A 157-patient multicenter trial investigates the effect of melatonin on sleep disorders associated with Alzheimer’s disease

f01a.jpg (6888 bytes)Secretion of the pineal hormone melatonin (N-acetyl-5-meth-oxytryptamine) occurs predominantly at night and is thought to play a crucial role in the coordination of the body’s many circadian rhythms, including sleep. Melatonin levels decline with age. While restoring “youthful” levels of melatonin in the healthy aged population has not been consistently shown to improve sleep, the value of nightly administration of this substance to patients with Alzheimer’s disease (AD) may be different. As part of a large consortium of 36 federally funded AD research centers, principal investigator Clifford Singer, MD, associate professor of psychiatry and neurology at the Oregon Health and Science University, Portland, and coauthor of this article, assisted by numerous colleagues, conducted a multicenter study, funded by the National Institute on Aging (NIA). The study’s findings were presented in part in February at the annual meeting of the American Association of Geriatric Psychiatry in Orlando, Fla.

The study sought to answer two questions: would nightly administration of melatonin provide an endocrine signal that augmented the diminishing output from the circadian pacemaker in AD patients and restore circadian rhythmicity to the sleep-wake cycle? And would a high dose of melatonin provide a greater soporific effect in AD patients than a low dose?

The study was conducted under the auspices of the Alzheimer’s Disease Cooperative Study (ADCS), funded by the NIA program designed specifically to coordinate large-scale clinical trials of therapies, which would not be pursued by the pharmaceutical industry due to a lack of patent protection. Melatonin, a naturally occurring substance, falls in this category. The principal investigator of the ADCS is Leon Thal, MD, professor of neurology at the University of California at San Diego.

The Alzheimer’s population was selected for this study because of the high prevalence of profound sleep disturbance and disturbed circadian rhythmicity. This sleep disturbance is extremely stressful for caregivers, who must remain awake at night to supervise people they are caring for and may also contribute to further functional impairment in patients. This can be a critical issue, and is frequently cited as a key reason for nursing home placement.

Having seen some pilot data suggesting that melatonin may have a sleep-promoting effect at high dose in people with Alzheimer’s disease, the study’s investigators sought to determine the possible benefits of this hormone in improving sleep in AD patients.

Melatonin and AD: An Overview
Melatonin levels are linked to the light-dark cycle, increasing at night and dropping with the dawning of daylight. The hormone also appears naturally in some foods. Consequently, the US Dietary Supplement Health and Education Act of 1994 allows it to be sold as a dietary supplement, which does not need the Food and Drug Administration’s approval.

It was hoped that melatonin would be much better tolerated than traditional sleeping medications among the frail AD population. AD patients are known to be very vulnerable to the cognitively deteriorating effects of sleeping medications, as well as associated balance problems and fall risk, and the potential of certain medications to worsen sleep apnea—a significant risk among the dementia population. Traditional sleep medications are largely untested among AD patients and it is reasonable to believe these drugs may be clinically risky. In contrast, investigators noted that melatonin appeared to be relatively well tolerated in the dementia patient, though a large study was needed to demonstrate safety as well as possible efficacy.

Scientifically, there was another reason this study sought to look at melatonin. Findings suggest that there may be a chronobiologic component to the sleep disturbance of patients with Alzheimer’s disease. This is a function of two factors: they get very little exposure to the natural light-dark cycle, and they may have a degenerative circadian pacemaker. One investigator says it is possible that there is little circadian input into the pacemaker and less circadian output than in healthy active people, thus potentially explaining why the sleep cycle of people with AD appears to lose circadian rhythmicity. The tendency is for these patients to sleep more during the day and less at night than healthier older people.

Alzheimer’s disease represents a great model and clinical imperative for developing chronobiologic interventions to improve sleep. However, the AD population is hard to study, and this is perhaps why there have been no multicenter or large clinical trials of medications published.

Study Protocol and Dosing
The ADCS study included 157 AD patients who scored 27 or less on the Mini-Mental state examination, indicative of at least mild dementia; however, some patients in the study had severe dementia. The average patient age was 83, ranging from 46 to 92. A power calculation based on pilot data determined the need to include 50 people in each of three arms in order to detect an average of a 30-minute increase in sleep—the amount determined to be a meaningful increase. The three treatment conditions were placebo, low dose (2.5-mg sustained-release melatonin), and high dose (10 mg). The primary entry criterion was less than 7 hours of sleep during the nighttime period, from 8 pm to 8 am. Even when looking for a common sleep disorder, recruiting people into a large clinical trial, particularly one that took months, was very difficult, especially given that the study was placebo-controlled and people wanted help with their sleep right away. More than 2 years were required for the 36 sites to recruit the required number of subjects.

Decisions regarding dose were based on pilot data. Physiologic dosing is defined as taking that quantity of melatonin that produces a natural melatonin level—one normally seen in the body at night. In old people, anything above tiny doses is not necessarily normal, but a dose of .5 mg or below would produce what would be seen as a natural level in younger people. The investigators did not detect a significant effect on sleep at physiologic dosing, although others have claimed such findings. However, they did see an effect at 10 mg, so that dose was selected for the large study. The investigators also wanted to see if giving a lower dose (2.5 mg), but in a sustained-release format, might also be beneficial.

Actigraphy: A Critical Component
Actigraphy was essential for conducting the research and for collecting valid data. An actigraphy device was used on all 157 patients. This small, lightweight (approximately 17 g), limb-worn activity monitoring device was selected for several important reasons.

Primarily, conducting a large-scale sleep study makes the use of polysomnography (PSG) prohibitive because it is an expensive procedure, and because it is not mobile. While PSG is the gold standard for sleep assessment studies in the sleep laboratory, when looking to document sleep change patterns over time and especially when studying something as variable as night-to-night sleep efficiency and total sleep time, many nights of data were required. Using PSG was therefore seen as prohibitively expensive and AD patients may not have tolerated electrodes and wires. Moreover, caregiver questionnaires, while potentially useful, represented a subjective data collection tool, not to mention that the majority of caregivers would be asleep at night and unable to report nighttime sleep behavior in a quantitative manner.

Thus, to conduct this research, a relatively inexpensive, unobtrusive, accurate, and quantifiable way to collect sleep data was needed. Actigraphy was selected as the best technology to accomplish these objectives. It was also critical that the company provided a high level of customer support during the research, competitive pricing, and a technology interface (the software output on the computer) that was intuitive, easy to use, and clear.

The actigraphy device used, which is wristwatch sized, relies on limb movement. There is a small accelerometer in the unit’s case that is capable of sensing any motion with a minimum resultant force of 0.01g, and capable of integrating degree and intensity of motion. The accelerometer records arm movement above a certain threshold of intensity on a 64-KB on-board memory chip with a programmable threshold. The actigraphy device records the most sensitive movements into memory. In the analysis software, low, medium, or high sensitivity can be selected. The software’s high sensitivity setting was used in the study.

Depending on the sample interval of the actigraphy instrument and how frequently the data are recorded, data can be collected continuously with this device from 1 week to 1 month between downloading it onto a computer. In this study, the device was placed on a “reader,” and using wireless transfer, data stored in the unit were transferred to a computer. The software also recognized the subject since it was preprogrammed with the subject’s age and other information about each person’s identity.

Actigraphy is useful for many different applications, noted an investigator, especially where a cost-effective estimate of total sleep time over a longitudinal period of study is needed, for example over a period of 1 month. Computer software evaluation of the data from this device can discern not only when a patient is sleeping, but also how active an individual is. It is, therefore, of benefit in both clinical situations or research applications where actual activity levels—motor activity—must be determined such as in measuring hyperactivity in children, periodic limb movement syndrome, or tremor movement disorders.

In the ADCS study, the primary data collection objective of the actigraphy device was to record total sleep time at night, during a 12-hour period, from 8 pm to 8 am. Other outcome variables were ratio of day/night sleep, sleep efficiency, and awakening after sleep onset. The actigraphy unit does not actually monitor sleep; rather, an algorithm in its software program evaluates each epoch and scores it for sleep based on movement. The lower the degree of movement, the greater the likelihood of sleep. The unit records movement during a particular period of time, which is programmable and stores activity counts in 1-minute epochs. The unit’s sleep algorithm scores each epoch, as well as neighboring epochs, to determine sleep probability. Thus, if a patient remained motionless for three or four epochs, it might score that 4-minute period as sleep. It was reported that the actigraphy device compared very well to PSG with an 84% correlation to PSG when the sleep scoring algorithm was on the highest sensitivity setting in AD patients. Compared to PSG, actigraphy provided accurate technology for scoring sleep at a fraction of the cost, while being fully mobile and extremely well tolerated by patients. The device, although easy to use, requires some experience and training.

Conducting multicenter trials relying on actigraphy technology is a reasonable strategy and is the best technology currently available for this application. If researchers were to do a large study or look at people over a long period of time, the investigators believed this technology to be the best available. While suitable for most populations, it has a great advantage among any population who will not tolerate coming into a sleep laboratory, for whatever reason, or for disorders requiring more than 1 night of observation.

According to the principal investigator, no difference was found between melatonin at either dose and placebo in the ADCS trial, although there was a trend for more sleep in the melatonin groups. Both doses were very well tolerated. There was a strong trend for less daytime sleep and more nighttime sleep in both melatonin groups, suggesting a modest chronobiologic effect.

Anecdotally, there was one individual who had a dramatic response to 2.5-mg melatonin. This subject had an unusual sleep disorder—a classic sleep-wake cycle reversal. This man started the study sleeping mostly during the day but little at night. The melatonin stabilized his sleep cycle into a normal pattern.

Although some subjects appeared to benefit overall, melatonin’s sleep effect in this population is modest. Some people get a small effect, a few people get a big effect, but it was not, overall, a robust or consistent effect.

In conclusion, this study found that melatonin provided limited benefits to most elderly people with AD and sleep disturbance. However, if melatonin is used as part of a chronobiologic intervention with bright light, and is targeted in people with a chronobiologic component to their sleep disturbance, it may well prove beneficial.

Josh Feldstein is a medical writer and journalist, Silver Spring, Md; Clifford Singer, MD, is associate professor of psychiatry and neurology at the Oregon Health and Science University, Portland, and principal investigator of the study.