CATEGORY: BRAIN & MENTAL HEALTH
Two antidepressants, months of waiting, and no real relief. Roughly a third of people treated for major depression know that dead end, and it has a clinical name: treatment-resistant depression.1 For them, a trial of 378 adults now offers a firm number. Used entirely on its own, esketamine nasal spray lowered depression scores by about 14 points in four weeks on the 60-point scale psychiatrists use, roughly double the drop seen with a placebo spray.1
A Spray Descended From an Anesthetic
Esketamine is a close chemical cousin of ketamine, the decades-old anesthetic. It works on the brain’s glutamate system, a chemical messenger network involved in forming connections between brain cells, which is a different target from the serotonin most antidepressants lean on. Since 2019 it had been approved only as an add-on, taken alongside a daily antidepressant pill. In January 2025, US regulators cleared it to stand alone, and this study is the trial behind that decision. It matters for a practical reason: many people with hard-to-treat depression can’t tolerate daily antidepressants or simply don’t want another one.
Twice a Week, Under a Clinician’s Eye
Neither patients nor doctors knew who was getting the real thing. All 378 participants had already tried at least two antidepressants without success. They came into one of 51 US clinics twice a week and inhaled either esketamine, at 56 or 84 milligrams, or a placebo spray designed to mimic it, then stayed for observation, since the drug can cause temporary sedation and a floating, detached feeling. After 28 days, scores on the Montgomery–Åsberg scale, a standard checklist where higher numbers mean deeper depression, had fallen 13.9 points with the higher dose and 12.7 with the lower one, versus about 7 with placebo.1 The gap was 6.8 points for the higher dose. Improvement showed up within 24 hours of the first dose. Typical antidepressants need weeks to do that.
The Trade: Same-Day Side Effects
About one in four users felt nausea, dissociation or dizziness, and roughly one in five got a headache. Nearly 90% of those episodes resolved the same day, before patients left the clinic.1 That’s the deal esketamine offers. It isn’t a take-home prescription; every dose happens under supervision in a certified clinic, which costs time and money. The trial was funded by Johnson & Johnson, the drug’s maker, and it lasted four weeks, so the durability question sits outside this study. An optional 12-week extension is following participants further.
Key Takeaways
- Esketamine nasal spray, taken with no accompanying antidepressant, beat placebo by 6.8 points on the standard depression scale after four weeks at the higher dose.
- Improvement was measurable within a day of the first dose, far faster than typical antidepressants.
- Side effects like nausea, dizziness and a temporary detached feeling were common but nearly always cleared before the patient went home.
- The trial ran four weeks, so how long the benefit lasts isn’t answered here.
References
- Janik A, Qiu X, Lane R, et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2025;doi:10.1001/jamapsychiatry.2025.1317. link