Esketamine Has the Deepest Trial Record in This Field

Esketamine nasal spray (marketed as Spravato) is the only ketamine-derived medication with FDA approval for a psychiatric indication, and it carries the largest randomized dataset of any treatment in this category. Between 2023 and 2025, three developments materially changed what clinicians can say about it: a head-to-head trial against an established augmentation drug, a monotherapy trial and subsequent FDA approval, and long-term extension data stretching past three years of continuous use.

1. ESCAPE-TRD: Esketamine vs. Quetiapine

Most trials compare a new treatment against placebo. ESCAPE-TRD (Reif et al., NEJM, October 2023) compared esketamine against extended-release quetiapine, a widely used augmentation option for treatment-resistant depression.

  • Design: Open-label, rater-blinded, phase 3b randomized trial
  • Participants: 676 adults with treatment-resistant depression (336 esketamine, 340 quetiapine), all continuing an ongoing SSRI or SNRI
  • Primary outcome: Remission at week 8, defined as a MADRS score of 10 or lower

Results: 27.1% of the esketamine group achieved remission at week 8 versus 17.6% on quetiapine (odds ratio 1.78; 95% CI, 1.23 to 2.55). The more demanding composite endpoint — in remission at week 8 and relapse-free through week 32 — favored esketamine as well, 21.7% versus 14.1%.

Secondary analyses published through 2025 found that early partial response at week 4 predicted week-32 outcomes, and that the benefit held in the subgroup matching US labeling. The main caveats are the open-label design, a single comparator drug, and a level of clinical contact higher than most real-world practices provide.

2. Monotherapy: A New Indication

Until 2025, esketamine was approved only as an add-on to an oral antidepressant. That changed after the TRD4005 trial (Janik et al., JAMA Psychiatry, published online July 2025), a placebo-controlled randomized trial in 378 adults with treatment-resistant depression who received esketamine without a concurrent new oral antidepressant.

  • Day-28 MADRS improvement versus placebo: −6.3 points for the 56 mg dose (95% CI, −9.8 to −2.8) and −7.1 points for 84 mg (95% CI, −10.5 to −3.7)
  • Week-4 remission was reported at 22.5% for esketamine versus 7.6% for placebo, with separation from placebo appearing as early as 24 hours

On January 21, 2025, the FDA approved esketamine as a monotherapy for adults with treatment-resistant depression — the first standalone approval of its kind. Practically, this matters for patients who cannot tolerate oral antidepressants or who have discontinued them.

3. Long-Term Use: SUSTAIN-3

One of the most common patient questions is what happens after a year or two of treatment. SUSTAIN-3 (Sanacora et al., International Journal of Neuropsychopharmacology, 2025) is the open-label long-term extension study addressing exactly that.

  • Participants: 1,148 patients, with mean esketamine exposure of roughly 43 months
  • Remission (MADRS 12 or lower): 35.6% at the end of induction, rising to 48.5% at week 112 and 49.6% at the maintenance endpoint
  • Depression scores were essentially flat during maintenance (MADRS change of +0.2), indicating that gains were held rather than eroding

The caveats are structural: SUSTAIN-3 is open-label, single-arm, and enriched for people who already responded and chose to stay in treatment. It shows that sustained benefit is achievable over years, not that it is typical for everyone who starts.

How Esketamine Compares to IV Ketamine

There is still no completed randomized head-to-head trial of IV racemic ketamine versus intranasal esketamine. The evidence that exists is indirect:

  • A 2025 systematic review and meta-analysis in Therapeutic Advances in Psychopharmacology (8 studies, 978 participants) found no statistically significant difference in response (OR 1.26; 95% CI, 0.92 to 1.71) or remission (OR 1.31; 95% CI, 0.93 to 1.86), with some signal of faster onset for IV
  • A 2024 meta-analysis in the Journal of Affective Disorders reported a much larger placebo-controlled effect size for IV ketamine (Hedges g = 1.52) than for intranasal esketamine (g = 0.31) — but these were separate trial populations with different designs, not a direct comparison
  • A randomized equivalence trial funded to compare the two directly began enrolling in 2025; results are not yet available

Anyone told that one route is definitively superior is being sold a conclusion the literature does not yet support.

What This Means for Patients

Esketamine's practical advantages are regulatory rather than pharmacological: it is FDA-approved, which means it is frequently covered by insurance, and it now has multi-year safety and outcome data. Its constraint is the REMS program — esketamine must be administered in a certified healthcare setting with a minimum two-hour post-dose observation period, and it cannot be dispensed for home use.

If insurance coverage is the deciding factor for you, see our breakdown of ketamine therapy costs and coverage. To compare programs offering Spravato in your area, browse clinics by state.

Sources

  • Reif A, et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. New England Journal of Medicine. 2023;389:1298-1309. PubMed 37792613
  • Janik A, et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2025. PubMed 40601310
  • Sanacora G, et al. Long-term safety and efficacy of esketamine nasal spray in treatment-resistant depression: SUSTAIN-3. International Journal of Neuropsychopharmacology. 2025. PubMed 40319349
  • Intravenous ketamine versus esketamine for depression: systematic review and meta-analysis. Therapeutic Advances in Psychopharmacology. 2025. PubMed 41244961
  • Seshadri A, et al. Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for major depression. Journal of Affective Disorders. 2024;356. PubMed 38537759