Study of Melatonin: Sleep Problems in Alzheimer's Disease

National Institutes of Health (NIH) logo

National Institutes of Health (NIH)

Status and phase

Phase 3


Alzheimer Disease


Drug: Melatonin

Study type


Funder types



3U01AG010483-08S2 (U.S. NIH Grant/Contract)

Details and patient eligibility


This protocol is a multicenter clinical trial of melatonin for sleep disturbances associated with Alzheimer's disease (AD). Frequent nocturnal awakening is a common behavioral symptom of AD. Nighttime wandering and agitated behavior may result in injuries and sleep disruption for caregivers. Alternatives are sorely needed to the currently available sleep medications that have marginal efficacy and serious side effects. Melatonin is a naturally occurring hormone secreted by the pineal gland. It has soporific effects with oral administration and is well tolerated. It enhances sleep in normal older people. Melatonin also may help sleep disturbances associated with AD; however, this remains to be proven.

Full description

In Alzheimer's disease , sleep disruption is one of the most common behavioral problems, occurring in 45 percent of patients. These nocturnal awakenings and agitation lead to considerable burden for caregivers and frequently lead families to the decision of nursing home placement. The proposed study is a randomized, double blind, parallel group, placebo controlled, clinical trial. Placebo will be compared with two doses of melatonin: a 2.5 mg, slow- release preparation and a 10 mg immediate release preparation. One hundred and fifty community-residing AD patients with disrupted sleep will be recruited. Included subjects will meet NINCDS-ADRDA criteria for probable AD. Prior to study entry, disrupted sleep will be documented by clinical history and by 1 to 2 weeks of recording using wrist activity monitors. The treatment period will last 8 weeks. Rest/activity patterns will be recorded by wrist activity monitors. The primary outcome measure will be the change in nocturnal sleep time from baseline to the end of the treatment phase.

Other outcomes also will be examined, including the time awake after sleep onset, sleep latency, sleep efficiency, daytime agitation, and changes in cognition. The relative effectiveness of high and low dose melatonin will be assessed. Adverse events and side effects will be compared by treatment. This study should provide the data necessary to determine whether melatonin is a safe and effective treatment for disrupted sleep associated with AD.




55+ years old


No Healthy Volunteers

Inclusion criteria

  • Patients must meet NINCDS-ADRDA criteria for probable Alzheimer's disease (AD). Patients must have disrupted sleep, documented by clinical history and by 1 to 2 weeks of recording using wrist activity monitors.
  • A diagnosis of probable AD.
  • MMSE score 0-26.
  • Hachinski Ischemia Scale score less than or equal to 4.
  • A 2-week history of two or more sleep disorder behaviors, occurring at least once weekly, as reported by the caregiver on the Sleep Disorder Inventory.
  • CT or MRI since the onset of memory problems showing no more than one lacunar infarct in a non-strategic area and no clinical events suggestive of stroke or other intracranial disease since the CT or MRI.
  • Physically acceptable for study as confirmed by medical history and exam, clinical laboratory results, and EKG.
  • Actigraph evidence of a mean nocturnal sleep time of less than 7 hours per night (at least 5 nights of complete actigraph data must be collected over a single week.
  • Stable home situation with no planned move during the 13-week investigational period.
  • Residing with responsible spouse, family member, or professional caregiver who is present during the night and will agree to assume the role of the principal caregiver for the 13-week protocol, including arranging transport for the patient to and from the investigators' clinic, answering questions regarding the patient's condition, and assuming responsibility for medication and actigraph procedures.
  • Ability to ingest oral medication and participate in all scheduled evaluations.
  • Six grades of education or work history sufficient to exclude mental retardation.
  • 55 years of age or older.
  • Hamilton Depression Rating Scale score of 15 or less.
  • Stable medication (dose and type) for non-excluded concurrent medical conditions for 4 weeks prior to the screening visit.

Exclusion criteria

  • Sleep disturbance is acute (within the last 2 weeks).
  • Sleep disturbance is associated with an acute illness with delirium.
  • Clinically significant movement disorder that would interfere with the actigraph readings.
  • Not having a mobile upper extremity to which to attach an actigraph.
  • Severe agitation.
  • Pain syndrome affecting sleep.
  • Unstable medical condition.
  • Use of investigational or unapproved medications within 4 weeks of the screening visit.
  • Patient unwilling to maintain caffeine abstinence after 2:00 pm for the duration of the protocol.
  • Patient unwilling to comply with the maximum limit of two alcoholic drinks per day, and only one alcoholic drink after 6:00 pm for the duration of the protocol.
  • Use of melatonin within 2 weeks of screening visit.
  • Clinically significant abnormal laboratory findings that have not been approved by the Project Director.
  • Residing in a facility without a consistent caregiver present during the night who can function as the primary informant.
  • Caregiver deemed too unreliable to supervise the wearing of the actigraph, to maintain the sleep diary, or to bring the patient to the scheduled visits.
  • Autoimmune disease, such as rheumatoid arthritis and polymyalgia rheumatica.

Trial design

Primary purpose




Interventional model

Parallel Assignment


Double Blind

Trial contacts and locations



Data sourced from

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