Scott Alexander takes a quick look at a recent discovery in medication for depression:
A few weeks ago, Nature published a bombshell study showing that ketamine’s antidepressant effects were actually caused by a metabolite, 2S,6S;2R,6R-hydroxynorketamine (don’t worry about the name; within ten years it’ll be called JOYVIVA™®© and you’ll catch yourself humming advertising jingles about it in the shower). Unlike ketamine, which is addictive and produces scary dissociative experiences, the metabolite is pretty safe. This is a big deal clinically, because it makes it easier and safer to prescribe to depressed people.
It’s also a big deal scientifically. Ketamine is a strong NMDA receptor antagonist; the metabolite is an AMPA agonist – they have different mechanisms of action. Knowing the real story behind why ketamine works will hopefully speed efforts to understand the nature of depression.
But I’m also interested in it from another angle. For the last ten years, everyone has been excited about ketamine. In a field that gets mocked for not having any really useful clinical discoveries in the last thirty years, ketamine was proof that progress was possible. It was the Exciting New Thing that everybody wanted to do research about.
Given the whole replication crisis thing, I wondered. You’ve got a community of people who think that NMDA antagonism and dissociation are somehow related to depression. If the latest study is true, all that was false. This is good; science is supposed to be self-correcting. But what about before it self-corrected? Did researchers virtuously say “I know the paradigm says NMDA is essential to depression, and nobody’s come up with a better idea yet, but there are some troubling inconsistencies in that picture”? Or did they tinker with their studies until they got the results they expected, then triumphantly declare that they had confirmed the dominant paradigm was right about everything all along?
