Treatment-Resistant Depression: Where Ketamine Fits In

What STAT's New Report Adds to the Treatment-Resistant Depression Conversation

Treatment-resistant depression (TRD) describes major depressive episodes that do not improve adequately after at least two trials of different oral antidepressants at proper doses and duration. STAT published a report on July 27, 2026, examining what options exist for patients whose symptoms persist despite oral antidepressant treatment, according to the outlet's coverage (STAT). For the estimated one in three adults with major depression who don't respond fully to standard medication, the question of "what's next" is not academic, it shapes years of treatment decisions, cost, and quality of life.

The report's framing, symptoms that persist despite oral antidepressants, matches a well-documented pattern in psychiatric research. According to the NIMH-funded STAR*D trial, one of the largest real-world antidepressant effectiveness studies ever conducted, remission rates dropped with each successive medication trial, and only about a third of patients achieved remission on their first prescribed antidepressant. That gap is exactly where interventional and rapid-acting options, including ketamine-based therapies, have moved into mainstream psychiatric practice over the past decade.

The Widening Menu of TRD Options

When oral antidepressants stop working, prescribers generally move through a hierarchy of next steps: augmentation with a second agent, switching drug classes, and, if symptoms remain, interventional psychiatry. That category now includes electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), esketamine (Spravato), an FDA-approved nasal spray formulation of ketamine's S-enantiomer for TRD, and off-label ketamine delivered by IV infusion, intramuscular injection, or sublingual troche.

Each route differs in onset, monitoring requirements, and where treatment happens. IV ketamine infusions are typically administered in a clinical setting with cardiac monitoring, taking roughly 40 minutes plus recovery time per session. Esketamine requires in-office administration under a REMS (Risk Evaluation and Mitigation Strategy) program, with at least two hours of monitoring per dose. Sublingual ketamine troches dissolve under the tongue and are generally prescribed through compounding pharmacies as part of an at-home maintenance protocol that follows an initial in-clinic induction phase, a distinction that matters for patients weighing cost, travel time, and how treatment fits around work and caregiving.

Cost and access are often the biggest practical differentiators. IV infusion series and esketamine can run into the thousands of dollars before insurance, and esketamine's REMS requirement means a missed appointment can disrupt an entire treatment schedule. Compounded ketamine troches are typically far less expensive per dose and easier to fold into a maintenance routine once induction is complete, though they remain off-label and are not FDA-approved for depression, so insurance coverage is inconsistent and out-of-pocket cost varies by clinic and compounding pharmacy.

What This Means for Patients Considering Ketamine Troches

For readers evaluating ketamine troches specifically, the report's core message, that persistent symptoms deserve a structured escalation plan rather than indefinite medication switching, points to three practical steps. First, confirm you actually meet clinical criteria for TRD, typically two or more failed adequate antidepressant trials, before pursuing interventional care, since clinical guidelines and coverage decisions are built around that threshold. Second, ask any prescribing clinic how troches fit into your overall plan: most protocols use troches for maintenance dosing between or after an induction series of higher-monitoring sessions, such as infusion or in-office dosing, rather than as a stand-alone starting point for someone who has never tried ketamine before. Third, verify that your compounding pharmacy and prescriber follow current USP compounding standards and individualize dosing rather than use a fixed template, since troche potency and absorption can vary meaningfully between compounding pharmacies.

The broader takeaway from ongoing TRD coverage like STAT's is that no single modality, troches included, functions as a universal fix. Responsible ketamine troche use sits inside a monitored treatment plan: a baseline psychiatric evaluation, cardiovascular screening, a defined induction-to-maintenance pathway, and scheduled check-ins using mood scales such as the PHQ-9 or MADRS. Readers should treat any provider who skips that structure, or who offers troches as a first-line replacement for oral antidepressants without a documented TRD diagnosis, as a signal to seek a second opinion.