Pharmacological nonchalance

In fact, the very theory for how these drugs work has been called into question. Nerve cells — neurons — talk to one another through chemical signals called neurotransmitters, which come in a variety of forms, like serotonin, dopamine and norepinephrine. For decades, a central theory in psychiatry has been that antidepressants worked by raising serotonin levels in the brain. In depressed brains, the serotonin signal had somehow been “weakened” because of a chemical imbalance in neurotransmitters. Prozac and Paxil were thought to increase serotonin levels, thereby strengthening the signals between nerve cells — as if a megaphone had been inserted in the middle.

But this theory has been widely criticized. In The New York Review of Books, Marcia Angell, a former editor of The New England Journal of Medicine, wrote: “After decades of trying to prove [the chemical-imbalance theory], researchers have still come up empty-handed.” Jonathan Rottenberg, writing in Psychology Today, skewered the idea thus: “As a scientific venture, the theory that low serotonin causes depression appears to be on the verge of collapse. This is as it should be; the nature of science is ultimately to be self-correcting. Ideas must yield before evidence.”

[...]

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 When Kirsch and his collaborators combined the published and unpublished studies of anti­depressants (they obtained the unpublished data from the F.D.A. via the Freedom of Information Act), the effects of the antidepressants were even more diluted — in some cases, vanishingly so.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But there are problems in analyzing published and unpublished trials in a “meta-trial.” A trial may have been unpublished not just to hide lesser effects but because its quality was poor — because patients were enrolled incorrectly, groups were assigned improperly or the cohort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.

In 2010, researchers revisited Kirsch’s analysis using six of the most rigorously conducted studies on antidepressants. The study vindicated Kirsch’s conclusions but only to a point. In patients with moderate or mild depression, the benefit of an antidepressant was indeed small, even negligible. But for patients with the most severe forms of depression, the benefit of medications over placebo was substantial. Such patients might have found, as Andrew Solomon did, that they no longer felt “the self slipping out” of their hands. The most severe dips in mood were gradually blunted. Like Dorothy, these patients most likely still experienced sorrow, but they experienced it in ways that were less self-destructive or paralyzing. As Solomon wrote: “The opposite of depression is not happiness, but vitality, and my life, as I write this, is vital.”

These slippery, seemingly contradictory studies converge on a surprisingly consistent picture. First, patients with severe depression tend to respond most meaningfully to antidepressants, while patients with moderate or mild depression do not. Second, in a majority of those who do respond, serotonin very likely plays an important role, because depleting serotonin in depressed patients often causes relapses. And third, the brain-as-soup theory — with the depressed brain simply lacking serotonin — was far too naïve.

And third, the brain-as-soup theory — with the depressed brain simply lacking serotonin — was far too naïve.

The UK and Canada have serious restrictions on the use of stimulants, partly due to the heart problems.