Nonresponders to Esketamine Nasal Spray plus Oral Antidepressants May Still Respond by 4 Weeks of Treatment

September 2022

Oral antidepressants are first-line treatments for major depressive disorder, and they often take 10 weeks to 12 weeks to reach a full response. As a result, patients may spend months trying to find an antidepressant that works, and one-third of patients are still resistant to treatment. The ability to decide quickly whether a patient is responding would reduce unnecessary treatments.

Esketamine, an N-methyl-d-aspartate receptor antagonist, is considered to be a rapid-acting antidepressant compared with oral antidepressants. Esketamine can be delivered as a nasal spray and taken at the same time as oral antidepressants.

In previous phase 3 clinical trials for esketamine (TRANSFORM trials), patients taking oral antidepressants plus esketamine showed improved responses at day 28 compared with placebo. In the new study using post-hoc analysis of TRANSFORM data, the investigators explored whether nonresponse to the drug combination by day 2 or days 2 and 8 was predictive of nonresponse at day 28.

Participants had recurrent major depressive disorder or a single episode of major depression (lasting ≥2 years) and had not responded to ≥1 oral antidepressants. Patients with suicidal behavior, bipolar disorder, or psychosis were excluded. The primary end point was the change in the score on the Montgomery-Åsberg Depression Rating Scale. A positive response was defined as an improvement in score of ≥50% from baseline at day 2 or days 2 and 8. Patients started a new oral antidepressant at the same time as they started esketamine nasal spray or placebo.

Of the 518 patients included in the analysis, the esketamine plus oral antidepressant group had a higher proportion of patients responding to treatment at days 2, 8, and 28 compared with the group receiving placebo plus oral antidepressant. Among the subgroups that had not responded by day 2 or day 8, the groups receiving esketamine plus oral antidepressant showed significantly greater proportions of patients responding at day 28 versus those receiving antidepressant plus placebo. Nonresponders at day 2 had a 61% increase in the odds of achieving a response to treatment at day 28 with esketamine, whereas nonresponders at day 8 had a 56% increase in the odds of achieving a response at day 28 with esketamine. The investigators used multiple statistical analyses of the data that all gave similar results.

The use of esketamine was associated with adverse events, including dissociation, vertigo, nausea, dizziness, and somnolence.

The investigators conclude that “if an early response is not observed with esketamine, evidence suggests that continued treatment can still result in a greater likelihood of response than that observed with an antidepressant alone.” Based on their results, they recommended a 4-week course of esketamine treatment as augmentation when prescribing a new oral antidepressant in patients with treatment-resistant depression.


Turkoz I, Daly E, Singh J, et al. Treatment response with esketamine nasal spray plus an oral antidepressant in patients with treatment-resistant depression without evidence of early response: a pooled post hoc analysis of the TRANSFORM studies. J Clin Psychiatry. 2021;82(4):20m13800.

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