Neuron Culture

[This is a revised, expanded version of the original heads-up I put up last night.]

A large new meta-analysis of SSRI antidepressant trials concludes that the drugs have essentially no therapeutic effect at all. The study, in PLOS Medicine today, comes on the heels of another study published a few weeks ago (I blogged on it here) showing that SSRIs have little therapeutic effect if you include the (unflattering) clinical trials the industry had previously hidden.

The PLOS study is a meta-analysis of 47 clinical trials that account for almost all full data on clinical trials of SSRIs such as Prozac and Paxil. It showed that “compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression” — and that (as the editors write) “the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective.”

If this holds up, this is a huge development. Many people who take SSRIs say they help them, and they know they have a physiological effect because of subtle or more blatant side-effects — everything from itching, dry mouth, and sexual problems to slight tingling or numbing of the lips or a sort of spacey feel. Those things often kick in within a few days. Then, for those who do feel better, the improvement follows 3 to 6 weeks later. But is the improvement a placebo effect and/or the result of attentive treatment via psychotherapy? The association of the felt physiological changes with improvement makes it seem clear the drug helps. This study appears to argue — adamantly — otherwise — or, at best, that SSRIs work because the drug’s felt physiological side-effects strengthen the placebo effect.

This is a profoundly consequential finding. Millions of people take these drugs, spending billions of dollars to do so. And many feel they are helpful. Are they being hoodwinked? Fooling themselves? All of the above? The finding that the drugs have no statistically significant effect is not necessarily the same as saying they don’t help anyone. It is saying that the drugs help about the same number of people as placebos do. And placebos help a fair number — generally between 30 and 50 percent in antidepressant trials. What’s producing the placebo effect? The power of expectancy comes into play here, as does the value of even a little bit of official attention to one’s despair. Back in 1963, Claude Levi-Strauss proposed some mechanisms behind the magic of placebo:

First, the sorcerer’s belief in the effectiveness of his
techniques; second, the patient’s or victim’s belief in the
sorcerer’s power; and, finally, the faith and
expectations of the group, which constantly acts as a
sort of gravitational field within which the relationship
between sorcerer and bewitched is located and
defined.

Whatever the mechanism, it’s clear that placebos have an effect. If SSRIs are helping some people — and they are, though apparently no more than placebo does — then they may be helping via a placebo effect. THis is valuable, of course. But is it worth the side-effects (and incredible expense)? An SSRI makes a pricey placebo whether from a medical or an economic perspective. But it carries the placebo’s effectiveness, which in depression seems to run about a third to a half.

Be nice, of course, if doctors could just prescribe placebos. But hoodwinking patients — telling the they’re getting a drug when they’re getting a placebo — violates informed consent, at least if the patient asks very many questions. A few years back, a NY Times Magazine article explored just this question — If placebos work so well, why can’t doctors use them?

This is not to suggest we should keep prescribing physiologically powerful, side-effect-heavy drugs just for a placebo effect. That’s not conscionable. But most therapists feel it’s clear that SSRIs, precisely BECAUSE they were so hyped and create such positive expectancy, have provided a tool that has helped many patients feel better and saved quite a few lives. What do we replace that with? This won’t be an easy question to answer.

It’ll be interesting to see how this plays out.

Some of the editors’ summary is below. The paper itself is here, and free.

What Did the Researchers Do and Find?

The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.

What Do These Findings Mean?

These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.