Esketamine and ketamine sit among the top-line, best-evidence options for treatment-resistant depression, and esketamine can be considered for some patients with bipolar depression. The show still ranks esketamine low: it is a fast, short-term lift without lasting benefit on its own, and it only works when paired with psychotherapy and hard lifestyle changes rather than used to paper over a life that keeps stress unmanageable.
When we reach for it
For treatment-resistant depression, the ketamines (esketamine and ketamine) are on the list of top-line interventions with the best evidence, alongside ECT, TMS, antipsychotics (aripiprazole most of all), lithium and thyroid supplement.
“The best evidence goes to ECT, TMS, TMS. antipsychotics, particularly aripiprazole has the best evidence and the biggest effect size, lithium, thyroid supplement, and the ketamines, esketamine and ketamine. So those would be our top line interventions”
6:46The Deficit Model in Psychiatry & Difficult to Treat Depression with Dr. Chris Aiken | Episode 18Mar 2025Guest episode For the depressive side of bipolar disorder, esketamine can be considered for some patients.
“wanted to mention also for the depression component beyond that, TMS, I am seeing some pretty good effect while your mood stabilized seems to be helpful. And you can consider esketamine for some patients”
51:20The Best Bipolar Medication Review From The Best Bipolar ExpertJan 2025
Pitfalls and myths
Esketamine is a short-term treatment that helps lift out the depression, and then you have to do hardcore lifestyle changes and psychotherapy on top of that.
“It is a short-term treatment that helps you lift out the depression and then you have to do hardcore lifestyle changes and psychotherapy on top of that”
1:03:18Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 Many patients now seek it out as a drug to ignore other problems, while making lifestyle choices that are almost bound to keep stress at unmanageable levels.
“there's so many patients now who are seeking it out to use it in a sense to ignore other problems and they're using it essentially as a drug as in they're making lifestyle choices that are That are almost bound to lead to stress levels that are not manageable”
1:04:11Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 Ketamine has a big effect size, but the benefit does not last, so it is not something to suggest to everyone.
“I'm not like suggesting everyone take ketamine even though it has a big effect size because it doesn't have lasting benefits”
36:37The Deficit Model in Psychiatry & Difficult to Treat Depression with Dr. Chris Aiken | Episode 18Mar 2025Guest episode
From these episodes
Every point above is something said on the Psychofarm podcast, with the words as spoken and a link to the moment in the episode. It is education, not medical advice, and an episode reflects what we thought when we recorded it.