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Esketamine Enhances Antidepressant Efficacy and Improves Sleep Among Patients With TRD

Esketamine was found to have efficacy as an antidepressant and to improve sleep quality among patients with treatment-resistant depression (TRD), according to results of a study, published in Neuropsychiatric Disease and Treatment.

The TRANSFORM-1 and TRANSFORM-2 trials were 4-week, double-blind, randomized, active-controlled, multicenter trials of esketamine nasal spray for the treatment of TRD. Patients were randomized to receive twice-weekly 56 or 84 mg esketamine (n=343) or placebo (n=222) in combination with an open-label antidepressant. The oral antidepressant were chosen by the physician from selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors.

Both trials assessed the safety and efficacy of esketamine up to 24 weeks. Clinically meaningful sleep improvement was defined as a ≥2-point decrease from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) item 4 score.

Patients were aged 18-64 years, 65.3% had sleep disturbance, and the current depressive episode lasted between 147.2-192.3 weeks. Patients with more severe depression reported more severe sleep disturbance (P <.001).

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Every 1-point greater MADRS sleep disturbance score at baseline associated with a 23% greater chance of responding to the antidepressant (odds ratio [OR], 1.23; 95% CI, 1.08-1.40; P =.001).

Compared with placebo, esketamine associated with response (OR, 2.05; 95% CI, 1.40-3.02; P <.001) and remission (OR, 1.81; 95% CI, 1.23-2.66; P =.003).

Sleep was significantly improved by esketamine by day 8 (between-group difference in MADRS score, -0.4; standard error [SE], 0.12; P =.001), continuing to day 28 (between-group difference in MADRS score, -0.3; SE, 0.15; P =.020). More esketamine recipients achieved a clinically meaningful improvement in sleep at day 8 (26.1% vs 15.7%; P =.004) and 28 (49.0% vs 41.4%; P =.038).

There was a relationship between sleep improvement and antidepressant efficacy, in which the more sleep improved during the first week, there was a higher likelihood of antidepressant response by day 28 (OR, 1.26; 95% CI, 1.12-1.42 per 1-point MADRS improvement; P <.001). A similar relationship was observed for remission (OR, 1.28; 95% CI, 1.14-1.43 per 1-point MADRS improvement; P <.001).

The adverse events occurring among >10% of esketamine recipients included dissociation, dizziness, dysgeusia, headache, hypoesthesia, hypoesthesia oral, nausea, paresthesia, somnolence, and vertigo.

This study was limited by not using objective sleep assessment tools such as actigraphy or polysomnography.

The study authors concluded that esketamine supported antidepressant efficacy and improved sleep quality among patients with TRD regardless of sleep disturbance status.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Borentain S, Williamson D, Turkoz I, et al. Effect of sleep disturbance on efficacy of esketamine in treatment-resistant depression: findings from randomized controlled trials. Neuropsychiatr Dis Treat. Published online November 30, 2021. doi:10.2147/NDT.S339090

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Source: Psychiatry Advisor