Sequencing ECT, Esketamine, and Ketamine
ECT still has the strongest response data of anything available for severe treatment-resistant depression — but this patient has already refused it, and that refusal has to shape the sequence, not just be noted and overridden.
P.H., a 39-year-old software project manager, has been on medical leave for four months with a depressive episode that has not responded to five adequate antidepressant trials over the past three years, including a prior lithium augmentation trial that produced no meaningful change. He has no psychotic features and no current safety crisis requiring emergent treatment, but the functional decline is real and severe: he has not returned a work email in six weeks, rarely leaves his apartment, and describes his concentration as too poor to follow a television show through to the end.
His psychiatrist raised ECT as the option with the strongest evidence for a case this resistant, and P.H. declined it directly and specifically — his aunt underwent ECT decades ago and, by his account, never fully regained her memory of that period of her life, and he has told the team plainly that he would rather try something else first, even something less effective, than risk that outcome himself. He has no other chronic illness and no contraindication to any of the options on the table; this is a preference, stated clearly and repeatedly, not a clinical limitation.
That refusal is what turns a fairly standard treatment-resistant-depression escalation into a genuine sequencing problem. ECT's response rates run in the 60-80% range in severe depression broadly, and nearer 50-60% in genuinely medication-resistant patients like him — still higher than either esketamine's or ketamine's controlled-trial effect sizes, and it remains the option the evidence most strongly favors on efficacy alone. Esketamine is FDA-approved for this indication and delivered under REMS monitoring in a certified clinic; racemic ketamine, given intravenously off-label, is pharmacologically related and often cheaper per session but carries none of esketamine's regulatory infrastructure and is rarely covered by insurance. The team's task is building a real plan around a treatment he has already ruled out, not simply documenting that ECT was offered and moving on.
At the treatment-planning consultation
I want to be honest about what we're setting aside. ECT's response rates in genuinely resistant depression are higher than anything else we're about to discuss, and part of my job is making sure his refusal is actually informed — that he understands the real evidence gap between it and what we're offering instead, not just that ECT exists as an option he's already said no to.
Granting that gap, esketamine is the more defensible next step of the two glutamatergic options — REMS monitoring means every dose is administered and observed in a certified setting, which gives us real safety infrastructure ketamine doesn't have when it's delivered off-label through an infusion clinic with no standardized monitoring requirement.
Ketamine's mechanism is closely related and the acute response data are comparable in small trials, but the lack of regulatory structure around dosing and monitoring is a real difference in how controlled the treatment actually is, not just a paperwork distinction.
I'd frame esketamine as the next real trial, not a placeholder — a full course, assessed on its own merits at four weeks, with ECT explicitly kept on the table and re-offered if it doesn't work, rather than treated as closed. If cost becomes the barrier instead of his stated preference, that's the point where a ketamine infusion series becomes the more honest fallback than simply declaring esketamine a failure.
Esketamine induction was started under REMS-monitored administration, with a four-week reassessment scheduled and ECT explicitly documented as remaining on the table rather than closed by today's decision.
The team continues maintenance dosing and the ECT conversation stays deferred, not because the evidence changed but because it worked.
ECT will be re-offered directly, and if declined again, racemic ketamine becomes the next real option discussed — not defaulted to silently as the only alternative left.
The psychiatrist's note recorded the refusal as informed and specific, not as a gap in the treatment plan to be worked around quietly — a distinction the team agreed mattered for how honestly the next visit's conversation would go if esketamine doesn't hold.