Do the Latest Antidepressants Work?

I’m continuing my review of the literature on antidepressants.  Today we cover a systematic review in PLoS Medicine, which is one of the new open access journals that anyone can access.  It’s been amazing to watch these open-source journals revolutionize access to the literature for people like me who don’t have university access.

Here’s the link to the full text article.

PLoS Med. 2008 February; 5(2): e45.

The authors are diverse and from different countries, and they’re only considering FDA submitted data.  I’ll let them summarize their findings:

“Using complete datasets (including unpublished data) and a substantially larger dataset of this type than has been previously reported, we find that the overall effect of new-generation antidepressant medications is below recommended criteria for clinical significance. We also find that efficacy reaches clinical significance only in trials involving the most extremely depressed patients, and that this pattern is due to a decrease in the response to placebo rather than an increase in the response to medication.”

Let me give my own translation:  Unless someone is VERY, VERY depressed, it was hard to justify using these new antidepressants, and then only because there are no non-pharmacological solutions that seem to work anymore.  In other words, it’s not that the drugs worked particularly well in any case, but the placebo effect was no longer of any benefit.  There’s a figure that illustrates this pretty well:

As you start at the left with the people who started out less severely depressed, placebo outperforms the new drugs by a small amount.  Then, as the benefit of placebo decreases, the difference between the two increases.  It’s not that the drugs get that much more effective in people with stronger symptoms, but the difference increases until finally we enter the “green zone”, the area where the drug outperforms the placebo enough to be clinically relevant.  By that point the drug is still not showing much improvement.

I personally found that pretty surprising, given that the data they are mining for the review was in the FDA’s hands.  I went into this evaluation with a general impression that SSRIs and the like work only in cases where there’s an underlying serotonin problem (brain chemistry issues), but now I see that this isn’t going to be that straightforward.

My one concern is that in grouping all these studies together, there seems to be a lot of diversity in the kind of results produced.  I wonder what caused those outlier triangles with high improvement (high on the Y axis).

The investigation continues!


4 comments on “Do the Latest Antidepressants Work?

  1. I was wondering, can these results be generalized to other countries too or do other countries have different antidepressants due to different regulations?

  2. Disclaimer: layman comment and question…
    I have to wonder whether there’s something wrong with the definition of “Clinically Significant Difference” in this field… Given the plethora of “brain” disorders and the severity of each, I’m guessing that brain chemistry is very diverse. Given that, wouldn’t “significance” be almost *any* improvement of symptoms over placebo for a brain-chemistry disorder? Wouldn’t too narrow a definition of “CSD” be looking for a cure-all rather than having doctors run through trial-and-error with their patients?

  3. As neuroscience progresses, much more is being learned about neurotransmitters, immune responses that affect the brain, genetic differences affecting brain function, and gene regulation (expression) under various environmental conditions.

    Serotonin exists in at least 9 forms in the brain, and IF serotonin imbalances are contributors to depression, then specially tailored antidepressants would have to be developed, which is currently being done. I am not arguing that there are not alternatives of superior efficacy.

    Recognizing the complexity of the neurtransmitter diversity and function is the basis for arguments that researchers cannot expect statistical results of significant power from clinical research studies. However, bascic, neuroscience research is making progress in these areas, just as any scientific discipline does. Maybe pharmaceuticals can be found to be useful on a cost/benefit basis for selective patients.

  4. Harriet Hall discussed some of the major limitations of the Kirsch et. al. (2008) study on the SBM blog in the entry “Antidepressants and Effect Size”. Hall explains that:

    – The actual effect size Kirsch found was 0.32, which closely reproduce the effect size of Turner et. al. (2008), which was 0.31.

    – Turner concluded that antidepressants were superior to placebo, while Kirsch did not, despite getting roughly identical results in terms of effect size.

    – Kirsch had used a deprecated and arbitrary standard for clinical significance from the National Institutes of Clinical Excellence of 0.5 (that is no longer used). Hall explains that such an argument is like saying that because a 1/3 full glass (~effect size of 0.32) is not 1/2 full (NICE previous standard), it is therefore practically empty (does not outperform placebo in a clinically relevant way).

    – For comparison, the effect size of psychotherapy is 0.22 (reference in the SBM entry). So if one rejects antidepressants because their effect size is too low, one would have to reject most standard treatments for depression. This seems strange, because that would mean that a mental health professional could not offer any standard treatment whatsoever.

    Obviously, the situation is not black-and-white and the efficacy of antidepressants have probably been hyped up in the media, but I suspect that it may not be as… depressing…as Kirsch concludes.

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