Alfred Lewy

Oregon Health and Science University | OHSU · Department of Psychiatry

Study objectives: To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD). Methods: Three sighted individuals with signs and/or symptoms of N24SWD were studied. Thirty-five to three-hundred and thirty-two day laboratory and home-based assessm...

A primary role for melatonin relates to the human circadian system. Endogenous melatonin production is the ideal marker for biological time. Its physiological function in humans probably relates to the fact that low physiological doses of melatonin cause phase delays when administered in the morning and cause phase advances when administered in the...

Özdemir and coworkers' present contribution to this journal invites the opportunity to outline some of the fundamentals concerning circadian rhythms and affective illness. Consensus or near-consensus has been reached on the tools for assessing and adjusting circadian rhythms, if not on the hypotheses for their role in seasonal affective disorder (S...

More than three decades ago, bright light was found to be able to suppress melatonin production in humans, a finding which quickly led to identification of seasonal affective disorder (SAD) and its treatment with light. However, current thinking supports a phase shift hypothesis (PSH), according to which SAD is a disorder primarily of phasedelayed...

To assess the interindividual and intraindividual variability in the circadian rhythms of blind individuals with non-24-h disorder and to quantify the influence of environmental time cues in blind subjects lacking entrainment (non-24-h individuals or N-24s). An observational study of 21 N-24s (11 females and 10 males, age 9-78 years) who kept a sle...

In the absence of the entraining light-dark cycle, most totally blind humans free-run, albeit with relative coordination to nonphotic zeitgebers. Such blind free-runners (BFRs) often attempt to maintain a 24-h sleep-wake schedule and consequently suffer from recurrent sleep disruption and daytime somnolence. This study was conducted to determine th...

This chapter is an update of what was originally published several years ago (Vessely and Lewy, 2002). Melatonin is a hormone produced by the pineal gland during nighttime darkness under the control of the endogenous circadian pacemaker (ECP) in the suprachiasmatic nucleus of the hypothalamus. The ECP is entrained (synchronized) to the 24-h light/d...

A primary role for melatonin relates to the human circadian system. Endogenous melatonin production is the ideal marker for biological time. Its physiological function in humans probably relates to the fact that low physiological doses of melatonin cause phase advances when administered in the morning and cause phase delays when administered in the...

Recent refinements in methodology allow chronobiological researchers to answer the following questions: is there circadian misalignment in sleep and mood disturbances, and, if so, is it of the phase-advance or phase-delay type? Measurement of the dim light melatonin onset-to-midsleep interval, or phase-angle difference, in sleep and mood disorders...

In conclusion, the melatonin onset is important in human circadian biology. It is used to determine baseline circadian phase position and (with the melatonin/mid-sleep interval) baseline circadian alignment/misalignment, which can then be used to phase type the individual and to optimize the use of phase-resetting agents by indicating the phase of...

In their monograph (1), Healy and Waterhouse quite thoughtfully distinguish between the altered shapes of circadian rhythms and their entrainment (synchronization). Although there is a great deal of evidence that various influences can alter the shape of circadian rhythms (“masking”), the literature on multiple time cues (zeitgebers) entraining dif...

It has been hypothesized that the circadian pacemaker plays a role in major depressive disorder (MDD). We sought to determine if misalignment between the timing of sleep and the pacemaker correlated with symptom severity in MDD. Depression severity correlated with circadian misalignment: the more delayed, the more severe the symptoms.

Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body's signal for nighttime darkness. Publis...

The phase-shift hypothesis (PSH) states that most patients who have seasonal affective disorder become depressed in the winter because of a delay in circadian rhythms with respect to the sleep/wake cycle. According to the PSH, these patients should respond preferentially to the antidepressant effects of bright light exposure when it is scheduled in...

Differences in morningness-eveningness among humans are commonly ascribed to circadian parameters, such as circadian period and responsivity to environmental time cues, as well as homeostatic sleep drive. Light is the primary synchronizer of the human biological clock, and if circadian differences exist between morning and evening types, they shoul...

DefinitionA large family of acidic adaptor proteins of ∼30 kDa that mainly (but not solely) interact with phosphoserine or -threonine sites on target proteins to facilitate their activity. 14-3-3 proteins have 9–10 alpha helices, generally form homo- or heterodimers, and contain a number of common modification sites (e.g. phosphorylation, divalent...

Pineal origin of plasma melatoninMelatonin as a Marker for Adrenergic FunctionMelatonin as a Marker for Effects of LightMelatonin as a Marker for Biological RhythmsTreatment of Winter Depression Using Bright Light ExposureThe Phase—response Curve and the Clock—gate Model‘Phase Typing’ Patients with Chronobiological Sleep or Mood DisordersReferences...

Abstract This study evaluated the Actillume® instrument and the modified Action 3 sleep-wake scoring algorithm, in which the scoring factor (P) was set at 0.10, 0.14, 0.20, 0.30, 0.40 and 0.50. Fifteen subjects, each of whom underwent polysomnography with simultaneous wrist actigraphy four times, yielded a total of 60 sleep studies. The sleep data...

To provide guidelines for collecting and analyzing urinary, salivary, and plasma melatonin, thereby assisting clinicians and researchers in determining which method of measuring melatonin is most appropriate for their particular needs and facilitating the comparison of data between laboratories. A modified RAND process was utilized to derive recomm...

The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.

Measuring the dim light melatonin onset (DLMO) is a useful and practical way to assess circadian phase position in humans. As a marker for the phase and period of the endogenous circadian pacemaker, the DLMO has been shown to advance with exposure to bright light in the morning and to delay with exposure to bright light in the evening. This ‘phase...

With the development of accurate and sensitive assays for measuring melatonin in plasma and saliva, it has been possible to advance our understanding of human chronobiology. In particular, the dim light melatonin onset (DLMO) is expected to have an increasingly important role in the diagnosis of circadian phase disorders and their treatment with ap...

The finding that bright light can suppress melatonin production led to the study of two situations, indeed, models, of light deprivation: totally blind people and winter depressives. The leading hypothesis for winter depression (seasonal affective disorder, or SAD) is the phase shift hypothesis (PSH). The PSH was recently established in a study in...

Psychiatrically high-risk women were recruited for a postpartum depression prevention trial. Participants were screened at entry (20-26 weeks gestation) by a psychiatrist prior to receiving randomized treatment. Of the 31 patients who did not complete the study, 10 (33%) were dropped because of diagnosed depression. Only two women developed major d...

The following test of the circadian phase-shift hypothesis for patients with winter depression (seasonal affective disorder, or SAD) uses low-dose melatonin administration in the morning or afternoon/evening to induce phase delays or phase advances, respectively, without causing sleepiness. Correlations between depression ratings and circadian phas...

Melatonin in humans can be an independent or dependent variable. Measurement of endogenous melatonin levels under dim-light conditions, particularly the dim-light melatonin onset (DLMO), has received increasing attention among researchers, and for clinicians it may soon become a convenient test that can be done at home using saliva collections in t...

Light is the primary synchronizer of the human biological clock. In more than half of those blind individuals who completely lack light perception, the absence of photic input to the hypothalamic circadian pacemaker results in rhythms that free-run (blind free-runners [BFRs]) with a period typically greater than 24 h. The remainder are entrained, a...

The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 microg) of this chemical signal for the "biological night": the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were d...

In the majority of totally blind individuals, the biological clock is no longer synchronized, or entrained, by the light/dark cycle. Despite exposure to regular social cues, meal times and sleep/wake schedules, the circadian phase (timing) of biological events in these individuals continues to drift to a progressively later (or, rarely, earlier) ho...

About 15% of the legally blind completely lack light perception. Most of these individuals have abnormally phased circadian rhythms and many free-run. Light treatment is not an option for them. However, melatonin treatment can be highly effective. A daily dose of 0.5 mg of melatonin usually results in entrainment. It has been suggested that treatme...

Chronobiological disorders and syndromes include seasonal affective disorder (SAD), total blindness, advanced and delayed sleep phase syndrome, jet lag, and shift work maladaptation. These disorders are treated by adjusting circadian phase, using appropriately timed bright light exposure and melatonin administration (at doses of 0.5 mg or less). In...

Four blind individuals who were thought to be entrained at an abnormal circadian phase position were reset to a more normal phase using exogenous melatonin administration. In one instance, circadian phase was shifted later. A fifth subject who was thought to be entrained was monitored over four years and eventually was shown to have a circadian per...

This chapter reveals that melatonin is a hormone produced by the pineal gland and secreted in a nocturnal circadian pattern under the control of the endogenous circadian pacemaker (ECP) in the suprachiasmatic nucleus of the hypothalamus. The ECP itself is entrained by photic stimuli from the 24-hr light/dark cycle. The secretory pattern of melatoni...

In a previous report, we were unable to entrain one out of seven totally blind people with free-running endogenous melatonin rhythms to 10 mg of exogenous melatonin. This person had the longest circadian period (24.9 h) of the group. We now find that this person can be entrained to 0.5 mg of melatonin, but not to 20 mg. These results are consistent...

We have recently shown that six of seven totally blind people (who had free-running circadian rhythms with periods longer than 24 h) could be entrained (synchronized) to a nightly dose of 10 mg melatonin. After treatment discontinuation and re-entrainment to the 10 mg dose, we further found in three of these subjects that the dose could be graduall...

To date, we have entrained (synchronized) eight totally blind people with free-running circadian rhythms to a nightly dose of 10 mg of melatonin. Each person entrained at a different phase angle of entrainment (PAE), which is the interval in hours between the time of the melatonin dose and the time of the endogenous melatonin onset. When the PAE wa...

The indoleamine melatonin, a well-known animal chemical, has been identified in extracts from several plant species. The function of melatonin in plants is unknown. Two major functions of melatonin in animals are dark signaling and antioxidant protection. Fruit ripening was used as a model physiological process that involves changes in the oxidativ...

As totally blind people cannot perceive the light-dark cycle (the major synchroniser of the circadian pacemaker) their circadian rhythms often "free run" on a cycle slightly longer than 24 h. When the free-running sleep propensity rhythm passes out of phase with the desired time for sleep, night-time insomnia and daytime sleepiness result. It has r...

Age-related changes in the intrinsic circadian period (tau) have been hypothesized to account for sleep symptoms in the elderly such as early morning awakening. The authors sought to determine whether the aging process produced quantifiable differences in the tau of totally blind men who had free-running circadian rhythms. The melatonin onset was u...

Most totally blind people have circadian rhythms that are "free-running" (i.e., that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours). This condition causes recurrent insomnia and daytime sleepiness when the rhythms drift out of phase with the normal 24-hour cycle. We investigated whether...

Previous studies have suggested that bipolar patients are supersensitive to light suppression of melatonin and that this may be a trait marker for genetic vulnerability. The present study was an attempt to replicate and extend this observation. Propranolol hydrochloride effects were compared with light effects because of the documented influence of...

In rodents, the nocturnal rise and fall of arylalkylamine N-acetyltransferase (AANAT) activity controls the rhythmic synthesis of melatonin, the hormone of the pineal gland. This rhythm involves the transcriptional regulation of the AANAT by two norepinephrine (NE)-inducible transcription factors, e.g. the activator pCREB (phosphorylated Ca2+/cAMP-...

The goals of this study were to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag. This was a randomized, double-blind trial of placebo and three alternative regimens of melatonin (5.0 mg at bedtime, 0.5 mg at bedtime, and 0.5 mg taken on a shifting sched...

The discovery and study of three kindreds with advanced sleep phase disorder shed light on how we can inherit tendencies to be early morning or late night kinds of people (pages 1062-1065).

Several circadian rhythms have been used to assess the phase of the endogenous circadian pacemaker (ECP). However, when more than one marker rhythm is measured, results do not always agree. Questions then inevitably arise. Are there multiple oscillators? Are some markers more reliable than others? Masking is a problem for all marker rhythms. Maskin...

The most useful marker for human circadian phase position is the dim light melatonin onset (DLMO). This is optimally obtained by sampling blood or saliva in the evening at intervals of 30 min or less. Ambient light intensity should not exceed 30-50 lx. For many years, the DLMO was determined mainly with the 'gold standard' GCMS technique for measur...

With the advent of RIAs capable of measuring the melatonin onset (60), the DLMO has been increasingly utilized as a marker for the phase of the ECP. Measurement of melatonin not only helps assess circadian phase but also has been important in developing the use of bright light to assess light sensitivity, as well as to shift the ECP in the treatmen...

Although not licensed as a drug, melatonin is widely sold as a nutritional supplement in the USA for its purported sleep-promoting and antiageing properties. In this article, we provide some guidelines for its use in sleep disorders medicine. In brief, melatonin appears to promote sleep by producing corrective circadian phase shifts, thereby improv...

Discusses the diagnosis and management of "non-24-hour sleep-wake syndrome," a form of cyclic insomnia to which people who are totally blind are prone. Covered are incidence and clinical features, formal diagnostic criteria, the biological basis of circadian sleep disorders, circadian rhythms in blind people, pharmacological entrainment, and the sy...

Five patients with winter depression received low doses of melatonin in the afternoon, and five patients received placebo capsules. Melatonin treatment significantly decreased depression ratings compared to placebo. If these findings are replicated in a larger sample with documentation of expected phase shifts, the phase shift hypothesis will be su...

Melatonin's 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 light's acute...

The present investigation used a placebo-controlled, double-blind, crossover design to assess the sleep-promoting effect of three melatonin replacement delivery strategies in a group of patients with age-related sleep-maintenance insomnia. Subjects alternated between treatment and "washout" conditions in 2-week trials. The specific treatment strate...

Objective: The goals of this study were to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag. Method: This was a randomized, double-blind trial of placebo and three alternative regimens of melatonin (5.0 mg at bedtime, 0.5 mg at bedtime, and 0.5 mg taken...

Melatonin's phase-shifting effects in humans are thought by some investigators to be subtle, particularly in comparison to those achieved with appropriately timed bright light exposure. The initial study in sighted people was only intermittently successful in phase advancing the endogenous melatonin profile. The study of free-running blind people s...

Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian des...

Differing conclusions regarding the sleep-promoting effects of melatonin may be the result of the broad range of doses employed (0.1-2000 mg), the differing categories of subjects tested (normal subjects, insomniac patients, elderly, etc.), and the varying times of administration (for daytime vs. nighttime sleep). We conclude that melatonin may ben...

Matsumoto M, Sack RL, Blood ML, Lewy AJ. The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. J. Pineal Res. 1997; 22:42–44. © Munksgaard, Copenhagen A physiological dose of melatonin (0.5 mg) or placebo was given at bedtime to night shift workers (n=21) for seven days, and endogenous melatonin profiles...

This chapter focuses on the role of melatonin and light in the human circadian system. Unique to melatonin is that its production can be acutely suppressed by exposure to light during the night. Consequently, it was concluded that humans, unlike other primates, lacked the neural pathways that mediated light input to the human circadian pacemaker. T...

The case of a 41-year-old sighted man with non-24-hour sleep-wake syndrome is presented. A 7-week baseline assessment confirmed that the patient expressed endogenous melatonin and sleep-wake rhythms with a period of 25.1 hours. We sought to investigate the underlying pathology and to entrain the patient to a normal sleep-wake schedule. No deficienc...

Melatonin is produced only during nighttime darkness. Its onset during the evening is a useful marker for circadian phase position, when melatonin levels are sampled frequently and under conditions of dim light or darkness. This marker is termed the dim light melatonin onset (DLMO). Recently, we have described a phase response curve (PRC) to melato...

Examination of the influence of the light-dark cycle on circadian rhythmicity has been a fundamental aspect of chronobiology since its inception as a scientific discipline. Beginning with Bünning's hypothetical phase response curve in 1936, the impact of timed light exposure on circadian rhythms of literally hundreds of species has been described....

The rationale for the treatment of sleep disorders by scheduled exposure to bright light in seasonal affective disorder, jet lag, shift work, delayed sleep phase syndrome, and the elderly is, in part, based on a conceptual framework developed by nonclinical circadian rhythm researchers working with humans and other species. Some of the behavioral a...

In addition to the well-established phase-shifting properties of timed exposure to bright light, some investigators have reported an acute alerting, or activating, effect of bright light exposure. To the extent that bright light interventions for sleep disturbance may cause subjective and/or central nervous system activation, such a property may ad...

Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure. Under entrainment to the 24-h day-night cycle, the sleep-wake pattern may assume various phase relationships to the circadian pacemaker, as indexed, for example...

Sleep maintenance insomnia is a major complaint among the elderly. As a result, an inordinate proportion of sleeping pill prescriptions go to individuals over 65 y of age. Because of the substantial problems associated with use of hypnotics in older populations, efforts have been made to develop nondrug treatments for age-related sleep disturbance,...

The unhealthy symptoms and many deleterious consequences of shift work can be explained by a mismatch between the work-sleep schedule and the internal circadian rhythms. This mismatch occurs because the 24-h zeitgebers, such as the natural light-dark cycle, keep the circadian rhythms from phase shifting to align with the night-work, day-sleep sched...

Sleep disturbances are an all-too-familiar symptom of jet lag and a prime source of complaints for transmeridian travelers and flight crews alike. They are the result of a temporary loss of synchrony between an abruptly shifted sleep period, timed in accordance with the new local day-night cycle, and a gradually reentraining circadian system. Sched...

Measuring the dim light melatonin onset (DLMO) is a useful and practical way to assess circadian phase position in humans. As a marker for the phase and period of the endogenous circadian pacemaker, the DLMO has been shown to advance with exposure to bright light in the morning and to delay with exposure to bright light in the evening. This 'phase...

Now that it has been established that experimental administration of melatonin has circadian phase-shifting effects in humans, we can speculate about its endogenous function. More specifically, melatonin in physiologic amounts can produce effects that are described by a phase response curve (PRC) (Lewy et al., 1990a; Lewy et al., 1992; Lewy et al.,...

This chapter highlights the use of melatonin as a marker for circadian phase and as a chronobiotic in blind-sighted humans. Melatonin is produced only at night in the dark. Levels of plasma melatonin are quite low during the day and increase to about 50–100 pg/ml at night. The GCMS assay continues to be the gold standard, because of its sensitivity...