. But there’s a serious point as well: internet comments are a much better medium for discussing and criticizing research than Letters To The Editor ever can be.

Why? The Letter may have been a bit slower, but it’s still out there, surely? Plus, it’ll have been read by far more people. My post has got about 400 pageviews so far. I don’t know how many people read the Letters page in the AJP, but I’d imagine it must be a good few thousand. So what’s the problem?

The problem is that it’s too late. Papers get cited by other papers fast (this one’s got 13 citations so far), and they change minds even faster. This article’s been out nearly a year, and I’m sure that in that time it will have convinced some psychiatrists to start their depressed patients on two drugs, rather than just one.

Now I’m not saying they shouldn’t do that. I don’t know. Anyway, I’m not a doctor. But I stand by my comment that this paper shouldn’t be what changes your opinion on that question; the design of the trial means it can’t tell you that. And I think that’s something that readers of the paper should have been told at the time, not 9 months later.

What’s the solution? I’ve written about this previously as well. Scientific journals should have open, blog-style comment threads attached to everything they publish, so that readers can say what they have to say, immediately. A number of major journals, e.g. the PLoS journals, some of the Nature ones, and the BMJ, already do this.

From what I’ve seen, the standard of comments is extremely high. Sure, some are rubbish. But the rubbish ones are almost always obviously bad, so I don’t think they’ll be doing much damage. The good ones, on the other hand, are often extremely insightful – whether they are criticizing, or praising, the paper.

ResearchBlogging.orgEl-Mallakh RS, Kaur G, & Lippman S (2010). Placebo group needed for interpretation of combination trial. The American journal of psychiatry, 167 (8) PMID: 20693473

  • Anonymous

    I have taken most SSRIs and SNRIs over the years.
    Multiple-neurotransmitter drugs work best for me: venlafaxine (currently taking 1 branded XR capsule QAM for just enough of a 'kick in the brain' to alleviate not wanting to get up and be productive – IMHO, desvenlafaxine is not worth time, $, and effort), mirtazapine (felt great, slept great, but gained weight – if it weren't for the last, I'd probably still be taking it), duloxetine (felt great but had anaphylactic rxns – fortunately my doc gave me samples), and nefazodone (felt good, but not available any more AFAIK due to hepatic issues) worked well for me. Tried milnacipran but didn't have a high enough dose to see if it really worked (off-label here for anything but fibromyalgia).

    SSRIs were somewhat helpful, but their efficacy decreased over time. I've taken fluoxetine (started when it first came out), sertraline (same as fluoxetine), paroxetine (makes me cranky), bupropion (same as paroxetine), escitalopram (didn't work – at least my doc gave me samples – never had citalopram).

    One of the problems was misdiagnosis – years after initial dx, my psychiatrist at the time evaluated me for bipolar disorder and ADD. What a big difference that made!
    Still take a lot of drugs – not antidepressants as much as mood stabilizers, ADD meds, and sleep drugs. Still have to tweak, but I'm getting far better relief and symptom control.

    I'm hoping that another company will pick up esmirtazapine since Merck killed it off, along with much of the remainder of Organon.

  • Anonymous

    Anon's prior post has to be a joke! LOL.

    In any event, Neuro, you should blow your own trumpet! You caught the problem right away! Good for you!

  • veri

    Anon.. woah.. you need a hug. *hugz* It's ok puppy :)

  • Anonymous

    Another answer is to put drafts up on the ArXive. The advantage of this is that errors can be caught before the research goes to publication.

    Before the internet, journals were necessary to disseminate information across the country. Now, they serve mostly as a categorization and referendum on the quality of research. This can still be true, but that way before the final version is out, embarrassment and anger can be avoided if someone points out fatal design flaws prior to publication.

  • Anonymous

    I may be missing something here. I admire the brilliant prescient prose of Neuro, but shouldn't peer reviewers of this most distinguished American journal have snatched the obvious design flaws prior to publication? Or were they all taking Pharm money and were intoxicated by the findings? Just asking.

  • Neuroskeptic

    Well, yes, they should have.

    What makes it especially bad is that the paper came with an attached Editorial which, although it made a few mildly critical points, didn't discuss this issue at all.

    As the new Letter says
    “it would have been important for the research article (1) and the accompanying editorial (2) to note this design flaw.”

  • Michael

    Hi neuro — “long time reader, first time commenter”…

    Are you aware of any press about the original research? I'm wondering because when I write news stories about this kind of research, I usually get comments from someone in the field, and often they raise this sort of issue.

    I wonder if any news stories included a discussion of this problem. (I'm talking about specialist publications of course — not the popular press.)

  • Marcos Hardy

    There is no doubt that you were right as to the lack of evidence regarding the greater efficacy of combining antidepressants in Blier’s et al paper.
    Unfortunately, you are also right that people simply do not analyze the clinical evidence, or lack of it thereof, and just take for granted that this study validates polypharmaceutical approaches to the treatment of depression. And by polypharmacy I mean the use of two drugs targeting identical receptors. Case in point is the May 2010 issue of Current Psychiatry. Its Editor-In-Chief, Henry Nasrallah, a Professor of Psychiatry at the University of Cincinatti, wrote an editorial entitled “Combination Therapy Is Here To Stay.” In it he states:
    “Although psychiatrists commonly combine psychotropic medications, researchers malign the practice as “not evidence-based.” Research is finally catching up with clinical practice, however, and evidence is rapidly accumulating that for many patients with severe psychiatric disorders, 2 drugs are better than 1.”
    Among other “evidences” he cites the Blier et al. paper in AJP, stating that in unipolar depression “Blier et al. demonstrated a remarkable superiority of 3 different combinations of 2 antidepressants compared with fluoxetine monotherapy.”
    There is no analysis of the research, just quotation from the abstract. More damning, residents take pronouncements like this as matter of faith, and are instructed to follow indications like those presented by Blier et al. So much for education.
    Another intriguing fact of the study in question is that the antidepressant that is present in the three “combined” arms is the tetracyclic mirtazapine, manufactured by Organon. Organon funded the study of Blier et al. Is it really surprising that they did not compare the effects of mirtazapine with placebo? Or that if they did they decided that it was not convenient to present the results?



No brain. No gain.

About Neuroskeptic

Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.


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