This is the conclusion of a much-publicized article just out in the BMJ: Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and SSRI controlled trials.Reboxetine was introduced to some fanfare, because its mechanism of action is unique - it's a selective norepinephrine reuptake inhibitor (NRI), which has no effect on serotonin, unlike Prozac and other newer antidepressants. Several older tricyclic antidepressants were NRIs, but they weren't selective because they also blocked a shed-load of receptors.
So in theory reboxetine treats depression while avoiding the side effects of other drugs, but last year, Cipriani et al in a headline-grabbing meta-analysis concluded that in fact it's the exact opposite: reboxetine was the least effective new antidepressant, and was also one of the worst in terms of side effects. Oh dear.
And that was only based on the published data. It turns out that Pfizer, the manufacturers of reboxetine, had chosen to not publish the results of most of their clinical trials of the drug, because the data showed that it was crap.
The new BMJ paper includes these unpublished results - it took an inordinate amount of time and pressure to make Pfizer agree to share them, but they eventually did - and we learn that reboxetine is:
- no more effective than a placebo at treating depression.
- less effective than SSRIs, which incidentally are better than placebo in this dataset (a bit).
- worse tolerated than most SSRIs, and much worse tolerated than placebo.
Claims that reboxetine is dangerous on the basis of this study are a bit misleading - it may be, but there was no evidence for that in these data. It caused nasty and annoying side-effects, but that's not the same thing, because if you don't like side-effects, you could just stop taking it (which is what many people in these trials did).Anyway, what are the lessons of this sorry tale, beyond reboxetine being rubbish? The main one is: we have to start forcing drug companies and other researchers to publish the results of clinical trials, whatever the results are. I've discussed this previously and suggested one possible way of doing that.
The situation regarding publication bias is far better than it was 10 years ago, thanks to initiatives such as clinicaltrials.gov; almost all of the reboxetine trials were completed before the year 2000; if they were run today, it would have been much harder to hide them, but still not impossible, especially in Europe. We need to make it impossible, everywhere, now.
The other implication is, ironically, good news for antidepressants - well, except reboxetine. The existence of reboxetine, a drug which has lots of side effects, but doesn't work, is evidence against the theory (put forward by Joanna Moncrieff, Irving Kirsch and others) that even the antidepressants that do seem to work, only work because of active placebo effects driven by their side effects.
So given that reboxetine had more side effects than SSRIs, it ought to have worked better, but actually it worked worse. This is by no means the nail in the coffin of the active placebo hypothesis but it is, to my mind, quite convincing.
Link: This study also blogged by Good, Bad and Bogus.
Eyding, D., Lelgemann, M., Grouven, U., Harter, M., Kromp, M., Kaiser, T., Kerekes, M., Gerken, M., & Wieseler, B. (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials BMJ, 341 (oct12 1) DOI: 10.1136/bmj.c4737
12 comments:
You are going to have to do a lot better than that to debunk the active side effect placebo hypothesis. Oh and SSRI's were "a bit" better than placebo is good news????? I don't think so!
I haven’t read the study or even the abstract, but what was being treated? Mild, moderate or severe depression? Antidepressants generally appear to be not much better than placebo for mild depression but are clearly better than placebo for major depression. This is consistent with the idea that Reboxetine might help a lot if you’re sick enough to be in the hospital, but not do much for you if you can manage on your own anyway.
Are the outcomes broken out by severity of depression in any way?
You might say that the drug reboxetine, which is highly selective as a norepinephrine reuptake blocker, is the most stringent test yet devised of the NE deficiency theory of depression. That theory goes back to 1959 and was formalized in 1964. So this new analysis is telling.
On the other hand, we already know that the extent of blockade of reuptake for either NE or serotonin is unrelated to clinical benefit. Charles Nemeroff’s data tell us that. See Figure 4 in Owens MJ et al. Estimates of serotonin and norepinephrine transporter inhibition in depressed patients treated with paroxetine or venlafaxine. Neuropsychopharmacology 2008; 33: 3210-3212. I tried to include the Figure but could not get it to paste in.
Barney Carroll.
Random fact, it's actually quite a good drug for ADHD-PI (Predominantly Inattentive, aka: ADD), which is what I use it for. It's essentially the equivalent of the much more expensive Strattera (also an NRI), which is why Eli Lilly lobbied the FDA to prevent Reboxetine from getting into the USA.
Alison: They didn't explicitly look at severity, but most of the trials were in people with a baseline Hamilton score of 24-27, the lowest was 22.8.
That's on the borderline between "Moderate" and "Severe" according to most interpretations of the HAMD, and it corresponds very well to other antidepressant trials, so I don't think reboxetine has been tried in especially mild patients, no milder than other antidepressants anyway.
Although this is assuming that you can trust the baseline HAMDs at all - the answer is, it depends on who's rating them. if it's someone who desperately needs to recruit 10 people this week or they won't get paid, and they have to reach a cutoff of HAMD 24, it is easy to fudge it so they do.
@Barney "... we already know that the extent of blockade of reuptake for either NE or serotonin is unrelated to clinical benefit. Charles Nemeroff’s data tell us that. See Figure 4 in Owens MJ et al..." This link takes you there.
Well, there it is for all to see! Thanks very much, Todd.
Is it similar to Wellbutrin in that it oft times INCREASES libido?
SSRIs are notorious for suppressing libido and sexual arousal as side effects.
Hi!
First of all: thanks for your great blog.
@Alison: I'd think twice before stating antidepressants generally are clearly better than placebo in major depression, after reconsidering the publication bias in this field of 'research':
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050045
http://content.karger.com/produktedb/produkte.asp?doi=318293
Best,
Marco
Whitehall: I don't think so, Wellbutrin hits dopamine which is probably why it can increase libido etc, and reboxetine doesn't. Although equally it doesn't cause SSRI-related sexual side effects which are serotonergic.
Regarding the active placebo theory, if it's true that side-effects = unblinding = inflated antidepressant effectiveness then there might be another interpretation of reboxetine being no better than placebo.
That is, it might actually be slightly *less* effective than placebo (i.e., it might increase or maintain depression) but unblinding due to noticeable side-effects provides a compensatory placebo effect, making it equivalent to placebo.
Another example of how important it is to publish clinical trials - and also continue to pursue oversight of the pharmaceuticals.
However, want to also second an earlier post -- it seems to be a useful drug for Attention Deficit. I've used it for brain fog from Chronic Fatigue Sydrome. Can't take regular "speed" focus drugs, had terrible reaction to welbutrin, but a low dose of reboxetine gives me ability to focus and follow through. Has made a very positive difference. So, not necessarily a useless drug, maybe just in the wrong category.
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