When Antidepressants Fail: What Comes Next for TRD?

What STAT Is Reporting

A new STAT News piece"When symptoms persist despite oral antidepressants: What's next for treatment-resistant depression?" (published July 27, 2026), examines the clinical question facing millions of patients: what happens when standard oral antidepressants don't work. Treatment-resistant depression, or TRD, generally refers to major depressive disorder that has not adequately improved after trying at least two different antidepressants at appropriate doses and duration. This is not a rare edge case, a substantial share of people treated for depression in primary care and psychiatric settings fall into this category at some point.

The RSS summary provided to us does not include the full body of the STAT article, so we cannot verify or restate its specific data, quotes, or clinical recommendations here. What we can offer instead is grounded context on the treatment landscape that patients and clinicians are typically navigating when oral antidepressants stop being enough, and where low-dose ketamine and related therapies fit into that picture as of 2026.

Where Ketamine and Esketamine Fit in the TRD Toolkit

When first- and second-line antidepressants fail, clinicians typically consider several next steps: switching to a different antidepressant class, augmenting with a second medication (such as an atypical antipsychotic or lithium), adding psychotherapy, or moving to procedural treatments like electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS). Esketamine, sold under the brand name Spravato, is a nasal spray formulation of one component of ketamine that the U.S. Food and Drug Administration approved in 2019 specifically for treatment-resistant depression, administered under direct medical supervision in certified settings. Intravenous or intramuscular ketamine, typically given at sub-anesthetic (low) doses, is used off-label for depression and is administered in specialty clinics rather than through a standard pharmacy prescription.

The distinguishing feature of ketamine-based approaches compared with standard oral antidepressants is speed. Where SSRIs and SNRIs often take four to eight weeks to show effect, low-dose ketamine has been associated in clinical research with rapid, sometimes same-day reductions in depressive symptoms for some patients. That speed is one reason it gets discussed as an option once oral medications have already been given a fair trial and failed. However, rapid response is not the same as durable response, the evidence base for ketamine's antidepressant effects is strongest in the short term, and researchers are still working out optimal dosing intervals, how long benefits last without repeat treatment, and which patients are most likely to benefit.

For readers following this space, the practical distinction to hold onto is between esketamine (Spravato), which has FDA approval and an established administration protocol for TRD, and off-label IV/IM ketamine, which many patients pursue through specialty infusion clinics without that same regulatory pathway. Both require in-clinic administration and monitoring; neither is a take-home daily pill like a traditional antidepressant.

Practical Questions to Bring to a Provider

For readers researching whether low-dose ketamine could be relevant to their own treatment-resistant depression, the STAT piece is a useful prompt to ask specific questions rather than a reason to self-diagnose treatment resistance. First, confirm with a psychiatrist whether prior antidepressant trials met the clinical threshold for "adequate", correct dose, sufficient duration (usually six to eight weeks), and confirmed adherence, before concluding that standard medication has genuinely failed. Second, ask what monitoring a ketamine or esketamine program includes: baseline and per-session blood pressure checks, observation time after dosing (typically at least two hours for esketamine), and a plan for tracking depression severity over multiple sessions using a standardized scale.

Third, ask directly about maintenance. A single ketamine session or short induction series is not typically a one-time fix; most protocols involve an induction phase followed by less frequent maintenance dosing, and patients should ask how their specific clinic decides when to taper, continue, or stop. Finally, ask how the clinic coordinates with an existing prescriber, since ketamine and esketamine are usually added alongside, not instead of, a broader depression treatment plan that may still include an oral antidepressant, therapy, or both.

The uncertainty that remains in this field is worth naming plainly: long-term safety and efficacy data for repeated ketamine use over years, rather than months, are still developing, and individual response varies considerably. Readers should treat ketamine-based options as a serious, evidence-supported tool for TRD, administered under medical supervision, rather than as a guaranteed fix or a substitute for a full diagnostic workup.