Credit: Adobe Stock/ Viacheslav Yakobchuk
A study showed that patients with comorbid insomnia and depression treated with dexmedetomidine plus esketamine had improved depression scores, longer total sleep time, greater N3 sleep, and enhanced deep sleep continuity.1
“Within the NREM sleep stages, our study found that [esketamine] prolonged the duration of both N2 and N3 sleep, consequently increasing total sleep time,” study investigator Yitong Ding, from Nanjing Medical University at People’s Republic of China, and colleagues. “[It] decreased the proportion of N2 sleep while increasing the proportion in N3 sleep.”
Dexmedetomidine, an α2-adrenergic agonist acting in the locus coeruleus, induces natural-resembling sleep and boosts delta oscillation waves, increasing N3 sleep. Research has demonstrated the benefit of dexmedetomidine for sleep issues, with 1.75 µg/kg identified as the 95% effective dose of dexmedetomidine to induce adequate sedation in patients with insomnia.2
However, the efficacy of dexmedetomidine does not extend to those with comorbid insomnia and depression.1 In this study, investigators evaluated whether esketamine, a potent antidepressant, could augment dexmedetomidine in this population. The primary outcome was a comparison of polysomnographic monitoring (PSG) parameters at baseline and on day 3.
Between November 2023 and March 2024, investigators recruited participants with insomnia defined by ICD-10 F51.0 criteria and PSQI ≥ 16 and depression defined by MADRS 22 – 35. Patients underwent dexmedetomidine titration and monitoring of electrocardiogram (ECG), pulse, blood pressure, and pulse oximetry before treatment.
Patients received dexmedetomidine 200 µg diluted in 48 mL 0.9% saline and administered at a continuous infusion rate of 40 mL per hour. The infusion stopped when delta waves appeared on the ECG, and the dose at this point served as a reference value for medication administration during this study. Investigators calculated the required nasal spray dose by dividing the intravenous target dose by 0.8.
In total, 78 patients were randomized 1:1 to dexmedetomidine plus esketamine (the DE arm; n = 38) or dexmedetomidine plus saline (the DS arm; D = 40). Participants in the DE arm received esketamine intravenously that was 0.2 mg/kg over 40 min or 2 mL:50 mg; participants in the DS arm received saline in the same volume.
After 3 days of treatment, both groups showed a significantly increased total sleep duration (DE group: mean difference, 163.32; P < .001 and DS group: 111.53.53; P < .001), but gains were greater with esketamine (between-group difference, 48.15; 95% confidence interval [CI], 23.33 – 72.98; P < .001). Esketamine also yielded longer and greater N3 duration (47.28 and 8.24, respectively; both P < .00), improved sleep continuity (P < .001), and greater REM proportion (P = .04).1
Compared with saline, esketamine significantly reduced SNRS, MADRS, and N2 and REM proportions (all P < .05). Sleep improvements were linked to improvements in MADRS and increases in serum brain-derived neurotrophic factor concentrations. The average change in MADRS negatively correlated with total sleep time (P = .025), deep sleep continuity (P < .001), and N3 duration and proportion (P < .001).1
Investigators observed no differences between arms in N2 sleep duration (P = .91) and the length of REM sleep by day 3 (P = .62).1
No serious adverse events occurred. The most common adverse events included oral dryness, nausea, and vomiting, which resolved within 1 hour.
“…our findings demonstrate that esketamine augments the sleep-improving effects of dexmedetomidine in patients with comorbid insomnia and depression,” investigators concluded.1 “The primary effects observed were…significant reductions in depression scores and enhanced N3 sleep quality. This therapeutic effect may involve upregulation of [serum brain-derived neurotrophic factor concentrations].”
References
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Ding Y, Wang Z, Huang J, Yi Y, Wu Z. Esketamine Optimized the Efficacy of Dexmedetomidine in Treating Sleep Disorders with Comorbid Depression. Neuropsychiatr Dis Treat. 2025;21:1409-1423. Published 2025 Jul 12. doi:10.2147/NDT.S530265
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Li M, Li G, Li Q, Cai Q. The 95% effective dose of dexmedetomidine to induce adequate sedation in patients with chronic insomnia disorder: a biased coin design up-and-down sequential allocation trial. BMC Anesthesiol. 2024;24(1):368. Published 2024 Oct 11. doi:10.1186/s12871-024-02759-4