Antidepressants and the placebo effect

I’m starting to shift the content of the blog beyond simple technical issues. My use of LiveJournal has diminished as everyone elses’ has. I’ll keep posting personal stuff there but more general stuff will end up here.

By Flickr user ~!. Used under A CC license.

Over the past few years I’ve heard rumors of studies that showed a negligible difference between the effectiveness of antidepressants and placebos at treating depression. Now one of the main researchers looking at this, Irving Kirsch, has published a book, The Emperor’s New Drugs: Exploding the Antidepressant Myth, so there’s more press around the question.

While Mark Morford’s take on the issue in SFGate is (as usual) hilarious yet mildly insightful, the Newsweek article it references is where the really interesting information lies.

Basically Kirsch’s research shows that antidepressants have little better than placebo effect for depression (not anxiety, bi-polar or other disorders) in people with mild to moderate symptoms. He based these conclusions on the studies that the drug companies themselves conducted in order to have the drugs approved by the FDA. Initially he used the studies published by the drug companies, but then using freedom of information laws got access to the rest of the studies. Since FDA approval only requires two positive studies (from any number of unsuccessful studies) and statistically significant benefits over placebo treatments it’s fairly straightforward to run a lot of studies and choose the favorable ones when seeking approval.

“By and large,” says Kirsch, “the unpublished studies were those that had failed to show a significant benefit from taking the actual drug.”

In just over half of the published and unpublished studies, he and colleagues reported in 2002, the drug alleviated depression no better than a placebo. “And the extra benefit of antidepressants was even less than we saw when we analyzed only published studies,”

About 82 percent of the response to antidepressants—not the 75 percent he had calculated from examining only published studies—had also been achieved by a dummy pill.

That’s pretty terrible, especially since the frequently significant side effects of antidepressant medication can actually aid their placebo effect:

That matters because belief in the power of a medical treatment can be self-fulfilling (that’s the basis of the placebo effect). The patients who correctly guess that they’re getting the real drug therefore experience a stronger placebo effect than those who get the dummy pill, experience no side effects, and are therefore disappointed. That might account for antidepressants’ slight edge in effectiveness compared with a placebo, an edge that derives not from the drugs’ molecules but from the hopes and expectations that patients in studies feel when they figure out they’re receiving the real drug.

All of this flies in the face of the common understanding of how and why antidepressants work. Our amateur brain chemistry knowledge tells us that serotonin is the chemical that triggers happiness in the brain. Its receptors are what drugs like ecstasy, cocaine and speed target, and the popular SSRI family of antidepressants (such as Celexa, Prozac, Paxil and Zoloft) act to keep brain serotonin levels higher than they would otherwise be, “fixing the chemical imbalance”. But between research that dismisses those effects (and suggests other theories for the effectiveness of SSRIs) and evidence that SSREs (which reduce serotonin levels) are also effective as antidepressants it seems like the science to explain the actions of antidepressants is at best really weak.

The other side of this story is that antidepressants help people. I have plenty of friends who’ve had their lives significantly improved when they began taking antidepressant medication. Are they just getting a placebo effect? Does it matter if they are?

Well, the side effects of SSRIs can be fairly severe. And they’re quite expensive – Prozac is $12 per dose (or $1.40 in generic). But the problem with prescribing sugar pills is that they’re only effective when patients believe them to be an expensive, dangerous drug. I’d personally prefer for people with mild forms of depression to receive non-drug therapy initially (as the NHS in the UK now recommends). If 80% of patients aren’t getting a chemical effect, but a psychological (placebo) effect then we should be able to help them equivalently with other non-chemical methods like therapy. Of course, even at $12 a pill, using antidepressants for their placebo effect is probably cheaper than using trained therapists.

Go read the Newsweek article. It’s really good!

4 replies on “Antidepressants and the placebo effect”

  1. Just to clarify something:

    “Its receptors are what drugs like ecstasy, cocaine and speed target” isn’t wholly accurate. MDMA releases serotonin, noradrenaline and dopamine (though it’s best known for its serotonin effects), cocaine is a serotonin-noradrenaline-dopamine reuptake inhibitor and amphetamines also affect serotonin and dopamine (again, reward linked to dopamine). While yes, there is serotonin involvement, I think it is simplistic in the extreme to imply that the 5-HT receptors are the main targets for these drugs (which exert significant effects through the mesolimbic system).

    1. I can’t get away with anything with you watching!
      Thanks for the correction. Still there is a perception that serotonin = happiness that prescription and illicit drug culture both play into.

  2. Plus some of the more modern anti-depressants (e.g. Efexor) are SNRIs that work on both serotonin and neo-dopamine pathways.

    But whatever works for the individual – the important thing is to have a great primary care physician. For me, better living through (bio-)chemistry, makes a great motto.

  3. I took a lot of anti-depressants and they didn’t help at all. If they had a little bit of methamphetamine in them I bet they would have though.

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