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

May 28, 2026 updated by: Dong-Xin Wang, Peking University First Hospital

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Beijing Municipality
      • Beijing, Beijing Municipality, China, 100034
        • Peking University First Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Aged ≥ 60 years.
  2. 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.
  3. Comorbid with sleep disorders (Pittsburgh Sleep Quality Index [PSQI] score ≥ 7).
  4. Signed informed consent.

Exclusion Criteria:

  1. Cognitive impairment/dementia due to other causes (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease dementia).
  2. Unsuitable for intranasal administration due to nasal cavity diseases (e.g., rhinitis, nasal polyps, or nasal congestion of any cause).
  3. Inability to communicate due to visual, auditory, language, or other reasons, or Mini-Mental State Examination (MMSE) score ≤ 9 or MoCA score ≤ 9.
  4. History of schizophrenia, epilepsy, or Parkinson's disease, or confirmed diagnosis of glaucoma, hyperthyroidism, pheochromocytoma, or myasthenia gravis.
  5. 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.
  6. History of stroke or transient ischemic attack within 12 months prior to enrollment, confirmed intracranial aneurysm, or elevated intracranial pressure from any cause.
  7. 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.
  8. 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).
  9. Uncontrolled diabetes (e.g., HbA1c > 9%, diabetic ketosis, hyperglycemic coma, or hypoglycemia).
  10. 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).
  11. Alcohol or drug dependence (manifested as strong cravings, uncontrolled use, and withdrawal symptoms upon cessation), or use of contraindicated medications.
  12. Major surgery under general anesthesia within 12 weeks prior to enrollment, or planned surgery within 12 weeks.
  13. Allergy to dexmedetomidine and/or esketamine.
  14. Participation in other interventional clinical studies.
  15. Any other conditions deemed unsuitable for study inclusion by the investigator.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention group

Participants in this arm will receive intranasal administration of 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: 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).
Placebo Comparator: Placebo group

Participants in this arm will receive intranasal administration of placebo (normal sline).

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).
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).
Other Names:
  • Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Pittsburgh Sleep Quality Index (PSQI) score from baseline to 1 month
Time Frame: Up to day 29 post-intervention initiation
Sleep quality will be assessed with the Pittsburgh Sleep Quality Index (PSQI) . This is a self-report questionnaire including 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored from 0 to 3; the global score ranges from 0 to 21, with higher scores indicating worse sleep quality.
Up to day 29 post-intervention initiation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Cognitive function will be assessed with the Montreal Cognitive Assessment (MoCA; scores range from 0 to 30, with higher scores indicating better function).
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
Sleep quality will be assessed with the Pittsburgh Sleep Quality Index (PSQI) . This is a self-report questionnaire including 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component is scored from 0 to 3; the global score ranges from 0 to 21, with higher scores indicating worse sleep quality.
Up to days 57 and 85 post-intervention initiation

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective sleep parameters assessed by actigraphy
Time Frame: During the night after each intervention (days 1, 4, 8, 11, 15, 18, 22, and 25)
Objective sleep parameters, including Total Sleep Time (TST), Sleep Efficiency (SE), Sleep Latency (SL), and Wake After Sleep Onset (WASO), will be monitored continuously using a wearable wrist actigraphy device.
During the night after each intervention (days 1, 4, 8, 11, 15, 18, 22, and 25)
Subjective sleep quality assessed by Numeric Rating Scale (NRS)
Time Frame: The morning following each intervention (days 2, 5, 9, 12, 16, 19, 23, and 26)
Subjective sleep quality will be evaluated using an 11-point Numeric Rating Scale (NRS). The score ranges from 0 to 10, where 0 represents the "best sleep" and 10 represents the "worst sleep".
The morning following each intervention (days 2, 5, 9, 12, 16, 19, 23, and 26)
Change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 1, 2, and 3 months
Time Frame: Up to days 29, 57, and 85 post-intervention initiation
Depression is assessed with the Patient Health Questionnaire-9 (PHQ-9). The PHQ-9 includes 9-item requiring responses of 0 (not at all) to 3 (nearly every day) to assess the occurrence of depressive symptoms over the last two weeks. It has 8 items on depressive symptoms and 1 focused on suicidal ideation. Total scores range from 0 to 27, with higher score indicating more severe symptoms.
Up to days 29, 57, and 85 post-intervention initiation
Change in Activities of Daily Living (ADL) score from baseline to 1, 2, an 3 months
Time Frame: Up to days 29, 57, and 85 post-intervention initiation
The Activities of Daily Living (ADL) scale evaluates basic activities of daily living (BADL) and instrumental activities of daily living (IADL). The total score ranges from 14 to 56, with higher scores indicating more severe impairment of daily living ability.
Up to days 29, 57, and 85 post-intervention initiation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peking University First Hospital

Investigators

  • Principal Investigator: Dong-Xin Wang, MD, PhD, Peking University First Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

June 1, 2026

Primary Completion (Estimated)

November 1, 2027

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

May 20, 2026

First Submitted That Met QC Criteria

May 20, 2026

First Posted (Actual)

May 27, 2026

Study Record Updates

Last Update Posted (Actual)

June 1, 2026

Last Update Submitted That Met QC Criteria

May 28, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2026-0208

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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