Intranasal Dexmedetomidine-esketamine on Sleep and Cognition in Older Adults With Mild-to-moderate Cognitive Impairment

Official title

Impact of Intranasal Dexmedetomidine-esketamine on Sleep Quality and Cognitive Function in Older Adults With Mild-to-moderate Cognitive Impairment: a Randomized, Double-blind, and Placebo-controlled Trial

Overview

Patients with cognitive decline are frequently comorbid with sleep disorders which may in turn aggravate cognitive decline. Sedative dose dexmedetomidine improved sleep quality but incresed bradycardia and hypotension; low dose dexmedetomidine produce less side effects, but the sleep promoting effects are relatively weak. Low dose esketamine also has sleep-promoting effects but may produce neuropsychiatric side effects. Both dexmedetomidine and esketamine are approved for intranasal administration. We suppose that intranasal administration of dexmedetomidine-esketamine combination may improve sleep quality and therefore cognitive function in older ptients with Alzheimer's disease cognitive impairment and sleep disorders.

Detailed description

Along with aging population, the number of older adults with cognitive decline (such as Alzheimer's disease) is also increasing and constitutes a great challenge to public health. Normal sleep is important for maintaining both physical and mental health. However, patients with cognitive decline are frequently comorbid with sleep disorders which are associated with increased need of health care; sleep disorders may in turn aggravate cognitive decline in these patients.

Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with sedative, anxiolytic, and analgesic effects. In previous studies, infusion of sedative dose dexmedetomidine improved sleep quality but incresed bradycardia and hypotension. Infusion of low dose dexmedetomidine is also effective in improving sleep quality with less side effects; however, the sleep promoting effects are relatively weak. Intranasal dexmedetomidine provides a non-invasive intervention and is used for sleep promotion in preoperative patients, but requires hemodynaamic monitoring due to potential side effects.

Ketamine is a noncompetitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist and has been used as a dissociative anesthetic for decades. Esketamine is the S-enantiomer and has approximately twice the potency of ketamine. Recent studies showed that low dose esketamine also has anti-depressive and sleep-promoting effects. Intranasal esketamine has been approved for treatment-resistant depression, and is also used as premedication in children and to relieve postoperative pain in adults.

Even low dose ketamine/esketamine may produce neuropsychiatric side effects, which can be relieved by dexmedetomidine. A study in pediatric patients reported that intranasal co-administration of dexmedetomidine and esketamine produced synergetic effects on sedation. A study in adults showed that dexmedetomidine-esketamine combination as a supplement to patient-controlled opioid analgesia improved both analgesia and sleep quality without increasing side effects. A recent trial in older adults indicated that intranasal dexmedetomidine-esketamine improved neurocognitive recovery after surgery.

We suppose that intranasal administration of dexmedetomidine-esketamine combination may improve sleep quality and therefore cognitive function in older ptients with Alzheimer's disease cognitive impairment and sleep disorders.

Interventions

• Drug Dexmedetomidine-esketamine combination
  The dosage will be calculated based on body weight (approximately 0.4 μg/kg of dexmedetomidine and 0.2 mg/kg of esketamine). The mixture of study drugs will be administered via a nasal spray device, alternating between the two nostrils every 5 minutes, until the target dose is reached. The combination will be administered twice a week for 4 consecutive weeks (8 sessions in total).
• Drug Placebo
  The dosage (volume) will be calculated based on body weight in the same way as that in the intervention group. The placebo (normal saline) will be administered via a nasal spray device, alternating between the two nostrils every 5 minutes, until the target dose is reached. The placebo will be administered twice a week for 4 consecutive weeks (8 sessions in total).

Primary outcome measures

• Change in Pittsburgh Sleep Quality Index (PSQI) score from baseline to 1 month [Time frame: Up to day 29 post-intervention initiation]

Secondary outcome measures (2)

• Changes in Montreal Cognitive Assessment (MoCA) score from baseline to 1, 2, and 3 months [Time frame: Up to days 29, 57, and 85 post-intervention initiation]
• Changes in Pittsburgh Sleep Quality Index (PSQI) score from baseline to 2 and 3 months [Time frame: Up to days 57 and 85 post-intervention initiation]

Eligibility criteria

Inclusion criteria

• Aged ≥ 60 years.
• Meeting the clinical diagnostic criteria for Alzheimer's disease, with mild cognitive impairment (MoCA score 18-25) or moderate cognitive impairment (MoCA score 10-17) due to Alzheimer's disease.
• Comorbid with sleep disorders (Pittsburgh Sleep Quality Index \[PSQI\] score ≥ 7).
• Signed informed consent.

Exclusion criteria

• Cognitive impairment/dementia due to other causes (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease dementia).
• Unsuitable for intranasal administration due to nasal cavity diseases (e.g., rhinitis, nasal polyps, or nasal congestion of any cause).
• Inability to communicate due to visual, auditory, language, or other reasons, or Mini-Mental State Examination (MMSE) score ≤ 9 or MoCA score ≤ 9.
• History of schizophrenia, epilepsy, or Parkinson's disease, or confirmed diagnosis of glaucoma, hyperthyroidism, pheochromocytoma, or myasthenia gravis.
• Confirmed diagnosis of restless legs syndrome or sleep apnea, or judged to be at high risk of moderate-to-severe sleep apnea according to STOP-Bang score, or Body Mass Index (BMI) > 30 kg/m2.
• History of stroke or transient ischemic attack within 12 months prior to enrollment, confirmed intracranial aneurysm, or elevated intracranial pressure from any cause.
• Uncontrolled hypertension (e.g., hypertensive crisis or systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg prior to enrollment), myocardial infarction, unstable angina, revascularization surgery within 12 months prior to enrollment, or NYHA class III.
• Sick sinus syndrome, severe sinus bradycardia (heart rate < 50 beats/min), atrioventricular block above degree II without a pacemaker, corrected QT interval (Fridericia-corrected QTcF) ≥ 450 ms, or other severe arrhythmias (e.g., frequent premature ventricular contractions).
• Uncontrolled diabetes (e.g., HbA1c > 9%, diabetic ketosis, hyperglycemic coma, or hypoglycemia).
• Severe hepatic dysfunction (Child-Pugh Class C), renal dysfunction (eGFR ≤ 30 ml/min/1.73m2), respiratory insufficiency (SpO2 < 93% on room air), or other severe diseases (e.g., frailty with inability to walk independently, advanced-stage tumors).
• Alcohol or drug dependence (manifested as strong cravings, uncontrolled use, and withdrawal symptoms upon cessation), or use of contraindicated medications.
• Major surgery under general anesthesia within 12 weeks prior to enrollment, or planned surgery within 12 weeks.
• Allergy to dexmedetomidine and/or esketamine.
• Participation in other interventional clinical studies.
• Any other conditions deemed unsuitable for study inclusion by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University First Hospital — Beijing

Publications

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• Zisapel N, Nir T. Determination of the minimal clinically significant difference on a patient visual analog sleep quality scale. J Sleep Res. 2003 Dec;12(4):291-8. doi: 10.1046/j.0962-1105.2003.00365.x. PMID 14633240
• Martin S, Chandran A, Zografos L, Zlateva G. Evaluation of the impact of fibromyalgia on patients' sleep and the content validity of two sleep scales. Health Qual Life Outcomes. 2009 Jul 10;7:64. doi: 10.1186/1477-7525-7-64. PMID 19591683
• Rodrigues NB, McIntyre RS, Lipsitz O, Lee Y, Cha DS, Shekotikhina M, Vinberg M, Gill H, Subramaniapillai M, Kratiuk K, Lin K, Ho R, Mansur RB, Rosenblat JD. A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions. J Affect Disord. 2021 Mar 1;282:160-164. doi: 10.1016/j.jad.2020.12.119. Epub 2020 Dec 29 PMID 33418362
• Podsiadlo D, Richardson S. The timed "Up & Go": a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991 Feb;39(2):142-8. doi: 10.1111/j.1532-5415.1991.tb01616.x. PMID 1991946
• Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990 Aug;10(4):244-51. PMID 2286697
• 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 Jul 12;21:1409-1423. doi: 10.2147/NDT.S530265. eCollection 2025. PMID 40673111
• Wu J, Liu X, Ye C, Hu J, Ma D, Wang E. Intranasal dexmedetomidine improves postoperative sleep quality in older patients with chronic insomnia: a randomized double-blind controlled trial. Front Pharmacol. 2023 Nov 16;14:1223746. doi: 10.3389/fphar.2023.1223746. eCollection 2023. PMID 38034987

Identifiers

NCT: NCT07610343 · 2026-0208

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗