Clifford M. Singer

Human Melatonin Production Decreases With Age

The purpose of this study was to investigate the effects of time of year and demographic variables on the amplitude of melatonin production in normal human subjects. Melatonin production was estimated by measuring the overnight excretion of its major urinary metabolite, 6‐hydroxymelatonin. Urine was collected on three consecutive nights in the summer from a sample of 60 normal subjects balanced for sex and age. The collections were repeated in a subgroup during the winter. Melatonin production clearly declined with age but was not influenced by other demographic variables or by season of the year.

The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light

Melatonins timekeeping function is undoubtedly related to the fact that it is primarily produced during nighttime darkness; that is, melatonin and light occur at opposite times. The human phase response curve (PRC) to melatonin appears to be about 12h out of phase with the PRC to light. These striking complementarities, together with lights acute suppressant effect on melatonin production, suggest that a function for endogenous melatonin is to augment entrainment of the circadian pacemaker by the light-dark cycle. The melatonin PRC also indicates correct administration times for using exogenous melatonin to treat circadian phase disorders.

Winter depression and the phase-shift hypothesis for bright light's therapeutic effects: history, theory, and experimental evidence.

3. Current address: Department of Animal Physiology, 318 Briggs Hall, University of California at Davis, Davis, California 95616. In both diurnal and nocturnal animals, melatonin production is quiescent during the day (Quay, 1964; Lynch and Ralph, 1970). Production of melatonin by the pineal gland begins after dusk and ends at or before dawn (Goldman and Darrow, 1983). Exposure to light during the night causes abrupt cessation of melatonin production (Minneman et al., 1974). For many years, it was generally accepted that human melatonin production was not affected by light (Vaughan et al., 1976; Jimerson et al., 1977; Lynch et al., 1977; Arendt, 1978; Weitzman et al., 1978; Wetterberg, 1978; Akerstedt et al., 1979; Vaughan et al., 1979; Perlow et al., 1980). However, a few years ago we showed that human melatonin production can be suppressed by light, providing it is sufficiently intense (Lewy et al., 1980). This finding had at least two potentially important implications. First, humans had biological rhythms that were cued to sunlight and that would not be confounded by the use of ordinary indoor light (which is not sufficiently bright to be effective). Two, bright artificial light could be used to experimentally, and perhaps therapeutically, manipulate these rhythms. In 1980, we first tested these implications in a patient who regularly became depressed each year as daylength shortened (Lewy et al., 1982). We hypothesized that he had a seasonal rhythm that, like the rhythms of other animals, was regulated by photoperiod. We further hypothesized that by exposing him to bright artificial light between 0600 and 0900 hr and between 1600 and 1900 hr, we could bring him out of his winter depression, similar to what normally happened to him in the spring. After 4 days of exposure to 2000-lux light scheduled so as to extend daylength, our patient began to emerge from his depression. Since then, many such patients have been similarly treated; dim-light exposure

Pain Assessment for the Dementing Elderly (PADE): Reliability and Validity of a New Measure

OBJECTIVES To establish the reliability and validity of a measure to assess pain in individuals with advanced dementia. DESIGN Sixty-five residents of long-term care facilities were assessed using a new rating tool, the Pain Assessment for the Dementing Elderly (PADE), in two separate studies: (1) Residents were assessed simultaneously by two different raters, at Time 1 and 2, to establish interrater reliability, stability, and internal consistency. (2) Validity was established by assessing the correlation between an agitation scale and the PADE; by comparing groups with pain as a significant clinical factor (as assessed by an independent rater) versus not a significant factor, and by assessing individuals receiving versus not receiving psychoactive medications. SETTING Four different long-term care facilities, three skilled nursing facilities, and a locked dementia assisted-living facility. PARTICIPANTS Twenty-five residents of long-term care facilities with advanced levels of dementia in Study 1, and 40 residents with similar level of dementia in Study 2; 42% of the total sample were rated as having significant painful conditions. MEASUREMENTS For Study 1, the PADE was administered; for Study 2, the PADE and the Cohen-Mansfield Agitation Inventory (CMAI) were administered. RESULTS Reliability coefficients were adequate (interrater = 0.54-0.95; stability = 0.70-0.98; and internal consistency = 0.24-0.88). Validity coefficients were likewise encouraging, with the PADE demonstrating the expected relationship with a measure of agitation. The PADE also differentiated between groups that were independently judged to suffer clinically problematic pain versus those who were not. CONCLUSION The PADE is a reliable and valid tool to assess pain in dementing elderly residents of long-term care facilities.

Development of diagnostic criteria for defining sleep disturbance in Alzheimer's disease.

This article proposes new standards for identifying, defining, and naming sleep/wake cycle disturbances associated with Alzheimers disease (AD) to aid in more effective research, including the development and testing of potential treatments. Many AD patients develop sleep/wake cycle disturbances associated with distress, depression, and sleep disturbances in the caregiver, as well as early nursing home placement for the patient. The Food and Drug Administration Psychopharmacological Drugs Advisory Committee has emphasized the need for a comprehensive diagnostic system. A key point made by the committee was that behavioral problems associated with dementia (including sleep and chronobiological disturbances) are scientifically and clinically valid targets of pharmacologic treatment. However, current diagnostic criteria preclude development of FDA-acceptable studies of pharmacological interventions because they do not include the required specific indications for treatment. This article attempts to develop better-defined provisional criteria with the goal of promoting epidemiological, physiological, and, especially, pharmacological research on sleep/wake disturbances. (J Geriatr Psychiatry Neurol 2003; 16:131-139)

The Sleep Disorders Inventory: an instrument for studies of sleep disturbance in persons with Alzheimer's disease

The Sleep Disorders Inventory (SDI) is an expanded version of one item of the Neuropsychiatric Inventory (NPI). It describes the frequency, severity, and caregiver burden of sleep‐disturbed behaviors during a period prior to its administration. We carried out post hoc analyses on baseline responses to the SDI in 104 persons with Alzheimers disease (AD) and live‐in caregivers who had been recruited for a trial of melatonin in the treatment of sleep disturbance. These patient‐participants averaged <7 h of sleep per night, measured by actigraph (sleep disturbance), for the 2–3‐week period prior to administration of SDI. Data were from the 2 weeks prior to the baseline visit (SDI, NPI) including actigraph‐derived sleep variables and 2 weeks’ worth of sleep quality ratings (SQR) kept in a diary by caregivers, plus Mini‐Mental State Examination and activities of daily living assessment at baseline. The prevalence of sleep disorder symptoms ranged from 34% (waking up at night thinking it is daytime) and 82% (getting up during the night). Worse SDI scores were associated with worse cognitive, functional, and behavioral status, but not with sex, age, education or duration of dementia. SDI scores were significantly worse in individuals meeting independently established criteria for a diagnosis of ‘sleep disturbance’ (<6 h total sleep time per night) whereas demographic variables and scores reflecting cognition and function were not significantly different across this grouping. The SDI covers a wide range of sleep behaviors and provides information independent of sleep time and SQR.

Symptoms of sleep disturbance in persons with Alzheimer's disease and normal elderly

We retrospectively analyzed sleep time and sleep disturbance symptoms in 399 healthy, non‐demented elderly (NDE) and 263 persons with a diagnosis of possible (n = 53) or probable (n = 210) Alzheimers disease (AD). Our primary objective was to determine differences in subjective sleep disturbance between these samples. Secondary objectives were to determine if subjects with time in bed (TIB) ≤6 h per night reported more sleep disturbance and whether sleep complaints were associated with more severe cognitive and/or functional impairment. The prevalence of ‘sleep problems’ (a single item) was significantly lower in NDE (18.3%) than AD (27.6%), and the proportions of each cohort reporting TIB ≤6 h per night were very low (NDE: 6.0%; AD: 3.5%) and not significantly different. Less TIB was correlated with better cognitive function for AD (P < 0.01), and cognition and function were significantly worse for AD subjects with estimates of >6 h of TIB compared with those with estimates of ≤6 h (P < 0.05). Greater sleep disturbance was correlated with greater functional impairment in both cohorts; but only in AD did greater estimated TIB also correlate with greater functional impairment (all P < 0.05). In general, estimated TIB was not associated with mood in either cohort; however, in both cohorts depression was significantly associated with sleep disturbance symptoms and was significantly worse in those who reported having ‘sleep problems’. There was no association between subjective perception of ‘sleep problems’, the number and frequency of sleep disturbance symptoms, and estimated TIB in either group.

Entrainment of A Free-Running Human with Bright Light?

The case of a 40-year-old sighted woman with free-running sleep-wake and melatonin rhythms is presented. The subject was studied for 102 days. During the pre-treatment period, both the sleep-wake and melatonin rhythms had a period of 25.1 hr, similar to the average period of humans living in temporal isolation. Treatment consisted of bright artificial light exposure (2500 lx Vita-Lite) for 2 hr each day upon awakening. Clock time of light exposure was held constant for 6 days and then slowly advanced until the subject was arising at her desired time of day. The subject continued the light treatment at home and was able to live on a 24-hr day for the 30-day follow-up study. While other factors may be operating in this situation, it is possible that the light treatment caused the stabilization of the free-running rhythms, advancement to a normal phase and entrainment to the 24-hr day. We suspect that the tendency to free-run was related to sleep onsets that were abnormally delayed relative to the circadian phase response curve for light. By scheduling a 2-hr pulse of bright light each morning, this tendency to delay would be counteracted by light-induced advances, resulting in normal entrainment.

The effects of shifting sleep two hours within a fixed photoperiod.

This study examined the effects of shifting the time of sleep within a constant photoperiod on the circadian rhythms of body temperature and melatonin secretion. Subjects lived under conditions of a long scotoperiod (dim light of less than 10 lux from 6 p.m. until 8 a.m.) for three weeks. In order to delineate dawn and dusk, subjects received one hour of bright light (2500 lux) before and after the scotoperiod (i.e., from 8 to 9 a.m. and from 5 to 6 p.m.). For the first week of the experiment they slept from 10 p.m. until 6 a.m. In the second week, sleep was advanced two hours; that is, subjects retired at 8 p.m. and arose at 4 a.m. The third week was a repeat of the first, resulting in a two-hour delay of sleep from week two to three. The six subjects who successfully completed this protocol had no significant changes in the timing of the body temperature minima and onset of secretion of melatonin. This indicates that the timing of allowed sleep has less of an immediate effect on circadian rhythms than the timing of the external light-dark cycle. The circadian effects of the timing of sleep may be due more to the light-dark cycle that is imposed by the sleep-wake cycle than from the timing of sleep itself.

Outcomes of Pain in Frail Older Adults With Dementia

OBJECTIVES: To describe the outcomes of pain in cognitively impaired older adults in a Program of All‐inclusive Care for older people (PACE) setting and to determine whether pain and psychotropic drug use, behavioral disturbances, hospital, nursing facility, and emergency department use, or mortality increases with the level of pain reported.