After Two Failed Antidepressants: TMS and Esketamine

A Call to Escalate Treatment Sooner, Not Later

A commentary published on KevinMD.com on September 27, 2026, titled "After 2 failed antidepressants, raise TMS and esketamine," argues that clinicians should move to transcranial magnetic stimulation (TMS) and esketamine sooner in a patient's treatment course, rather than continuing to cycle through additional oral antidepressant trials. The piece is framed as physician commentary rather than a clinical trial or guideline update, and the publicly available summary does not include the full clinical reasoning, patient population, or data the author cites. Still, the core message reflects a longstanding tension in psychiatry: how long should a patient try standard antidepressants before moving to a different treatment category.

In psychiatric practice, treatment-resistant depression (TRD) is commonly defined as depression that has not adequately responded to at least two antidepressant trials of adequate dose and duration, typically six to eight weeks each. That definition is why the "two failed antidepressants" threshold in the KevinMD headline is clinically meaningful rather than arbitrary. TMS, a noninvasive procedure that uses magnetic pulses to stimulate specific brain regions, received FDA clearance for depression in 2008. Esketamine, sold under the brand name Spravato, is an FDA-approved nasal spray for treatment-resistant depression, cleared by the agency in 2019 for use alongside an oral antidepressant and administered under medical supervision due to sedation and dissociation risks.

Why This Matters for Ketamine Therapy Readers

Readers of Low Dose Ketamine should understand that esketamine and the low-dose ketamine infusions or compounded formulations discussed on this site are related but not identical. Esketamine is the S-enantiomer of ketamine, delivered as an FDA-approved intranasal product with a specific approved indication, dosing protocol, and REMS (Risk Evaluation and Mitigation Strategy) monitoring requirement. Off-label low-dose ketamine, typically given as IV infusions, intramuscular injections, or compounded sublingual troches at specialty clinics, has not received the same FDA approval for depression and is used under physician discretion rather than a standardized federal protocol. Both approaches share a mechanism rooted in NMDA receptor modulation, and both are typically reserved for patients who have not responded to first-line antidepressants, but the regulatory status, insurance coverage, and monitoring requirements differ meaningfully between them.

What the Evidence Does and Does Not Show

The KevinMD piece appears to be a physician opinion article rather than a peer-reviewed study, and the available summary does not specify a data source, sample size, or outcome measure. That distinction matters for readers evaluating how much weight to give the recommendation. Clinical guidelines from bodies such as the American Psychiatric Association have historically supported considering TMS or ketamine-based treatments for patients who have not responded to two or more antidepressant trials, but the exact sequencing, whether TMS or esketamine should come first, and how patient-specific factors like prior response, medical history, or access to a treatment center should influence that choice, remains a matter of clinical judgment rather than a single fixed rule.

Practical Steps If You Have Had Two Failed Antidepressants

For readers who have already tried two adequately dosed antidepressants without meaningful improvement, a few practical steps can help structure the conversation with a psychiatrist or treatment center. First, confirm that both prior trials met the standard threshold of adequate dose for six to eight weeks, since a trial that was too short or too low-dose does not count toward the treatment-resistant definition and may mean a third standard antidepressant is still worth trying. Second, ask about the specific mechanism, monitoring, and cost structure for TMS, esketamine, and off-label low-dose ketamine separately, since they are not interchangeable options and a clinic offering one may not offer or recommend the others. Third, ask what maintenance schedule each option involves. Esketamine typically requires an induction phase followed by less frequent maintenance dosing under REMS supervision, TMS involves a multi-week course of daily sessions, and low-dose ketamine protocols vary by clinic, so understanding the time and monitoring commitment upfront helps set realistic expectations. Finally, because this KevinMD piece is a single physician's commentary and not a clinical guideline, readers should treat it as one voice in an ongoing discussion and raise the specific recommendation directly with their own prescriber rather than acting on the headline alone. The original commentary is available via KevinMD.com, published September 27, 2026.