Esketamine Rapidly Improves Sleep in Treatment-Resistant Depression

In a recent study, esketamine provided rapid improvement in sleep quality among patients with treatment-resistant depression (TRD).¹

Patients with TRD often report sleep issues, including insomnia, restless sleep, or early awakening. A poor sleep quality may not only exacerbate depressive symptoms and impair quality of life but can interfere with treatment.

“Insomnia, which often coexists with drug-resistant depression, is one of the key aspects influencing the effectiveness of treatment,” wrote investigators, led by Daniel Szawarnoga, from the departments of psychiatry and neurology at the Medical University of Silesia in Poland.¹

The US Food and Drug Administration (FDA) approved esketamine (SPRAVATO) CIII nasal spray for adults with TRD earlier this year, announced by Johnson & Johnson on January 21, 2025.² Phase 4 data showed esketamine as a monotherapy brought a rapid and superior improvement in the Montgomery-Asberg Depression Scale (MADRS) total score at 4 weeks compared with placebo.

Esketamine can also address sleep issues, such as nocturnal awakening or early awakening, by modulating the circadian rhythm. A study back in 2011 showed that ketamine influences the circadian rhythm, modulating CLOCK:BMAL1-mediated transcriptional activation.³ The study had shown that ketamine results in a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes.

With esketamine being a derivative of ketamine, and with its unique mechanism of action on NDMA receptors that improves neuronal plasticity, this treatment may help reduce nighttime wakefulness and improve sleep quality.¹ Research has shown that standard antidepressants, such as escitalopram and aripiprazole, have a limited impact on sleep quality. Some traditional antidepressants can even lead to chronic daytime sleepiness.

Investigators sought to compare the effectiveness of esketamine up to 84 mg/day vs other standard antidepressants in improving sleep quality in patients with TRD. The primary endpoint was the difference in Athens Insomnia Scale scores between arms at 6 months. In total, 50 patients (56% women; aged 20 – 50 years) were randomized to 2 arms: esketamine alongside other antidepressants (n = 25) or only other antidepressants (n = 25). Both arms had similar insomnia levels at baseline.

Participants in the control arm took either fluoxetine, paroxetine, or sertraline. The esketamine arm also took fluoxetine or sertraline. Participants did not take any medications that could impact sleep.

Investigators found insomnia occurs less frequently among people using esketamine than other antidepressants (P < .001). With increased esketamine use and dose, insomnia levels decreased, as seen on the Athens Insomnia Scale (P < .001).¹

At 6 months, insomnia levels in patients treated with esketamine reduced significantly (P = .016); only 1 participant from the esketamine group reported insomnia at this point. Insomnia was mostly satisfactory (48%) or slightly unsatisfactory (48%), with only 4% clearly unsatisfactory and none completely unsatisfactory (0%).¹

Participants on esketamine experienced significantly improved well-being the next day, with significantly fewer reporting worse well-being (0%; P = .003), as well as significantly improved mental and physical performance (P < .001).¹

In the control arm, participants experienced similar sleep quality and well-being from baseline to 6 months, with no significant differences. Participants only taking antidepressants also had stable mental and physical performance from baseline (P = .62).¹

“Even though the cost of esketamine treatment is high, the demonstrated effectiveness of the drug in reducing insomnia is very important from a clinical point of view,” investigators wrote.¹ “Esketamine treatment is therefore possible with the introduction of drug reimbursement or because of an individual patient’s decision after the doctor presents various therapeutic options.”

References

1. Szawarnoga D, Fojcik J, Górski M, Pałasz A, Krzystanek M. Insomnia and Esketamine Add-On Therapy to Antidepressant Therapy in Patients with Treatment-Resistant Depression-A Pilot Study. Pharmaceuticals (Basel). 2025;18(7):1066. Published 2025 Jul 19. doi:10.3390/ph18071066

2. Derman, C. FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression. HCPLive. January 21, 2025. https://www.hcplive.com/view/fda-approves-esketamine-first-monotherapy-treatment-resistant-depression. Accessed August 14, 2025.

3. Bellet MM, Vawter MP, Bunney BG, Bunney WE, Sassone-Corsi P. Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression. PLoS One. 2011;6(8):e23982. doi:10.1371/journal.pone.0023982