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Am Fam Physician. 2024;109(2):online

Clinical Question

For patients with treatment-resistant depression, is an esketamine (Spravato) nasal spray superior to the antipsychotic quetiapine?

Bottom Line

Esketamine nasal spray is safe and slightly more effective than extended-release quetiapine at inducing remission at eight weeks (number needed to treat [NNT] = 10) and 32 weeks (NNT = 7) in patients with treatment-resistant depression. (Level of Evidence = 1b−)


In the trial, treatment-resistant depression was defined as a score of 34 or higher on an 84-point depression scale (higher scores are worse) and failure of two to six treatment regimens from at least two different drug classes with 25% or less reduction in symptoms. All patients were taking the maximally tolerated dose of a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor that was continued during the trial. At baseline, patients had a mean age of 45 years (range: 18 to 74 years of age), 66% were women, and 39% had tried three or more treatments that were ineffective. The mean duration of the current episode of major depression was 66 weeks. Groups were balanced, and allocation to groups was concealed. The trial was open label, but outcome assessors were masked to treatment assignment. The authors initially screened 811 participants in 27 countries, but after a two-week run-in period, they randomized only 676 to esketamine nasal spray or extended-release quetiapine. The initial esketamine dose ranged from 28 to 56 mg once, then the dosage was increased to up to 84 mg twice weekly, then once weekly, and then once or twice weekly. Quetiapine was started at 50 mg, with a maximum dosage of 300 mg once daily. Patients were followed for 32 weeks after randomization. The primary outcome was remission, defined as a Montgomery-Åsberg Depression Rating Scale score of 10 or less (range: 0 to 60) at week 8, and occurred more often in the esketamine group (27.1% vs. 17.6%; P = .003, NNT = 11). Remission at week 32 was also more common with esketamine (49.1% vs. 32.9%; P value not reported; NNT = 7). Among the patients with remission at week 8, absence of relapse at week 32 was more likely with esketamine (21.7% vs. 14.1%; P < .05; NNT = 14). Serious treatment-related adverse events occurred in 5% to 6% of patients in each group, although events leading to discontinuation of the medication were more common with quetiapine (11.0% vs. 4.2%). Hospitalization for suicide attempt or worsening depression was uncommon and similar between groups.

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POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see Copyright Wiley-Blackwell. Used with permission.

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