Esketamine Nasal Spray vs. Troches: What TRD Data Shows

Esketamine Review Puts Spotlight on Ketamine's Expanding Role in Depression Care

A June 2026 review published in Psychiatric Times examined the safety and efficacy of intranasal esketamine for both major depressive disorder (MDD) and treatment-resistant depression (TRD). The review comes at a moment when clinicians and patients are weighing a growing menu of ketamine-based options — from in-office IV infusions and FDA-approved nasal spray to compounded oral troches used at home.

For anyone currently using or considering ketamine troches, this kind of clinical literature matters. Esketamine nasal spray (marketed as Spravato) and compounded ketamine troches are not the same product, but they share a common pharmacological root: both work primarily through NMDA receptor antagonism to produce rapid antidepressant effects that traditional SSRIs and SNRIs cannot achieve on the same timeline. Understanding where esketamine's evidence base stands helps troche patients put their own treatment in context — and make more informed decisions with their prescribers.

What the Esketamine Evidence Base Actually Shows

Esketamine — the S-enantiomer of racemic ketamine — was first approved by the FDA in 2019 for treatment-resistant depression and later for MDD with acute suicidal ideation or behavior. The clinical trials supporting those approvals showed statistically significant reductions in depressive symptoms compared to placebo, with meaningful response often appearing within days rather than the weeks associated with conventional antidepressants.

A review of this type in Psychiatric Times typically synthesizes the accumulated trial data, real-world safety signals, and clinical considerations that have emerged since initial approval. The fact that researchers are continuing to publish structured analyses of esketamine's safety and efficacy profile in 2026 reflects both the ongoing clinical interest in the drug and the legitimate questions that remain — particularly around long-term use, patient selection, and the management of dissociative side effects.

Safety signals documented across esketamine trials have consistently included transient dissociation, dizziness, nausea, and sedation occurring in the hours following administration. These effects are why Spravato carries an FDA Risk Evaluation and Mitigation Strategy (REMS) program: every dose must be administered in a certified healthcare setting, and patients must be monitored for at least two hours afterward before being allowed to leave. That monitoring requirement is a meaningful structural difference from troche-based treatment.

Troches vs. Nasal Spray: A Practical Comparison for Patients

For patients currently using ketamine troches, one of the most important things to understand about esketamine nasal spray is how differently these two forms of ketamine reach the brain — and how those differences shape the clinical experience.

Ketamine troches are compounded formulations dissolved sublingually or buccally, meaning the ketamine is absorbed through the mucous membranes of the mouth. Bioavailability through this route is generally estimated in the range of 25–50%, and absorption can vary meaningfully depending on how long the troche is held in the mouth, individual salivary chemistry, and the specific compounding formulation. This variability is clinically relevant: it means the effective dose a patient experiences at home may differ from session to session, even with the same prescribed milligram dose.

Intranasal esketamine, by contrast, is delivered through a calibrated device that releases a fixed quantity of drug directly to nasal mucosa. Nasal bioavailability for esketamine is generally higher and somewhat more predictable than oral mucosal absorption, though it is still subject to individual factors like nasal congestion. The clinical setting requirement for Spravato also means each dose is given under professional supervision — a guardrail that compounded at-home troche protocols typically do not have.

None of this makes one approach categorically superior. The in-office Spravato model offers oversight and standardization; the troche model offers accessibility, cost flexibility, and the comfort of a familiar home environment. Many patients who use troches do so precisely because IV infusion or supervised nasal spray sessions are logistically or financially out of reach. The troche's lower bioavailability can actually be a feature for patients who do better with gentler, more gradual effects.

What This Review Signals for the Ketamine Treatment Landscape

The continued publication of safety and efficacy analyses for esketamine in major psychiatric journals reflects a broader normalization of ketamine-class treatments in mainstream psychiatry. As recently as a decade ago, ketamine for depression was largely confined to academic medical centers and research trials. Today, it occupies a recognized, albeit carefully gatekept, corner of the standard-of-care conversation for TRD.

That shift matters for troche patients in a few ways. First, clinicians who were once skeptical of any ketamine-based treatment are increasingly familiar with the mechanism and the evidence — largely because of Spravato's presence in the psychiatric literature and in formularies. This can make conversations about compounded troches less fraught. A psychiatrist who has reviewed esketamine data is at least working from a shared pharmacological framework, even if they have questions about the compounded form.

Second, ongoing safety surveillance of esketamine generates population-level data on NMDA antagonist tolerability that is broadly informative for the ketamine field. If researchers identify a safety signal in esketamine populations — for example, around cardiovascular effects, abuse potential, or cognitive impact with long-term use — that finding is at minimum worth discussing in the context of troche protocols as well, even though the drugs, doses, and settings differ.

Third, the TRD designation matters for access. Esketamine's FDA approval for treatment-resistant depression has opened coverage conversations with some insurers that would have been impossible before 2019. Compounded troches, as non-FDA-approved products, generally remain out of pocket for patients. The visibility esketamine brings to the TRD space can indirectly support advocacy for broader ketamine access — though those policy conversations remain unresolved.

Practical Steps for Troche Patients Following This Research

If you are using ketamine troches as part of a treatment plan for depression, here is how to contextualize research like this Psychiatric Times review in your own care:

• Bring the literature to your prescriber. If your physician or psychiatrist is not closely tracking ketamine research, sharing summaries of peer-reviewed reviews can anchor more productive conversations about your dosing protocol and safety monitoring.
• Ask about your monitoring plan. One difference between supervised esketamine sessions and at-home troches is clinical oversight. If your troche protocol doesn't include a clear plan for checking in after sessions — particularly early in treatment — ask your prescriber to establish one.
• Understand your formulation. Troches vary in concentration, base compound, and absorption profile depending on the compounding pharmacy. Ask your provider to walk through what your specific formulation is designed to deliver and how that compares to the doses studied in clinical trials.
• Track your response. Because troche bioavailability is more variable than a metered nasal device, consistent self-monitoring — mood tracking, side effect logging, session notes — gives you and your provider better data to optimize your protocol over time.

Esketamine's growing evidence base is good news for patients with treatment-resistant depression regardless of which delivery format they use. More data, better prescriber familiarity, and increased public awareness of ketamine-class treatments all contribute to a treatment environment where patients have more options and more informed advocates in their corner.