At first glance, these studies seem to suggest that there is no link between serotonin and depression. But an important fact stands out in the McGill experiment: lowering serotonin does not have any effect on healthy volunteers with no history of depression, but serotonin-lowering has a surprisingly brisk effect on people with a family history of depression. In these subjects, mood dipped sharply when serotonin levels dropped. An earlier version of this experiment, performed at Yale in 1990, generated even more provocative findings. When depressed patients who were already responding to serotonin-enhancing drugs, like Prozac, were fed the serotonin-lowering mixture, they became acutely, often profoundly, depressed. Why would serotonin depletion make such a difference in a patient’s mood unless mood in these patients was, indeed, being controlled by serotonin?

Other experiments showed that though depressed patients generally didn’t have consistently lower levels of serotonin, suicidal patients often did. Might contemplating suicide be the most extreme form of depression? Or is it a specific subtype of mood disorder that is distinct from all the other forms? And if so, might depression have multiple subtypes — some inherently responsive to treatment with serotonin-enhancing drugs and some inherently resistant?

We may not understand how serotonin-enhancing antidepressants work, but do we know whether they work at all?

In the late 1980s, studies examined the effect of Prozac on depressed subjects. Several of these trials showed Prozac reduced the symptoms of depression when compared with a placebo. Depression is usually assessed using a standardized rating scale of different symptoms. In general, some patients reported clinically meaningful improvements, although the effects were often small and varied from trial to trial. In real-world terms, such a change could be profound: a transformation in anxiety, the lifting of the ache of guilt, an end to the desire to commit suicide. But for other patients, the changes were marginal. Perhaps the most important number that emerged from these trials was the most subjective: 74 percent of the patients reported feeling “much” or “very much” better on antidepressants.

In 1997, a psychologist, Irving Kirsch, currently at the Harvard Medical School, set out to look at the placebo effect in relation to depression. In part, the placebo effect works because the psyche acutely modifies the perception of illness or wellness. Kirsch wondered how powerful this effect might be for drugs that treat depression — where the medical condition itself happens to involve an alteration of the psyche.

To measure this effect, Kirsch combined 38 trials that included patients who had been given antidepressants, placebos or no treatment and then applied mathematical reasoning to estimate how much the placebos contributed to the improvements in mood. The analysis revealed two surprises. First, when Kirsch computed the strength of the placebo effect by combining the trials, he found that 75 percent of an antidepressant’s effect could have been obtained merely by taking the placebo. When Kirsch and his collaborators combined the published and unpublished studies of anti­depressants (they obtained the unpublished data from the F.D.A. via the Freedom of Information Act), the effects of the antidepressants were even more diluted — in some cases, vanishingly so. Now, the placebo effect swelled to 82 percent (i.e., four-fifths of the benefit might have been obtained by swallowing an inert pill alone). Kirsch came to believe that pharmaceutical companies were exaggerating the benefits of antidepressants by selectively publishing positive studies while suppressing negative ones.

But there are problems in analyzing published and unpublished trials in a “meta-trial.” A trial may have been unpublished not just to hide lesser effects but because its quality was poor — because patients were enrolled incorrectly, groups were assigned improperly or the cohort sizes were too small. Patients who are mildly depressed, for example, might have been lumped in with severely depressed patients or with obsessive-compulsives and schizophrenics.