There’s an interesting analysis in the latest PLoS Medicine on the clinical effectiveness of four modern antidepressant drugs: Prozac (fluoxetine), Effexor (venlafaxine), the partially discontinued Serzone (nefazodone), and Paxil (paroxetine). The authors compared all the published placebo-controlled studies on these drugs, and further included all the regulatory filing data. (Update: not so! See below). The result made headlines all over the place yesterday, because one of the things they found was that these drugs hardly seem, compared to placebo, to do anything at all.
Here’s the odd part: that shouldn’t have been such a big surprise. It wasn’t surprising to the authors of the paper – in fact, they started with the belief that this would be the case, because that analysis has been done before. Their interest was in seeing if there was some difference between different populations of depressed patients – is there some group for which the drugs really show efficacy or not?
As it turns out, there is, but perhaps not for the reasons you’d think. The most severely depressed cohort do seem to show a statistically meaningful response, but that seems largely because the placebo group’s response goes down. That’s been the difficulty with antidepressant clinical trials forever: there is a huge placebo response. This isn’t news; people have been studying this effect and trying to figure out what it means (or figure out a way around it) for years.
So, what does this do to the whole popular culture around the SSRI drugs – you know, “Listening to Prozac”, “Prozac Nation”, all that sort of thing? In this case, popular culture probably has it wrong. These drugs are not magical happy pills, but “Placebo Nation” just doesn’t have the same ring to it. The whole subject is too tangled to make for a catchy title.
It makes sense, though, that this is the area of drug discovery where the biggest placebo effect would turn up – you’d have to think that for depressed patients, a big step would have to be the thought that something can actually affect their condition. It’s bound to help for them to believe (correctly) that their moods aren’t necessarily part of the drab fabric of the universe, but depend instead on the (changeable) chemical weather inside their brains. Knowing those things, and the act of taking a medication that is supposed to work, is enough to help between a quarter and a half of depressed patients right there.
The actual mechanism of the placebo effect is a field of great interest and potentially great importance. (See here, here, here, and here). News like this makes a person wonder, though: if large parts of the public become convinced that antidepressant drugs don’t work, will they? And the question remains: do the SSRI drugs do anything at all through their supposed chemical mechanisms? (It's not like we know). One way to find out would be to run a placebo versus placebo trial. You could blind things at the start, even though everyone was getting the same sugar pills, and you’d presumably see the same response in each group. Then you unblind and cross everyone over, telling people that they’d been in one group and were now headed to the other. Careful work would give you four study arms: (1) people who responded to placebo, and who were then told they’d been taking sugar but were now getting the real drug, (2) people who responded and were told that they were taking a real drug but were now being switched off of it, (3) people who didn’t respond, but were told that this was because they’d been taking sugar, but help was now on the way, and (4) people who didn’t respond, and were told that they’d been getting (apparently ineffective) drug, but were now coming off even that. Fascinating stuff, but we’re going to have to wait for the North Koreans to set it up for us, because no other regulatory agency would let it through.
But from this latest analysis, we can conclude something interesting. The fact that the placebo effect diminishes in the most severely depressed patients, but that the drugs continue to show the same level of efficacy, suggests that they do have some effects of their own. To me, that’s the real news from this study. It reminds me of G. K. Chesterton’s line about journalism being the business of saying “Lord Jones Is Dead” to people who never knew he was alive. In this case, the headlines have been “Antidepressants Don’t Work”, but that should have been the headline years ago. This one should have come in as “Antidepressants Might Actually Do Something”.
Update: A closer look, as suggested in the comments section, shows that the trials included in the meta-analysis were mostly quite short (six weeks or less), when a good deal of evidence would suggest that these drugs take longer to become truly worthwhile. And there is only one study on moderate depressed patients, making it hard to draw conclusions about that group. See the comments page on the article here for more criticisms. So, do antidepressants work or not? You can find an answer that fits, no matter what you need it to be. . .