History Forget: How not to explain the impact of Prozac

Having escaped the usual abode for the weekend, there were a pile of the accumulated newspapers to digest on the train this morning. The Sunday Globe Ideas section caught my eye with an item by Jonah Lehrer titled "Head Fake: How Prozac sent the science of depression in the wrong direction". It's not an awful article -- once you get past that subtitle. But, it isn't a great article either.

The article puts forth the thesis that Prozac led to a chemical theory of depression, which recent literature has seriously upended. Alas, that greatly distorts the history.

Prozac was not the first successful drug nor the real antecedent to a chemical theory of depression. Early antidepressives such as the tricyclics and monoamine oxidase inhibitors opened the path to thinking that depression was due to imbalances in specific neurotransmitters. Prozac itself, as a Selective Serotonin Reuptake Inhibitor (SSRI), was an outgrowth of that work -- given the previous success with psychoactive drugs which seemed to affect many neurotransmitters and evidence that specific neurotransmitters might be more important for specific psychological diseases, it was natural to try to zoom in on one neurotransmitter. Prozac then is not a paradigm shifter (ala Kuhn) but was an extension of the existing paradigm. The success of SSRIs, partly due to a significantly attenuated side effect profile and partly due to a lot of popular press and partly due to marketing, merely pushed an existing theory up the ranks, particularly in the popular zeitgeist.

Lehrer does do a nice job of summarizing some recent work suggesting how antidepressants may really work, which is that they may help neurons heal (a new paradigm of depression as a neurodegenerative disease). In a recent conversation a clinician acquaintance noted to me some of the same key points (I'll confess to having not read the literature myself), so there's nothing wrong here. He also notes that it was the investigation of inconsistencies of observation with the predictions of the chemical imbalance theory, such as the frequently observed time lag between beginning antidepressant therapy and seeing results, which led to the new theory.

But getting back to that irksome subtitle, did Prozac steer "the science of depression in the wrong direction" or simply on a winding path? Yes, the chemical imbalance theory looks like it may be down for the count. However, it was that very same theory, via its shortcomings, that led to the new theory. This is how science works -- it's often indirect & messy. That's an important message that's lost (or nearly so) in the piece. SSRIs were perhaps a blunt tool, but they are the tool which has unlocked a new understanding of the topic.

Could we have gotten to the current understanding of depression without SSRIs and other chemical antidepressants? That's an exercise in alternative history best left to experts in the field, if anyone. Perhaps we might have, but perhaps not -- or would have via an even more tortuous path. It is important to get out the story of how pharmaceutical antidepressants do and do not work, but it is equally important to get out the story of how science really works.