Four years ago I examined the claim that SSRIs are little better than placebo. Since then, some of my thinking on this question has changed.

First, we got Cipriani et al’s meta-analysis of anti-depressants. It avoids some of the pitfalls of Kirsch and comes to about the same conclusion. This knocks down a few of the lines of argument in my part 4 about how the effect size might look more like 0.5 than 0.3. The effect size is probably about 0.3.

Second, I’ve seen enough to realize that the anomalously low effect size of SSRIs in studies should be viewed not as an SSRI-specific phenomenon, but as part of a general trend towards much lower-than-expected effect sizes for every psychiatric medication (every medication full stop?). I wrote about this in my post on melatonin:

The consensus stresses that melatonin is a very weak hypnotic. The Buscemi meta-analysis cites this as their reason for declaring negative results despite a statistically significant effect – the supplement only made people get to sleep about ten minutes faster. “Ten minutes” sounds pretty pathetic, but we need to think of this in context. Even the strongest sleep medications, like Ambien, only show up in studies as getting you to sleep ten or twenty minutes faster; this NYT article says that “viewed as a group, [newer sleeping pills like Ambien, Lunesta, and Sonata] reduced the average time to go to sleep 12.8 minutes compared with fake pills, and increased total sleep time 11.4 minutes.” I don’t know of any statistically-principled comparison between melatonin and Ambien, but the difference is hardly (pun not intended) day and night. Rather than say “melatonin is crap”, I would argue that all sleeping pills have measurable effects that vastly underperform their subjective effects.

Or take benzodiazepines, a class of anxiety drugs including things like Xanax, Ativan, and Klonopin. Everyone knows these are effective (at least at first, before patients develop tolerance or become addicted). The studies find them to have about equal efficacy as SSRIs. You could almost convince me that SSRIs don’t have a detectable effect in the real world; you will never convince me that benzos don’t. Even morphine for pain gets an effect size of 0.4, little better than SSRI’s 0.3 and not enough to meet anyone’s criteria for “clinically significant”. Leucht 2012provides similarly grim statistics for everything else.

I don’t know whether this means that we should conclude “nothing works” or “we need to reconsider how we think about effect sizes”.