You Read It Here First

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By Neuroskeptic
Aug 26, 2010 6:00 PMNov 5, 2019 12:17 AM


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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.

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

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