The XX Factor

How Do Antidepressants Work? Newsweek Gets It Wrong.

Newsweek has just weighed in with a cover story (“Antidepressants Don’t Work”) based on the recent JAMA antidepressant study and previous summary analyses of FDA and drug-company data. Here and elsewhere , I have had my say on this research. Newsweek thinks it shows that for most sorts of depression, antidepressants are no better than placebo; I think that the studies are weak.

But the Newsweek piece goes further. It says that when antidepressants do work (even Newsweek says that they are effective for severe depression), it is not by the means that most scientists have been studying. The prevailing theory is that, whatever they do downstream, the initial effect of antidepressants is through their action on the way that the brain handles neurotransmitters-substances, like serotonin and norepinephrine, that the brain uses for internal communication.

The relevant passage in the Newsweek piece is about an antidepressant, widely available in Europe and Latin America, called tianeptine. Newsweek relies on Irving Kirsch , a psychologist whose research triggered the placebo debate, for interpretation:

And a new drug, tianeptine, which is sold in France and some other countries (but not the U.S.), turns out to be as effective as Prozac-like antidepressants that keep the synapses well supplied with serotonin. The mechanism of the new drug? It lowers brain levels of serotonin. “If depression can be equally affected by drugs that increase serotonin and by drugs that decrease it,” says Kirsch, “it’s hard to imagine how the benefits can be due to their chemical activity.’”

But tianeptine is hardly new. A fact-checker would have had only to look at the Wiki on tianeptine to see that the drug dates back to the 1980s. Many antidepressants block brain cells’ tendency to re-absorb serotonin-so that the neurotransmitter remains active for a longer time; grossly, tianeptine does the opposite-that is, it enhances serotonin re-uptake. For decades, then, tianeptine was presented as a counterexample to prevailing theories; looking at old files, I see that I discussed tianeptine in public lectures dating back to the mid-1990s. But recent evidence suggests that (much like other antidepressants) tianeptine actually increases serotonin levels regionally-for instance, in an area of the hippocampus thought to be related to mood regulation. And even the prior research , again dating back to the 1990s (it is out of Bruce McEwen ‘s laboratory, a reliable source), found that after 14 days of use, tianeptine alters serotonin transport in the same fashion as yet older antidepressants. More generally, tianeptine’s effects are very much in accord with the current theory of the mechanism of action of other antidepressants, through the induction of neuroresilience in the hippocampus and elsewhere. I reference this evidence in Against Depression , published in 2005; the end notes provide a short bibliography on the topic.

So (contra Kirsch) it remains easy, in the face of evidence that tianeptine works, to imagine that the benefits of antidepressants are due to their chemical activity. While there has always been reason to doubt the ” chemical imbalance” theory of depression causation, decades of research ranging across a range of scientific disciplines support the idea that antidepressants operate initially via the drugs’ main effects, namely by altering the way the brain handles neurotransmitters. That’s why we have structurally diverse “me-too” drugs, ones that, however else they differ, all affect serotonin and norepinephrine pathways. To set aside the testimony of animal model research, brain enzyme research, the new work on neurogenesis, and on and on-this stance has the whiff about it of science denial. It is one that a major magazine should have showcased cautiously, if at all, and only after having done some serious homework.