Chronobiology and Mood Disorders

ISSN 1294-8322
Dialogues
in
Chronobiology and Mood Disorders
2003
Vo l u m e 5 . N o . 4
clinical neuroscience
Dialogues
Editor-in-chief Jean-Paul MACHER, MD, Rouffach, France Editorial Board Manfred ACKENHEIL, MD, Mnchen, Germany Csar CARVAJAL, MD, Santiago de Chile, Chile Marc-Antoine CROCQ, MD, Rouffach, France Michael DAVIDSON, MD, Tel Hashomer, Israel Margret R. HOEHE, MD, Berlin, Germany Barry D. LEBOWITZ, PhD, Rockville, Md, USA Deborah J. MORRIS-ROSENDAHL, PhD, Johannesburg, South Africa Rajesh M. PARIKH, MD, Bombay, India David RUBINOW, MD, Bethesda, Md, USA Pierre SCHULZ, MD, Chne-Bourg, Switzerland Carol A. TAMMINGA, MD, Baltimore, Md, USA International Consultant Jorge-Alberto COSTA E SILVA, MD, Rio de Janeiro, Brazil Publication Director / Directeur de la Publication Jean-Philippe SETA, MD, Neuilly-sur-Seine, France
Editorial
ear Colleagues,
The concept of chronobiology combines the notion of rhythms with objective phenomena reflecting the functioning of the living organism. Rhythms give a framework to this functioning and are of great importance to our everyday life. Indeed, rhythms are present due to night and daylight cycles, meal periodicity, and social interactions, and even in the work place. All these synchronizersfor which the German word Zeitgeber is often used, as a result of Jrgen Aschoffs seminal researchleave an imprint on our lives. There are endogenous rhythms that correspond to these exogenous rhythms, such as sleep-wake cycles, rhythms in hormonal secretions, and other biological rhythms in general. In pathophysiology, some rhythms acquire an abnormal character, and some disorders exhibit specific rhythms. Examples include recurring episodes of manic-depressive illness, schizoaffective psychoses, and recurrent depression. The understanding of this chronological symptomatology and its correlation with chronobiology is essential for two reasons. First, clinically or biologically suitable markers must be defined, and, second, treatments stimulating or regulating rhythms must be devised. For instance, rhythms may be stimulated by antidepressant drugs in depression, or regulated by chronobiotic substances, such as mood-regulating drugs. We are convinced of the importance of a progress report on the current state of the art in these various fields, and we believe that the articles in this issue will provide plenty of food for thought.
Yours sincerely,
Jean-Paul Macher, MD
Marc-Antoine Crocq, MD
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Dialogues in Clinical Neuroscience is a quarterly publication that aims to serve as an interface between clinical neuropsychiatry and the neurosciences by providing state-of-the-art information and original insights into relevant clinical, biological, and therapeutic aspects. Each issue addresses a specific topic, and also publishes free contributions in the field of neuroscience as well as other nontopic-related material. All contributions are reviewed by members of the Editorial Board and submitted to expert consultants for peer review. Indexed in EMBASE and Elsevier BIOBASE. EDITORIAL OFFICES Editor in Chief Jean-Paul MACHER, MD FORENAP - Institute for Research in Neuroscience and Neuropsychiatry BP29 - 68250 Rouffach - France Tel: + 33 3 89 78 70 18 / Fax: +33 3 89 78 51 24 Secretariat and submission of manuscripts Marc-Antoine CROCQ, MD FORENAP - Institute for Research in Neuroscience and Neuropsychiatry BP29 - 68250 Rouffach - France Tel: +33 3 89 78 71 20 (direct) or +33 3 89 78 70 18 (secretariat) Fax: +33 3 89 78 51 24 / E-mail: macrocq@forenap.asso.fr Production Editor Sarah A. NOVACK, PhD Servier International - Medical Publishing Division 192 avenue Charles-de-Gaulle 92578 Neuilly-sur-Seine Cedex - France Tel: +33 1 55 72 33 10 / Fax: +33 1 55 72 68 88 E-mail: sarah.novack@fr.netgrs.com
PUBLISHER Les Laboratoires Servier 22 rue Garnier - 92578 Neuilly-sur-Seine Cedex - France E-mail: mail.dialneuro@fr.netgrs.com Copyright 2003 by Les Laboratoires Servier All rights reserved throughout the world and in all languages. No part of this publication may be reproduced, transmitted, or stored in any form or by any means either mechanical or electronic, including photocopying, recording, or through an information storage and retrieval system, without the written permission of the copyright holder. Opinions expressed do not necessarily reflect the views of the publisher, editors, or editorial board. The authors, editors, and publisher cannot be held responsible for errors or for any consequences arising from the use of information contained in this journal. ISSN 1294-8322
Design: Christophe Caretti / Layout: Graphie 66 Imprim en France par SIP 1, rue Saint Simon - 95310 Saint-Ouen-lAumne
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Contents
Page
309 313 315 327 343 353 366 371 389 399
Editorial
Jean-Paul Macher, Marc-Antoine Crocq
In this issue
Manfred Ackenheil
State of the art

Chronobiology and mood disorders Anna Wirz-Justice Concepts in human biological rhythms Alain Reinberg, Israel Ashkenazi
Basic research
Melatonin and animal models Paul Pvet
Pharmacological aspects
Light treatment of mood disorders Barbara L. Parry, Eva L. Maurer
Poster
Sleep deprivation and antidepressant treatment Ulrich Voderholzer
Clinical research
Diagnosis and treatment of sleep disorders: a brief review for clinicians Vivien C. Abad, Christian Guilleminault Treatment of seasonal affective disorders Nicole Praschak-Rieder, Matthus Willeit Clinical applications of melatonin in circadian disorders Alfred J. Lewy
ISSUE COORDINATED BY: Manfred ACKENHEIL
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Contributors
Anna Wirz-Justice, PhD Ulrich Voderholzer, MD, PhD Author affiliations: Centre for Chronobiology, Psychiatric University Clinic, Basel, Switzerland Author affiliations: Department of Psychiatry and Psychotherapy, Klinikum of the Albert-Ludwig-University, Freiburg, Germany
Alain Reinberg, MD, PhD
Vivien C. Abad, MD, MBA
Author affiliations: Unit de Chronobiologie, Fondation Adolphe de Rothschild, Paris, France
Author affiliations: Stanford University Sleep Disorders Clinic and Research Center, Stanford University, School of Medicine, Stanford, Calif, USA
Paul Pvet, PhD
Nicole Praschak-Rieder, MD
Author affiliations: Laboratoire de Neurobiologie des Rythmes, UMR 7518 CNRSUniversit Louis Pasteur, Strasbourg, France
Author affiliations: Centre for Addiction and Mental Health, PET Centre, Toronto, ON, Canada
Barbara L. Parry, MD
Alfred J. Lewy, MD, PhD
Author affiliations: Department of Psychiatry, University of California, San Diego, USA
Author affiliations: Sleep and Mood Disorders Laboratory, Oregon Health Science University, Portland, Ore, USA
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In this issue...
This issue of Dialogues in Clinical Neuroscience is devoted to circadian rhythms and related disorders. Many patients with psychiatric disorders show disturbances in circadian rhythms and frequently sleep disorders. These disorders are considered either to be the cause or the symptoms of the corresponding psychiatric disorder. Whether they be the cause or the effect, it is important to take them into consideration for treatment decisions. Specific treatments, such as melatonin, light therapy, advanced and delayed sleep phase, and sleep deprivation, are reported here. Chronobiology (circadian, ultrarapid, and seasonal rhythms) is an essential component of human and animal lives. Disturbances in these rhythms result in behavior abnormalities and mental and somatic symptoms. Exceptionally, in this issue two State of the art articles illustrate the current knowledge of the complexity of circadian rhythms. In the first, Anna Wirz-Justice (page 315) refers to diurnal variations of mood and sleep disturbances in depression, leaving open the question of its etiological significance. Antidepressant treatments, medication, sleep deprivation, and exposure to bright light (corresponding to sunlight) are discussed. The opposite of lightdarkness and the hormone melatonin are examined, as well as future aspects, which are delineated in an extensive manner. The second State of the art article by Alain Reinberg and Israel Ashkenazi (page 327) is more conceptualized, relating biological rhythms to environmental factors as adaptive phenomena to the movement of the earth. In this sophisticated text, they focus on human chronobiology and the problem of desynchronization, which can occur without clinical symptoms (which they call allochronism) or with numerous pathological symptoms (dyschronism). They describe diseases with chronic sleep disturbances, for example, night shift workers who are intolerant to desynchronization. The Basic research article by Paul Pvet (page 343) focuses on the sleep hormone melatonin. The paper elucidates the role of melatonin in animals with special respect to circadian and seasonal rhythms. The administration of exogenous melatonin shows the complexity of melatonins actions. Depending on the dosage, the time of administration, and the sensitivity of melatonin receptors, different effects are reported. Melatonin has various effects, which are mediated through the different melatonin receptors. Pharmacological treatment with melatonin or similar substances has to consider this complexity. Two articles in this issue deal with chronobiological disorders and techniques of light therapy. In the Pharmacological aspects article, Barbara L. Parry and Eva L. Maurer (page 353) focus on phototherapy and its possible mechanisms in various psychiatric conditions and subsyndromal states, including gender issues like premenstrual dysphoric disorder. It is a comprehensive article covering most of the existing relevant literature related to this topic. More clinical aspects are covered in the Poster by Ulrich Voderholzer (page 366) on sleep deprivation therapy, which is one of the most effective therapies for severe depression. Unfortunately, it is only short-lasting, but its effect can be prolonged in combination with pharmacotherapy, advanced sleep phase therapy, and light therapy. Predictors for the response to sleep deprivation therapy from brain imaging and endocrine studies are discussed. Sleep disorders are strongly related to disturbances of circadian rhythms and are comprehensively described in the Clinical research article by Vivien C. Abad and Christian Guilleminault (page 371). They describe exactly the different forms of sleep disorders and present guidelines for treatment. Additionally, other circadian rhythm disorders are mentioned and options for treatment with chronotherapy and light therapy are given. Restless legs syndrome, periodic limb movement disorders, obstructive sleep apnea, narcolepsy, and parasomnia are comprehensively discussed. The second article to deal with light therapy is a Clinical research article from Nicole Praschak-Rieder and Matthus Willeit (page 389). It covers the treatment of mood and also seasonal affective disorder (SAD), which may be a subform of major depression, recurrent, or bipolar disorder. The current knowledge of the pathophysiology of SAD and the various treatments with bright light are presented as a first-line option for SAD. Recommendations for the general management of such disorders are given, also mentioning a combination of therapies with psychotropic drugs.
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In this issue...
In a Clinical researchoriented article, Alfred J. Lewy (page 399) describes two major melatonin activities in humans as a marker of biological rhythms and a modulating hormone for the circadian phase. The regulation of melatonin secretion is described. The consequences for treatment with exogenous melatonin are mentioned. Thus, exogenous melatonin (2 mg/day) should be given 2 h before the dim light melatonin onset and therapeutic light should be given at waketime. Sighted people are compared with blind (sightless) people. Interestingly, such studies show that low dosages of melatonin (1 mg/day) have better effects than higher dosages (>3 mg/day). Guidelines for treatment of circadian sleep disorders in blind people are recommended. Delayed sleep phase syndrome, advanced sleep phase syndrome, and jet lag are also described. Recommendations for treatment or how to avoid these syndromes are given. The problem of shift work maladaptation is briefly discussed.
Manfred Ackenheil, MD
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State of the art

Chronobiology and mood disorders
Anna Wirz-Justice, PhD
n order for Dialogues in Clinical Neuroscience to be truly designated dialogues, I will raise specific and critical questions about the putative circadian rhythm disturbances in depression, provide a model within which to understand them, and summarize the present status and application of chronobiological therapies. This short overview will not go into detail of the clinical and experimental findings related to biological rhythms in depression, which have been extensively reviewed elsewhere.1-9 Chronobiologists predicate their work on a primary axiom, that temporal order is essential for health. Psychological, behavioral, physiological, and hormonal rhythms are specifically and functionally timed (entrained or synchronized) with respect to sleep and the day-night cycle. The converse premise implies that temporal disorder must have clinical correlates. Rhythmic characteristics of The clinical observations of diurnal variation of mood and early morning awakening in depression have been incorporated into established diagnostic systems, as has the seasonal modifier defining winter depression (seasonal affective disorder, SAD). Many circadian rhythms measured in depressive patients are abnormal: earlier in timing, diminished in amplitude, or of greater variability. Whether these disturbances are of etiological significance for the role of circadian rhythms in mood disorders, or a consequence of altered behavior can only be dissected out with stringent protocols (eg, constant routine or forced desynchrony). These protocols quantify contributions of the circadian pacemaker and a homeostatic sleep process impacting on mood, energy, appetite, and sleep. Future studies will elucidate any allelic mutations in circadian clockrelated or sleep-related genes in depression. With respect to treatment, antidepressants and mood stabilizers have no consistent effect on circadian rhythmicity. The most rapid antidepressant modality known so far is nonpharmacological: total or partial sleep deprivation in the second half of the night. The disadvantage of sleep deprivation, that most patients relapse after recovery sleep, can be prevented by coadministration of lithium, pindolol, serotonin (5-HT) reuptake inhibitors, bright light, or a subsequent phase-advance procedure. Phase advance of the sleepwake cycle alone also has rapid effects on depressed mood, which lasts longer than sleep deprivation. Light is the treatment of choice for SAD and may prove to be useful for nonseasonal depression, alone or as an adjunct to medication. Chronobiological concepts emphasize the important role of zeitgebers to stabilize phase, light being the most important, but dark (and rest) periods, regularity of social schedules and meal times, and use of melatonin or its analogues should also be considered. Advances in chronobiology continue to contribute novel treatments for affective disorders.
2003, LLS SAS Dialogues Clin Neurosci. 2003;5:315-325.
Keywords: major depression; seasonal affective disorder; circadian rhythm; sleep deprivation; light therapy; melatonin Author affiliations: Centre for Chronobiology, Psychiatric University Clinic, Basel, Switzerland Copyright 2003 LLS SAS. All rights reserved
Address for correspondence: Prof Dr Anna Wirz-Justice, Centre for Chronobiology, Psychiatric University Clinic, Wilhelm Klein Strasse 27, CH4025 Basel, Switzerland (e-mail: anna.wirz-justice@pukbasel.ch)
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www.dialogues-cns.org
State of the art

Selected abbreviations and acronyms
HPA 5-HT PVN rTMS SAD SCN SSRI hypothalamo-pituitary-adrenal (axis) serotonin (5-hydroxytryptamine) paraventricular nucleus repetitive transcranial magnetic stimulation seasonal affective disorder suprachiasmatic nucleus selective serotonin reuptake inhibitor masked by psychophysiological response. Melatonin, the pineal hormone considered to provide the best estimate of circadian rhythm phase, is suppressed by light, particularly in the evening: it is sensitive to masking by light as low as ca 100 lux.10 Thus, even indoor room light may delay the apparent onset of nocturnal secretion. Only in the last decade have controlled protocols using state-ofthe-art chronobiological techniques provided unequivocal circadian markers. The fourth question concerns which models are useful. Concepts of an underlying genetic and stress-related vulnerability for depression can be discussed in terms of both neurotransmitter and circadian rhythm dysregulation. Here, I will draw on the two-process model of sleepwake regulation11 as a way of understanding some aspects of depressive symptomatology. The final question is whether we can find out about putative circadian mechanisms underlying affective disorder through understanding clinically successful chronobiological treatments. Circadian rhythm or sleep manipulations do improve depression and provide some fascinating clues.
mood disorders were precisely described as far back as ancient times. However, it is still unclear whether circadian rhythms are reliably linked with psychopathology, if they provide clues to underlying mechanisms, and how they can be understood with respect to the established neurotransmitter models of depression. The first question is common to all clinical research: what do we mean by biologically homogeneous groups? Here too, diagnostic issues are the crux. In addition to the distinction unipolar, bipolar, or seasonal affective disorder (SAD), the stage of the illness may be important for chronobiological disturbances. Acute depression is probably different from chronic, and in rapid cyclers it is known that there is a continuous shift in circadian phase during depression and that this reverses during mania.1 Given that antidepressants act on neurotransmitter mechanisms also involved in circadian rhythm generation and entrainment, only untreated patients may reveal an endogenous rhythm disturbance, if present. The second question regards conceptual clarity. What do we mean by a clock disturbance in depression? What one sees clinically may have its origins at a variety of different levelsnot necessarily the hypothalamic biological clock itself, but epiphenomena related to altered rhythmic behavior, disturbed sleep, or abnormal environmental input. The third question is whether the studies purporting to document circadian rhythm disturbances in depression have been adequately carried out. Alas, methodological issues characterize most investigationsnot in terms of scientific caliber or intent, but because it was previously not sufficiently recognized how strongly masking (behavioral or environmental factors that modify the variable measured) obscures the underlying endogenous rhythms. This is a particular problem with measuring the core body temperature rhythm, since temperature is easily and rapidly masked by motor activity, postural change, meals, etc. Cortisol increases with stress, particularly at the evening nadir; thus, this circadian marker is also often
Clinical observations
Periodicity in affective disorders (from seasonal recurrence to 48-h rapid cycling) is the clinical observation; diurnal variation of mood, early morning awakening, and sleep disturbances are the classical symptoms that have linked depression with circadian rhythm function. Many rhythms, such as core body temperature, cortisol, monoamine metabolism, are different in depressive patients: phase advanced (timed earlier) with respect to the sleep-wake cycle, diminished in amplitude, and/or with day-to-day variability in their synchronization to social cues (entrainment).1 However, altered rhythmicity could be either a cause or an effect of altered affective state. Both could independently reflect abnormalities in a third system, such as psychomotor activity. Apparent lability may be caused solely by lack of appropriate feedback to the circadian system (eg, reduced activity). In addition, sleep disturbances are inextricably linked with depressive illness. These clinical observations can be formalized in terms of circadian and sleep physiology.
The neurobiology of circadian rhythms

Circadian rhythms are generated by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the ante-
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Dialogues in Clinical Neuroscience - Vol 5 . No. 4 . 2003
rior hypothalamus.12 Individual, genetically determined endogenous periodicity is slightly different from 24 h (usually longer) and requires daily synchronization to the 24-h day by zeitgebers, which are regularly recurring environmental signals. Light is the major zeitgeber for the SCN, transmitted by novel photoreceptors in retinal ganglion cells.13 This nonvisual, nonimage-forming pathway via the retinohypothalamic tract counts photons, in particular the transitions at dawn and dusk, and is actively gated by a second clock in the eye.14 An indirect visual pathway reaches the SCN via the intergeniculate leaflet of the lateral geniculate complex. From the raphe nucleus, a serotonergic pathway provides nonphotic input to the SCN, and it is perhaps of some importance in the context of depression that concentrations of serotonin (5-HT) in the brain are highest in these nuclei.An important output leads from the SCN to the paraventricular nucleus (PVN) and via a multisynaptic pathway to the pineal gland, where melatonin is synthesized at night and suppressed by light during the day. Melatonin transduces the night signal for the body as the nocturnal duration of hormone secretion (the day within).15 Melatonin onset in the early evening has proved to be the most reliable biological marker of circadian timing (provided samples are taken under dim light conditions).16 The PVN is also the site of corticotropinreleasing factor synthesis, ie, part of the hypothalamo-pituitary-adrenal (HPA) axis.The nadir of the cortisol rhythm provides a reliable output of the SCN clock (whereas the maximum is influenced by environmental factors).17 Zeitgeber stimuli, of which light is the most important, can phase shiftand thus entrainthe SCN.18,19 Light during the early part of the night induces phase delays, whereas light given in the second half of the night (after the core body temperature minimum) induces phase advances.18,19 Administration of exogenous melatonin shows patterns nearly opposite to phase shifting to light.20 Other nonphotic zeitgebers (exercise, perhaps sleep or darkness, and nutrients) have been less well investigated and are probably weaker zeitgebers than light.21 Social zeitgebers (jobs, social demands or tasks, and personal relationships) may act directly or indirectly on the SCN, since they determine the timing of meals, sleep, physical exercise, and outdoor light exposure. These social factors also have the potential to disrupt circadian rhythms.22 Some of the particular psychosocial precipitants of depressive disorder, such as life events, chronic stresses, or lack of appropriate social support systems, may act as precipitants by disrupting circadian rhythms.
Clocks everywhere The concept of a master pacemaker driving all circadian rhythms has been very useful. It needs to be supplemented by the concept of peripheral clocks distributed in every organ and perhaps in every cell.23 Each organ has its own relevant and specifically timed circadian rhythmsof heart rate, liver metabolism, and kidney transport, and also of gene expression. Under normal conditions, all rhythms are synchronized by the SCN.23 The SCN signal is translated mainly by the PVN into a hormonal and autonomic signal to peripheral organs. Visceral, sensory, and hormonal information feeds back on the hypothalamus, providing fine-tuning to synchronize time-of-day input from the external light-dark cycle with metabolic information from the inside. The phase of each rhythm can be adjusted by differential responses of a given tissues circadian clock to a signal from the SCN or from the environment. Such a system can adjust well to small, gradual changes in the input signal (such as seasonal changes in daylength), but may become temporarily and severely disorganized if the change in phase of this signal is abrupt and large (as is most obvious for rapid transmeridian travel and shift work). How could this system go wrong in affective disorders? Consider the vegetative symptoms that are an integral part of the depressive syndrome, and often appear as forerunners. If sleep is no longer in correct alignment with the inner or outer clock, if food intake decreases, or if behavior turns inward so that motor activity declines and the amount of outdoor light exposure is reduced (as well as social contact), is it not conceivable that these behaviors each act on different clocks, shifting their timing with respect to each other and the day-night cycle to different degrees? This temporal cacophony could initiate an internal stress reaction. Given the concept of a final common neuroendocrine pathway of depression via hyperactivity of the HPA axis, this may be an important mediating system from physiology to psyche. Clock genes, sleep genes Individual preference in timing of the sleep-wake cycle (chronotype, ie, whether larks or owls)24 is determined by clock genes, of which 10 have been cloned so far.25 Individual sleep and wake duration (long sleepers versus short sleepers) is also probably programmed in certain sleep genes26). Since the timing of sleep appears
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State of the art

to be rather important for mood, these genetic factors may be relevant to a chronobiological vulnerability for depression, in that wrong or poor alignment of internal phase with the outdoor world increases susceptibility to depressive mood swings. Although familial forms of circadian sleep disorders (such as advanced or delayed sleep phase syndrome) have been found, with allelic mutations on one or other of the clock genes,27-29 the first studies in depression have been negative (eg, the clock gene in major depression30 or the per2 gene in bipolar disorder31). Circadian clock-related polymorphisms seem to be related, interestingly enough, to susceptibility to SAD together with evening chronotype.32 This research is still in its infancy. Circadian rhythm desynchronization It is unlikely, however, that affective disorders will be characterized as simple clock gene mutations. Rather, internal desynchronization may be a major contributing factor to mood state. New findings on desynchronization in clock gene expression illustrate this vividly. The clock genes in the SCN gradually adapt to a phase shift of the light-dark cycle (as found in shift work and transmeridian travel), whereas clock genes in muscle, liver, and lung resynchronize at their own rates.33 This results in a double desynchronization, not only between internal (SCN) and external time, but also between different clocks and organs within the body itself. The temporal orchestra can quickly get out of tune. Moreover, the different organ clocks respond to different, specific zeitgebers; for example, food can shift the clock in the liver rather fast, but light does not affect it; the SCN clock reacts to light, but is not influenced by meals.34 Peripheral clocks in muscle may be synchronized by exercise. This provides a new view on circadian rhythm disturbances in depression. Since peripheral clocks complement the central clocks function of maintaining temporal order, more clocks in body and brain only add to the possibilities of this organization going awry. There may be different patterns of desynchronization that result in similar physiological or psychological consequences. The classical idea of internal circadian phase disturbances in depression can be extended to zeitgeber phase disturbances.6 Even an apparently minor reduction in zeitgeber strength or diminished behavior can loosen temporal coordination, not only between internal rhythms, but also with respect to the social and physical clock, resulting in mood detriments, diurnal variation, and day-to-day mood variability. However, the precise neurobiological mechanisms by which altered circadian phase relationships lead to altered mood state remain unknown. Bipolar disorder, in particular rapid cycling, is the most striking example of a mood disorder linked to abnormal or changing circadian rhythm phase.1 Here the environment (light or dark) as well as behavior (sleep or its deficit)35 strongly modulate affective state and, recently, these factors have begun to be used as treatments.36-39 Sleep regulation The sleep-wake cycle is the most obvious circadian rhythm in humans, and sleep disturbances are a prominent feature of depression. In the two-process model of sleep regulation, a homeostatic process S increases during waking and declines exponentially during sleep; it interacts with a circadian process C to determine the timing and architecture of sleep.11 This model can also be used to describe possible disturbances in either process during depression (Figure 1A). The clinical sleep disturbance with early morning awakening could arise from an impaired build-up of S during waking (diminished sleep pressure) or an earlier timing of process C. There are a number of sleep manipulations that improve clinical state (see below and Table I). The rapid antidepressant effect of one nights sleep deprivation is proposed to act by a short-term increase in process S to normal levels.40 The slower antidepressant effect of a phase advance of the sleep-wake cycle8 may be related to more gradual shifts towards a correct phase relationship with respect to process C. Other possibile abnormalities could lie in the decline of S during sleep, or circadian period, phase, or amplitude (process C).
How to measure process C and S

The model helps clarify which biological markers could be measured to test these hypotheses (Figure 1B). Correct methodology is important to define experimental conditions where masking is reduced. There are two major approaches, both requiring subjects to undergo demanding and highly controlled protocols. The first protocol is the constant routine, in which subjects remain awake during an entire 24-h cycle or longer, with external and behavioral conditions constant (very low light levels not to affect the circadian pacemaker, supine pos-
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ture in bed, and regular small isocaloric meals). The constant routine provides information about process C: amplitude and phase estimates of rhythms in, for example, melatonin, cortisol, and core body temperature.18 Only such parameters that are little affected by sleep deprivation are valid as circadian markers. The second protocol is forced desynchrony, in which subjects live on very long or very short sleep-wake cycles, while the clock remains at its endogenous period, somewhat longer than 24 h. This protocol allows quantification of many measures with respect to either time of day (process C) or to duration of prior wakefulness (process S).18
Process C and S in SAD Both the constant routine and forced desynchrony protocols have been employed in patients with SAD, both when depressed and euthymic, in winter and summer. The endogenous period appears normal.41 A phase delay in process C (as measured by core body temperature or melatonin rhythms in constant routine) has been found,42 but not in all studies or all markers.41,43 The decline in process S (as measured by spectral analyses of the sleep electroencephalogram [EEG]) was no different in SAD patients compared with controls.44,45 However, the rise in process S (as measured by spectral analyses of the wake EEG) was different, indicating a factor related to daytime vigilance.46,47 Wake EEG patterns in evening chronotypes are similar to this,48 which may mean that the above finding is not pathogenetic for SAD, since the patient chronotype is skewed towards owls, shows the above tendency to phase delay, and has common clock-related polymorphisms.32 War of the zeitgebers? What is fascinating is that both circadian and wake-dependent factors contribute to a subjective measure such as mood. This has been demonstrated in healthy subjects in both protocols.6,41,49,50 The day-to-day change in patterns of diurnal mood variation in a forced desynchrony protocol has remarkable similarities to the day-to-day variability in diurnal mood variation found in depressive patients, and
Figure 1. A. The two-process model of sleep regulation, considered in terms of what could go wrong in depression. The homeostatic component (process S) builds up during wakefulness and declines during sleep. The circadian pacemaker (process C) ticks along at its individual (genetically programmed) endogenous period. Decreased amplitude would increase variability of daily timing and it would be more vulnerable to phase shifts. If the rhythm was advanced or delayed in phase, the resultant altered phase relationships between process C and sleep timing could explain many depressive phenomena. B. Biological markers of process S and process C. The exponential rise in sleep pressure can be followed by theta-alpha (/) power in the wake electroencephalogram (EEG). The exponential decline in sleep pressure is evident in slow-wave activity in the sleep EEG. In a constant routine protocol, the rhythms of core body temperature (CBT), melatonin, and cortisol provide estimates of circadian phase and amplitude. In a forced desynchrony protocol, the endogenous period of the circadian pacemaker can be reduced as well as the relative contributions of process C and process S to any given measure, from psychological to physiological.
A. Where can it go wrong in depression?

Homeostatic process
Build-up of S S decline
Circadian process
Phase
Phase relationship between C and sleep
Amplitude Zeitgebers
Endogenous period
B. How can we get evidence for disturbances?

Homeostatic process (EEG)
Wake EEG / Sleep EEG, slow wake activity
Circadian process (constant routine)

Phase advance and decreased amplitude CBT, melatonin, cortisol Decreased Zeitgebers Social, light, food, activity
Abnormal/unstable phase relationship between C and sleep
Endogenous period Separate C and S (forced desynchrony)
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State of the art

even more similarity to the mood patterns following a phase advance of the sleep-wake cycle.8 Thus, mood fluctuations can indeed be understood in terms of abnormal or changing phase relationships. Mood-related cognitive and attributional disturbances have been postulated to be sequelae of shifting circadian rhythms.5 This is an important point for the above findings. If SAD patients are vulnerable to short winter days, is this an abnormality of the biological clock, or is it rather a subjective interpretation of internal temporal disorder? The following findings are perhaps relevant to this argument. Some subjects in experiments where they live free of time cues manifest spontaneous internal desynchronization, in that their sleep-wake cycle desynchronizes from circadian rhythms such as core body temperature. They do not notice that this phenomenon has occurred, nor do they show any decrement in mood or performanceon the contrary, they feel rather well.51 This is in marked contrast to the situation resulting from external desynchronization, when sleep timing is shifted by shift work or transmeridian travel. Here the internal desynchronization between sleep and the clock is additionally in conflict with light and social zeitgebers in the outer world; and it is postulated that this aspect may underlie the often-associated depressive disturbances.5,52 It may not only be phase relationships that are important, but perhaps also the light-dark ratio (daylength or photoperiod). Some of the evidence for SAD suggests that the duration of nocturnal melatonin secretion is important for
Sleep manipulations TSD PSD (second half of the night) Phase advance of the sleep-wake cycle TSD followed by phase advance Repeated TSD or PSD Repeated TSD or PSD with antidepressants Single or repeated TSD or PSD plus: Light therapy Light therapy and phase advance rTMS Single or repeated TSD or PSD plus Lithium SSRIs Pindolol
triggering psychopathology in winter.53 Conversely, in a study of healthy subjects kept on long winter nights, one volunteer became severely suicidal, even though all the others felt remarkably well on this protocol.54 Diurnal variation or instability of mood can thus be quite well explained by considering changing phase relationships between processes C and S. Even in healthy subjects, some phase relationships are favorable, others unfavorable. Modest but reliable mood decrements occur after a phase delay of the sleep-wake cycle55 (reviewed in reference 5). Sudden delays (as induced by night shift or westwards flights across time zones) can even precipitate depressive symptoms in predisposed individuals with a history of affective illness.56,57 This points to a particular vulnerability of mood state when sleep is shifted later with respect to circadian rhythms. Such an association also appears to be valid for the circadian sleep disorder of delayed sleep phase syndrome (inappropriately late sleep timing with respect to the endogenous circadian clock). In these persons there is a high comorbidity of depressive symptoms.58 Conversely, flying east may be more correlated with hypomanic or manic states.56,57
Psychopharmacology and circadian rhythms

The earliest link between psychopharmacology and circadian rhythms came from the observation that lithium slows down circadian periodicity in plants.59 These effects of lithium are consistent across species, including humans,60
Zeitgebers Light therapy (SAD) Light therapy (nonseasonal MD) Light therapy as adjuvant to SSRIs (nonseasonal MD) Dark or rest therapy (rapid-cyclers) Dark therapy (mania)
Table I. Chronobiological therapies of major depression. Therapies in italics are for one or two studies only. TSD, total sleep deprivation; PSD, partial sleep deprivation; rTMS, repetitive transcranial magnetic stimulation; SSRI, selective serotonin reuptake inhibitor; SAD, seasonal affective disorder; MD, major depression.
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and are measurable even at the level of individual SCN neurones.61 However, attempts to generalize across various classes of antidepressant drugs have not been successful7: even though the monoamine oxidase inhibitor (MAOI) clorgyline lengthened circadian period,62 the MAOI moclobemide shortened it,63 and selective serotonin reuptake inhibitors (SSRIs) had no effect.63 When considering the model (Figure 1A), it is clear that drugs could act not only on circadian period but may also change phase position or phase relationships with the sleep-wake cycle, to enhance circadian amplitude or sensitivity to zeitgebers. Evidence that imipramine and lithium modify the phase angle between the circadian temperature rhythm and the rest-activity cycle is interesting,64 as is the concept that stabilization of circadian rhythms may be a key action of clinically effective mood-stabilizing drugs.65 In addition, sensitivity to light could be affected, as is the case with chronic clorgyline and lithium treatments.66
Nonpharmacological therapies
Sleep deprivation Well documented is the rapid, usually short-lasting improvement following total sleep deprivation and the rapid return of depressive symptoms after subsequent recovery sleep, indicating that the depressive process is strongly sleep dependent.8 Additionally, sleep deprivation needs to coincide with an early morning circadian phase for optimal antidepressant response. Partial sleep deprivation in the second half of the night or phase-advance of the sleep-wake cycle are equally efficacious (see Table I for a list of therapeutic modalities). The spontaneous switch out of depression (and into hypomania and mania) often occurs after a natural sleep deprivation. This remarkable and immediate antidepressant modality has been recognized for 30 years, but is little used in everyday clinical practice. Perhaps it is the paradox of taking sleep away from the depressive insomniac that has a negative connotation for both patient and psychiatrist (wake therapy would be a more positive alternative name). Perhaps it is also the short-term nature of the response that has hindered its use, though the magnitude of the clinical changes brought about by sleep deprivation still remain highly intriguing and may provide clues for understanding the pathophysiology of depression. Sleep deprivation is the paradigm par excellence for depression research: rapid, nonpharmacological, and short
lasting. It may be the nonpharmacological nature of sleep deprivation (it cannot be patented) that has contributed to its status as an orphan drug.67 It is surprising that no pharmaceutical company has focused on this model to search for that much-needed rapid-acting antidepressant.8 This lack may be remedied in the future; new research reveals that, whereas sleep induces very few genes, wakefulness increases expression of several groups of genes,68 and here comparisons with the effects of antidepressant drug treatment may narrow down the candidates. Some committed proponents of sleep deprivation have recognized its clinical usefulness to initiate rapid improvement, particularly in the most severely depressed patients in whom time is of the essence. Sleep deprivation is effective in all diagnostic subgroups of depression. The problem is the relapse after recovery sleep, and new strategies have sought treatments to prevent this. Response appears to be well maintained by treatment with lithium, antidepressants (in particular SSRIs), or the 5-HT1A receptor antagonist pindolol, as well as nonpharmacological adjuvants such as repetitive transcranial magnetic stimulation (rTMS),69 light therapy, or phase advance of the sleep-wake cycle, or various combinations thereof (see, for example, reference 36 and 70, reviewed in reference 8; Table I). Light therapy Light therapy can be considered to be the most successful clinical application of circadian rhythm concepts in psychiatry to date. Light is the treatment of choice for SAD.71 The quality of recent SAD studies has been exemplary, and the response rate is well above placebo (in fact, superior to analogous trials with antidepressant drugs).72 The success of this nonpharmacological treatment has been astonishing, but it has taken rather long for light therapy to be accepted by establishment psychiatry,72 and trials of other indications are still in the research phase. Its very success in SAD has limited use in other forms of depression (characterized as its a chronobiological treatment for a chronobiological subset of depressive patients). However, light acts on the same neurotransmitters, in particular serotonin, as the major antidepressant drugs.71 This has been shown with tryptophan deletion tests, where relapse after successful light therapy is induced, as well as the successful treatment of SAD patients by SSRIs.71 More direct evidence of the immediate effects of light on serotonin turnover in
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the brain has come from an in vivo study in healthy subjects: not only is serotonin turnover high in spring and summer and low in autumn and winter (the pattern following the hours of available sunshine), but serotonin turnover increases immediately after light exposure.73 Assuming that mood state is at least partially linked to serotonin turnover, the conclusions are obvious: more light, better mood. The serotonin connection suggests that a broader use of light therapy is indicated.A rapid response within a week in SAD does not mean that other major depressive disorders will improve so fast: trials of light therapy over at least 4 to 6 weeks, as would be standard for a drug treatment trial, are required.There is already good evidence for efficacy in bulimia, preliminary evidence for usefulness in prepartum and postpartum depression (clinical indications where new nondrug therapies are sorely needed),74 and promising findings in major depression, particularly as an adjuvant (Table I).74 Light is being recognized not only as a major zeitgeber necessary for our daily well-being (with applications in the work place and in architecture), but also as a drug that can be prescribed in dose, timing, and duration for specific diagnoses.71 An important step forward for the clinician has been that all available randomized studies of light therapy for both SAD and nonseasonal depression are being analyzed for efficacy, and will soon be published in the Cochrane Library (www.cochrane.de). Dark therapy Single case studies of rapidly cycling bipolars have shown that extending darkness (or rest, or sleep) immediately stops the recurring pattern, which is a rather astonishing result in these therapy-resistant patients.38,39 Further support comes from recent findings that extended darkness (not rest and not sleep) in manic bipolar patients can control their symptoms within days (B. Barbini, personal communication). The pineal hormone melatonin is designated the hormone of darkness. Physiologically, it is important for timing the cascade of events initiating sleep in humans.20 The nocturnal onset of melatonin secretion opens the gateway for sleep propensity, involving peripheral thermoregulatory mechanisms.75 The warm feet effect underlies its soporific action and use in a variety of sleep disorders.20 The few studies administering melatonin to depressed patients have indeed found improvements in sleep, but not in mood.76,77 Emerging therapies New drugs, such as agomelatine (a melatonin agonist and 5-HT2c antagonist), with a core action on circadian rhythms, are currently in development for the treatment of mood disorders. A large multicenter study investigating agomelatine in major depression has yielded an excellent antidepressant response,78 which has been linked to the action of the compound on the melatonergic and serotonergic systems. Moreover, the 5-HT2c receptor subtype is considered to be relevant to the therapeutic properties of SSRIs, and to link this to chronobiology5-HT2c receptor agonists, which mimic the effects of light in rat CNS.79 Sleep shifts and zeitgebers as therapy The above concepts point toward a multimodal approach to using chronobiological therapies in major depression. Wake therapy (increasing the level of process S) induces rapid clinical improvement in all diagnostic subgroups; phase advance (changing the timing of sleep) maintains the response, as does light, drugs acting on the serotonergic system, or rTMS (which acts on the SCN80). Increasing zeitgeber strength improves the consistency of entrainment and circadian amplitude: this may be one mechanism underlying the therapeutic efficacy of bright light and the melatonin agonist. There is evidence that depressed patients, including those with SAD, have greater day-today and within-day mood variability than controls.81,82 In SAD patients, it has been shown that increasing zeitgeber strength with light therapy reduced or eliminated both group differences in mean level and variability of mood.82 Other zeitgebers (social cues, activity, and food) are important for improving behavioral feedback from peripheral clocks to overall entrainment stability. This is extremely important in bipolar patients.37 The combination needed by the clinician for the sought-after rapid and long-lasting antidepressant, might well be an eclectic mix of these nonpharmacological modalities with antidepressant drugs.
Conclusion
We live in a 24-h society that is no longer strongly synchronized to the change in daylength or temperature across the seasons. A permanent summer day is the result of artificial lighting, yet it is of insufficient intensity for stable entrainment. Too little is known of the seque-
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lae of irregular patterns of light exposure on a vulnerable circadian system, and how light could trigger or alleviate a depressive phase. Could part of the increase in prevalence of depression in modern society be related to such factors? Genetic predisposition, hormonal fluctuations, environmental stress, and altered light-dark cycles could all induce rhythm disturbances. Conversely, altered sleep patterns, hyperarousal, eating behavior, and mood state could feed back onto the circadian system via hormones and effects on peripheral oscillators. These new REFERENCES
1. Wehr TA, Goodwin FK. Biological rhythms in manic-depressive illness. In: Wehr TA, Goodwin FK, eds. Circadian Rhythms in Psychiatry. Pacific Grove, Calif: The Boxwood Press; 1983:129-184. 2. Wu JC, Bunney WE. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry. 1990;147:14-21. 3. Kuhs H, Tlle R. Sleep deprivation therapy. Biol Psychiatry. 1991;29:1129-1148. 4. Leibenluft E, Wehr TA. Is sleep deprivation useful in the treatment of depression? Am J Psychiatry. 1992;149:159-168. 5. Healy D, Waterhouse JM. The circadian system and the therapeutics of the affective disorders. Pharmacol Ther. 1995;65:241-263. 6. Wirz-Justice A. Biological rhythms in mood disorders. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:999-1017. 7. Rosenwasser AM, Wirz-Justice A. Circadian rhythms and depression: clinical and experimental models. In: Redfern PH, Lemmer B, eds. Physiology and Pharmacology of Biological Rhythms. Berlin, Germany: Springer Verlag; 1997:457-486. 8. Wirz-Justice A, Van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry. 1999;46:445-453. 9. Boivin DB. Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. J Psychiatry Neurosci. 2000;25:446-458. 10.Zeitzer JM, Dijk DJ, Kronauer RE, Brown EN, Czeisler CA. Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression. J Physiol. 2000;526:695-702. 11.Daan S, Beersma DGM, Borbly AA. Timing of human sleep: recovery process gated by a circadian pacemaker. Am J Physiol. 1984;246:R161-R183. 12.Klein DC, Moore RY, Reppert SM. Suprachiasmatic Nucleus: The Mind's Clock. New York, NY: Oxford University Press; 1991. 13.Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295:1070-1073. 14.Rem CE, Wirz-Justice A, Terman M. The visual input stage of the mammalian circadian pacemaking system: I. Is there a clock in the mammalian eye? J Biol Rhythms. 1991;6:5-29. 15.Wehr TA. Photoperiodism in humans and other primates: evidence and implications. J Biol Rhythms. 2001;16:348-364. 16.Lewy AJ. The dim light melatonin onset, melatonin assays and biological rhythm research in humans. Biol Signals Recept. 1999;8:79-83. 17.Linkowski P, Van Onderbergen A, Kerkhofs M, Bosson D, Mendlewicz J, Van Cauter E. Twin study of the 24-h cortisol profile: evidence for genetic control of the human circadian clock. Am J Physiol. 1993;264:E173-E181. 18.Czeisler CA, Khalsa SBS. The human circadian timing system and sleepwake regulation. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders Company; 2000:353-375. 19.Honma KI, Hashimoto S, Nakao M, Honma S. Period and phase adjustments of human circadian rhythms in the real world. J Biol Rhythms. 2003;18:261-270.
insights provide us with useful strategies and a variety of methods to improve robustness of the circadian pacemaker and better synchronize its timing with respect to the day-night cycle. It is interesting to reconsider those empirically developed 19th century psychiatric treatments, which consisted of establishing regularity in social schedules and meal times, and manipulating sleep (albeit with cures) and temperature (with cold baths), in terms of modern chronobiology and the importance of correctly timed zeitgebers.
20.Czeisler CA, Cajochen C, Turek FW. Melatonin in the regulation of sleep and circadian rhythms. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders Company; 2000:400-406. 21.Danilenko KV, Cajochen C, Wirz-Justice A. Is sleep per se a zeitgeber in humans? J Biol Rhythms. 2003;18:170-178. 22.Monk TH, Kupfer DJ, Frank E, Ritenour AM. The Social Rhythm Metric (SRM): measuring daily social rhythms over 12 weeks. Psychiatry Res. 1991;36:195-207. 23.Buijs RM, Kalsbeek A. Hypothalamic integration of central and peripheral clocks. Nature Rev Neurosci. 2001;2:521-526. 24.Roenneberg T, Wirz-Justice A, Merrow M. Life between clocks: daily temporal patterns of human chronotypes. J Biol Rhythms. 2003;18:80-90. 25.Roenneberg T, Merrow M. The network of time: understanding the molecular circadian system. Curr Biol. 2003;13:R198-R207. 26.Franken P, Chollet D, Tafti M. The homeostatic regulation of sleep need is under genetic control. J Neurosci. 2001;21:2610-2621. 27.Jones CR, Campbell SS, Zone SE, et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med. 1999;5:1062-1065. 28.Ebisawa T, Uchiyama M, Kajimura N, et al. Association of structural polymorphisms in the human period 3 gene with delayed sleep phase syndrome. EMBO Rep. 2001;2:342-346. 29. Iwase T, Kajimura N, Uchiyama M, et al. Mutation screening of the human Clock gene in circadian rhythm sleep disorders. Psychiatry Res. 2002;109:121-128. 30.Desan PH, Oren DA, Malison R, et al. Genetic polymorphism at the CLOCK gene locus and major depression. Am J Med Genet. 2000;96:418-421. 31.Shiino Y, Nakajima S, Ozeki Y, Isono T, Yamada N. Mutation screening of the human period 2 gene in bipolar disorder. Neurosci Lett. 2003;338:82-84. 32.Johansson C, Willeit M, Smedh C, et al. Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology. 2003;28:734-739. 33.Yamazaki S, Numano R, Abe M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science. 2000;288:682-685. 34.Schibler U, Ripperger J, Brown SA. Peripheral circadian oscillators in mammals: time and food. J Biol Rhythms. 2003;18:250-260. 35.Wehr TA, Sack DA, Rosenthal N. Sleep reduction as a final common pathway in the genesis of mania. Am J Psychiatry. 1987;144:201-204. 36.Benedetti F, Barbini B, Campori E, Fulgosi MC, Pontiggia A, Colombo C. Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model? J Psychiatr Res. 2001;35:323-329. 37.Frank E, Swartz HA, Kupfer DJ. Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biol Psychiatry. 2000;48:593-604. 38.Wehr TA, Turner EH, Shimada JM, Lowe CH, Barker C, Leibenluft E. Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep. Biol Psychiatry. 1998;43:822-828. 39.Wirz-Justice A, Quinto C, Cajochen C, Werth E, Hock C. A rapid-cycling bipolar patient treated with long nights, bedrest, and light. Biol Psychiatry. 1999;45:1075-1077.
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Cronobiologa y trastornos afectivos
Las observaciones clnicas de la variacin diurna del nimo y el despertar precoz en la depresin se han incorporado a sistemas diagnsticos establecidos, como es el caso de la modificacin estacional que define la depresin invernal (trastorno afectivo estacional, TAE). Muchos ritmos circadianos medidos en pacientes depresivos son anormales: por ocurrir antes del tiempo que corresponde, tener una amplitud disminuida o una mayor variabilidad. Para precisar si estas alteraciones tienen un significado etiolgico en el rol que cumplen los ritmos circadianos en los trastornos afectivos o si son una consecuencia de conductas alteradas se requiere de un anlisis minucioso con protocolos muy estrictos (por ejemplo, rutina constante o desincrona forzada). Estos protocolos cuantifican las contribuciones del marcapaso circadiano y del proceso de sueo homeosttico que influyen en el nimo, la energa, el apetito y el sueo. Estudios futuros aclararn algunas mutaciones allicas de genes relacionados con el reloj circadiano o el sueo en la depresin. Respecto al tratamiento, los antidepresivos y los estabilizadores del nimo no tienen efectos consistentes en la ritmicidad circadiana. La estrategia antidepresiva ms rpida conocida hasta la fecha es de tipo no farmacolgico: la privacin total o parcial de sueo durante la segunda mitad de la noche. La desventaja de la privacin de sueo es que la mayora de los pacientes recaen despus de recuperar el sueo; esto puede prevenirse mediante la coadministracin de litio, pindolol, inhibidores de la recaptacin de serotonina (5-HT), luz brillante, o a travs de un procedimiento posterior de avance de fase. El avance de fase del ciclo sueo vigilia en forma exclusiva tiene tambin rpidos efectos en el nimo depresivo, lo que dura mayor tiempo que la privacin de sueo. La luz es el tratamiento de eleccin para el TAE y puede resultar til en la depresin no estacional al administrarla sola o en combinacin con medicamentos. Los conceptos cronobiolgicos enfatizan el importante papel de los zeitgebers para estabilizar la fase, siendo la luz el ms importante, pero tambin se deben considerar los perodos de oscuridad (y reposo), la regularidad de los horarios sociales y de las comidas y el empleo de melatonina o de sus anlogos. Los avances en la cronobiologa continan para contribuir a nuevos tratamientos para los trastornos afectivos.
40.Borbly AA, Wirz-Justice A. Sleep, sleep deprivation and depression. Hum Neurobiol. 1982;1:205-210. 41.Koorengevel KM, Beersma DGM, den Boer JA, Van den Hoofdakker RH. A forced desynchrony study of circadian pacemaker characteristics in seasonal affective disorder. J Biol Rhythms. 2002;17:463-475. 42.Avery DH, Dahl K, Savage MV, et al. Circadian temperature and cortisol rhythms during a constant routine are phase-delayed in hypersomnic winter depression. Biol Psychiatry. 1997;41:1109-1123. 43.Wirz-Justice A, Kruchi K, Brunner DP, et al. Circadian rhythms and sleep regulation in seasonal affective disorder. Acta Neuropsychiatrica. 1995;7:41-43. 44.Brunner DP, Kruchi K, Dijk DJ, Leonhardt G, Haug HJ, Wirz-Justice A. Sleep electroencephalogram in seasonal affective disorder and in control women: effects of midday light treatment and sleep deprivation. Biol Psychiatry. 1996;40:485-496. 45.Koorengevel K, Beersma D, Den Boer J, van den Hoofdakker R. Sleep in seasonal affective disorder patients in forced desynchrony: an explorative study. J Sleep Res. 2002;11:347-356. 46.Cajochen C, Brunner DP, Kruchi K, Graw P, Wirz-Justice A. EEG and subjective sleepiness during extended wakefulness in seasonal affective disorder: circadian and homeostatic influences. Biol Psychiatry. 2000;47:610-617. 47.Putilov A, Donskaya OG, Jafarova OA, Danilenko KV. Waking EEG power density in hypersomnic winter depression. 12th Annual Meeting of the Society for Light Treatment and Biological Rhythms. 7-9 May 2000. Evanston, Ill. Abstracts p24. 48.Taillard J, Philip P, Coste O, Sagspe P, Bioulac B. Circadian and homeostatic buildup of sleep pressure during extended wakefulness in morning and evening chronotypes. J Sleep Res. 2003. In press.
49.Boivin DB, Czeisler CA, Dijk DJ, et al. Complex interaction of the sleepwake cycle and circadian phase modulates mood in healthy subjects. Arch Gen Psychiatry. 1997;54:145-152. 50.Schrder C, Knoblauch V, Renz C, Kruchi K, Wirz-Justice A, Cajochen C. Circadian modulation of mood under differential sleep pressure conditions. Sleep. 2003;26(suppl):A101. 51.Wever RA. The Circadian System of Man: Results of Experiments under Temporal Isolation. New York, NY: Springer Verlag; 1979. 52.Healy D, Minors DS, Waterhouse JM. Shiftwork, helplessness and depression. J Affect Disord. 1993;29:17-25. 53.Wehr TA, Duncan WCJ, Sher L, et al. A circadian signal of change of season in patients with seasonal affective disorder. Arch Gen Psychiatry. 2001;58:1108-1114. 54.Wehr TA, Moul DE, Barbato G, et al. Conservation of photoperiodresponsive mechanisms in humans. Am J Physiology. 1993;265:R846-R857. 55.Surridge-David M, MacLean A, Coulter ME, Knowles JB. Mood change following an acute delay of sleep. Psychiatry Res. 1987;22:149-158. 56.Jauhar P, Weller MP. Psychiatric morbidity and time zone changes: a study of patients from Heathrow airport. Br J Psychiatry. 1982;140:231-235. 57.Young DM. Psychiatric morbidity in travelers to Honolulu, Hawaii. Compr Psychiatry. 1995;36:224-228. 58.Regestein QR, Monk TH. Delayed sleep phase syndrome: a review of its clinical aspects. Am J Psychiatry. 1995;152:602-608. 59.Engelmann W. Lithium slows down the Kalanchoe clock. Z Naturforsch [B]. 1972;27:477. 60.Johnsson A, Engelmann W, Pflug B, Klemke W. Influence of lithium ions on human circadian rhythms. Z Naturforsch [C]. 1980;35:503-507.
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Chronobiologie et troubles de lhumeur

Les observations cliniques de variations diurnes de lhumeur et de rveil matinal prcoce dans la dpression ont t intgres dans des systmes diagnostiques tablis tel le facteur saisonnier qui dfinit la dpression hivernale (trouble affectif saisonnier, TAS). Beaucoup de rythmes circadiens mesurs chez les patients dpressifs sont anormaux : plus prcoces, diminus en amplitude ou de plus grande variabilit. Seuls des protocoles rigoureux (par exemple, routine constante ou dsynchronisation force) sont mme de dterminer si ces perturbations ont une signification tiologique quant au rle des rythmes circadiens dans les troubles de lhumeur ou si elles sont la consquence dune modification comportementale. Ces protocoles quantifient les participations respectives de loscillateur circadien et dun processus homostatique li au sommeil ayant des rpercussions sur lhumeur, lnergie, lapptit et le sommeil. Les tudes venir mettront en vidence, si tant est quelles existent, les mutations allliques des gnes qui interviennent dans les phnomnes dhorloge ou de sommeil au cours de la dpression. En ce qui concerne le traitement, les antidpresseurs et les rgulateurs de lhumeur nont pas deffet constant sur le rythme circadien. Leffet antidpresseur le plus rapide connu ce jour nest pas pharmacologique : cest la privation totale ou partielle de sommeil dans la seconde moiti de la nuit. Linconvnient de la privation de sommeil, constitu par la rechute de la plupart des patients aprs le sommeil de rcupration, peut tre prvenu par ladministration concomitante de lithium, de pindolol, dinhibiteurs de la recapture de la srotonine (5-HT), de lumire vive ou par une procdure davance de phase. Lavance de phase dans les cycles veille-sommeil exerce par elle-mme galement des effets rapides sur lhumeur dpressive qui se maintiennent plus longtemps que ceux de la privation de sommeil. La photothrapie est le traitement de choix du TAS et pourra savrer utile dans la dpression non saisonnire, seule ou en association un traitement mdicamenteux. Les concepts chronobiologiques soulignent le rle important des synchroniseurs dans la stabilisation de phase, la lumire tant le plus important. Cependant, les priodes dobscurit (et de repos), la rgularit des repas et des rythmes sociaux et lutilisation de la mlatonine ou de ses analogues doivent tre galement considres. Les avances en chronobiologie continuent contribuer au dveloppement de mdicaments nouveaux dans les troubles affectifs.
61.Abe M, Herzog ED, Block GD. Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport. 2000;11:3261-3264. 62.Wirz-Justice A, Campbell IC. Antidepressant drugs can slow or dissociate circadian rhythms. Experientia. 1982;38:1301-1309. 63.Wollnik F. Effects of chronic administration and withdrawal of antidepressant agents on circadian activity rhythms in rats. Pharmacol Biochem Behav. 1992;43:549-561. 64.Nagayama H. Chronic administration of imipramine and lithium changes the phase-angle relationship between the activity and core body temperature circadian rhythms in rats. Chronobiol Int. 1996;13:251-259. 65.Klemfuss H, Kripke DF. Antimanic drugs stabilize hamster circadian rhythms. Psychiatry Res. 1995;57:215-222. 66.Duncan WC, Johnson KA, Wehr TA. Decreased sensitivity to light of the photic entrainment pathway during chronic clorgyline and lithium treatments. J Biol Rhythms. 1998;13:330-346. 67.Wirz-Justice A. Why is sleep deprivation an orphan drug? Psychiatry Res. 1998;81:281-282. 68.Cirelli C. How sleep deprivation affects gene expression in the brain: a review of recent findings. J Appl Physiol. 2002;92:394-400. 69.Eichhammer P, Kharraz A, Wiegand R, et al. Sleep deprivation in depression stabilizing antidepressant effects by repetitive transcranial magnetic stimulation. Life Sci. 2002;70:1741-1749. 70.Colombo C, Lucca A, Benedetti F, Barbini B, Campori E, Smeraldi E. Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: replication of main effects and interaction. Psychiatry Res. 2000;95:43-53. 71.Lam RW, Levitt AJ. Canadian Consensus Guidelines for the Treatment of Seasonal Affective Disorder. Canada: Clinical & Academic Publishing; 1999.
72.Wirz-Justice A. Beginning to see the light. Arch Gen Psychiatry. 1998;55:861-862. 73.Lambert GW, Reid C, Kaye DM, Jennings GL, Esler MD. Effect of sunlight and season on serotonin turnover in the brain. Lancet. 2002;360:1840-1842. 74.Lam RW. Seasonal Affective Disorder and Beyond. Light Treatment for SAD and Non-SAD Conditions. Washington DC: American Psychiatric Press; 1998. 75.Kruchi K, Wirz-Justice A. Circadian clues to sleep onset mechanisms. Neuropsychopharmacology. 2001;25:S92-S96. 76.deVries MW, Peeters FP. Melatonin as a therapeutic agent in the treatment of sleep disturbance in depression. J Nerv Ment Dis. 1997;185:201-202. 77.Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry. 1998;155: 1119-1121. 78.Lo H, Dalery J, Macher JP, Payen A. Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatoninergic agonist and selective 5-HT2C receptors antagonist, in the treatment of major depressive disorders. Encephale. 2003;28:356-362. 79.Kennaway DJ. Light, neurotransmitters and the suprachiasmatic nucleus control of pineal melatonin production in the rat. Biol Signals Recept. 1997;6:247-254. 80.Ji R, Schlaepfer T, Aizenman C, et al. Repetitive transcranial magnetic stimulation activates specific regions in rat brain. Proc Natl Acad Sci U S A. 1998;95:15635-15640. 81.Hall DP, Sing HC, Romanoski AJ. Identification and characterization of greater mood variance in depression. Am J Psychiatry. 1991;148:418-419. 82.Krauss SS, Depue RA, Arbisi PA, Spoont M. Behavioral engagement level, variability, and diurnal rhythm as a function of bright light in bipolar II seasonal affective disorder: an exploratory study. Psychiatry Res. 1992;43:147-160.
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Concepts in human biological rhythms
Alain Reinberg, MD, PhD; Israel Ashkenazi, PhD
he rhythmic (as opposed to linear) expression of biological variables and the temporal organization of these rhythms represent an adaptation of organisms to the rhythmic changes in the external environment. Periodic oscillations (rhythms) have been documented in biological variables in a whole spectrum of living organisms (from unicellular to multicellular).1,2 However, this phenomenon is not merely a reaction to environmental changes; it is generally held that the rhythms are governed by an active system capable of self-sustained oscillations (endogenous rhythms).1 Consequently, the shape of rhythms and the Biological rhythms and their temporal organization are adaptive phenomena to periodic changes in environmental factors linked to the earths rotation on its axis and around the sun. Experimental data from the plant and animal kingdoms have led to many models and concepts related to biological clocks that help describe and understand the mechanisms of these changes. Many of the prevailing concepts apply to all organisms, but most of the experimental data are insufficient to explain the dynamics of human biological clocks. This review presents phenomena that are mainly characteristic ofand unique tohuman chronobiology, and which cannot be fully explained by concepts and models drawn from laboratory experiments. We deal with the functional advantages of the human temporal organization and the problem of desynchronization, with special reference to the period () of the circadian rhythm and its interindividual and intraindividual variability. We describe the differences between right- and left-hand rhythms suggesting the existence of different biological clocks in the right and left cortices. Desynchronization of rhythms is rather frequent (one example is night shift workers). In some individuals, desynchronization causes no clinical symptoms and we propose the concept of allochronism to designate a variant of the human temporal organization with no pathological implications. We restrict the term dyschronism to changes or alterations in temporal organization associated with a set of symptoms similar to those observed in subjects intolerant to shift work, eg, persisting fatigue and mood and sleep alterations. Many diseases involve chronic deprivation of sleep at night and constitute conditions mimicking that of night shift workers who are intolerant to desynchronization. We also present a genetic model (the dian-circadian model) to explain interindividual differences in the period of biological rhythms in certain conditions.
Keywords: biological rhythm; temporal organization; desynchronization; allochronism; dyschronism; shift work; affective disorder Author affiliations: Unit de Chronobiologie, Fondation Adolphe de Rothschild, Paris, France (Alain Reinberg); Department of Human Genetics and Molecular Medicine, School of Medicine, Tel Aviv University, Ramat Aviv, Israel Copyright 2003 LLS SAS. All rights reserved
Address for correspondence: Alain Reinberg, Unit de Chronobiologie, Fondation Adolphe de Rothschild, 29 rue Manin, 75940 Paris Cedex 19, France (e-mail: areinberg@wanadoo.fr)
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A CRT DH L:D M NDH PS REM RT SCN SD SRT amplitude choice reaction time dominant hand light/dark mean nondominant hand acrophase (peak time) paradoxical sleep rapid eye movement reaction time suprachiasmatic nucleus Sprague-Dawley (rat) single reaction time period bers,10 or entraining agents.7 The range of period entrainment of circadian rhythms by the zeitgebers may vary between =20 h and =28 h. There is a general ubiquity7,8 of the properties of the biological rhythms quoted above, from unicellular eukaryotes8,11,12 to humans.2,5,13 However, some variability exists and some differences can be observed among plants,12 animals,13 strains of the same species,14 and even different human individuals.5,13,15,16 The master clock versus temporal organization In recent years, a large amount of information has accumulated about the genetic, molecular, physiological, and environmental induction of biological rhythms and about how they function in various genera and species. Due to the variety and variability of this vast literature, it is no longer an easy task to review concepts in human biological rhythms. We will first try to present the reasons for this difficulty. Two schools of thoughts coexist in chronobiology. One considers that the study of biological rhythms must involve an analytical approach to phenomena and confine itself to reductionism.17 A relatively simple molecular genetic model is proposed,18-20 as is the existence of one domineering master clock (the suprachiasmatic nucleus [SCN] in mammals and certain species of birds) that controls almost all rhythmic functions.21,22 Consequently, most studies of the circadian system focused on the recording of one overt rhythm (eg, activity/rest), especially in rodent animal models, such as hamsters, rats, and mice.18,19 Although this school of thought has recently recognized the existence of peripheral pacemakers and oscillators, they are placed in a lower hierarchical level than the master clock. The other school of thought favors a holistic perspective and considers that the studied subject (ie, man) as a whole is engulfed by normal habitat and time cues.4,5,23-26 Both the living organism and the rhythmic and nonrhythmic changes in its environmental factors are taken into account.Thus, a whole range of biological clocksand not just oneplay a role, as well as a rather large set of genes, many with pleiotropic effects,16,27 rather than just a few.18-20 Another important point about this approach is the emphasis on temporal organization,4-7,23-26,28 rather than the study of one or two rhythms. For an organisms synchronized with =24 h, the study will document a set of biological variables each characterized by its specific (Figure 1).26 A review of the literature shows that even
temporal order are products of the interaction between endogenous (genetically controlled) oscillators and the phases (synchronizing, entraining) of external cues. Features of biological rhythm The parameters of a biological rhythm are as follows1-6: The period (24 h in circadian rhythm; and <20 h in ultradian rhythm). The acrophase (, the peak time of the rhythm). This parameter usually includes a phase reference within the time axis of the rhythm (eg, for the circadian rhythm the acrophase relates to a phase reference like midnight, local time, or mid-sleep). The amplitude (A), the peak-to-trough difference. The mean level, or mesor (M). Rhythms that follow a cosine curve can be characterized by all four of these parameters, and rhythms that do not follow cosine shape are mostly characterized by M and . The majority of the rhythms studied in nature, and especially in humans, exhibit circadian periodicity, and this review will focus mainly on these (though most of discussions herein also apply to rhythms with other periodicities). Circadian rhythms have the following properties1-8: They have a genetic origin. They are controlled by biological clocks (or oscillators or circadian pacemakers). The biological clocks are reset () and calibrated (=24 h) by environmental signals that also have =24 h, such as dawn/dusk (photic signals), activity/rest, or noise/silence (nonphotic signals). These periodic environmental factors are called synchronizers,9 zeitge-
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Concepts in human biological rhythms - Reinberg and Ashkenazi
unicellular eukaryote organisms such as Acetabularia (an algae) and Euglena (a protist), which possess no nervous or endocrine systems, contain a population of oscillators and a temporal structure can be demonstrated.8-11 Terms such as temporal organization, temporal structure, temporal order, and time structure are synonymous. Various models have been proposed to better understand the hierarchy and the coupling between oscillators and/or biological clock systems.13,22,23 We propose that these two schools of thoughts are complementary rather than exclusive, but it is clear that an accurate and objective definition is far from easy to make. Another difficulty resides in the fact that some authors recommend avoiding investigations on human subjects, since they believe that humans can only produce sloppy rhythms.29 It should be noted that this statement was made
Physiological function Sleep Blood flow Heart rate Systolic blood pressure Diastolic blood pressure Blood volume Blood Renin activity Aldosterone Cortisol Adrenaline Noradrenaline Atrial natriuretic factor Platelets (number) Platelets (aggregability) Fibrinogen Hypercoagulability Urine Adrenaline Noradrenaline Potassium Sodium
Midnight 6 AM Midday 6 PM Midnight
Figure 1. Aspects of the human temporal organization: physiological functions of the cardiovascular system. The acrophase () location (blue circles) of any of the considered rhythms is not randomly distributed over 24 h. On the contrary, acrophases represent physiologically validated temporal relationships. The healthy young human adults synchronization was approximately 16 h of diurnal activity and 8 h of nocturnal rest.
Reproduced from reference 26: Reinberg A. Chronobiologie Mdicale, Chronothrapeutique. Paris, France: Flammarion Mdecine-Sciences; 2003. Copyright 2003, Flammarion Mdecine-Sciences.
without providing a definition of human rhythm sloppiness.This appears to come from the idea that many of the studies carried out 20 years ago were investigations on mammalian rhythms conducted on laboratory hamsters, rats, and mice, for which the prominent synchronizer is light/dark (L:D) alternation. In these species, a photic signal of few lux is powerful enough to synchronize rhythms, which should be compared with the 2500 lux (bright light) needed to synchronize human rhythms.13,30,31 Recent studies show that even human rhythms can be entrained by low intensity light.32 Another example that illustrates the confusion in defining a concept due to a focus on the rhythm of one variable rather than on the temporal order is the following. In the 1970s, most sleep studies were extensively carried on cats, using electroencephalography (EEG). It was shown that most individuals of this species are frequent sleepers, with a polyphasic rhythmicity. According to Jouvet,33 no more than 30% of cats exhibit a sleep/wake rhythm with =24 h. As a result, it was believed by some authors that cat is a species that does not possess a circadian organizationan idea that was a source of conflict between sleep and biological rhythm specialists. However, cats exhibit circadian rhythms in their feeding behavior and activity/rest rhythm.34,35 It proved difficult to bridge the gap between those involved in sleep research in cats and those studying circadian rhythms in laboratory rodents.33 The final source of misunderstanding in concept definition relates to the fact that the meaning of a given term evolves as time passes. Let us take the term chronobiotic as an example.25,26,36-38 Simpson et al36 hypothesized that a drug might be able to phase shift all circadian rhythms by resetting their respective s. In fact, there is still no such wonderdrug.37,38 Thereafter, the meaning of the term chronobiotic was restricted to a drug able to phase shift or reset one39 or a limited number25,26 of rhythms. The latter demonstrates once again the importance of studying systems or temporal order rather than just one rhythm. Considering the above examples, the definitions and concepts presented in this paper have been updated with reference to the recent state of art.
Temporal organization
Temporal organization refers to the sequential array of rhythms of various variables, each with a specific phase on the time axis. An examination of the array provides information about the phase relationship between the
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rhythms, but does not show whether there is a causal interaction between them. One example is body temperature rhythm and paradoxical sleep (PS) or rapid eye movement (REM) rhythm. In humans, a physiological trough in temperature coincides in time with the longest
A. Physiological variables 30 30
episodes of PS.40,41 Animal experiments have demonstrated that hypothermia influences PS.42 Thus, while a phase relationship between the two rhythms does not in itself imply a causal relationship, the physiological interaction between the two variables raises the strong possiC. Hormones 30
B. Cognitive function
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Figure 2. Distributions of circadian rhythm acrophases () according to the variables function. A to G illustrate the 24-h acrophase frequency distribution of 7 groups of variables, and the dendrogram H shows the similarities along the groups by clusters on correlation scale (r). The upper cluster in H presents the greater similarities among the physiological variables (A), cognitive function (B), and hormones (C), where most of the acrophases occur in the late afternoon. In the inorganic molecules (D) and the organic molecules (E) groups (middle cluster H), most acrophases aggregate around midday. The third cluster (lower cluster, H) contained cellular components (F) and enzymes (G), in which most acrophases were distributed around midnight.
Reproduced from reference 24: Ticher A, Ashkenazi IE, Reinberg A. Preservation of the functional advantage of human time structure. FASEB J. 1995;9:269-272. Copyright 2003, Federation of American Societies for Experimental Biology.
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bility that they are coupled to the same oscillator or that there is a causal interaction between the two. A simplified circadian map of the temporal cardiovascular organization of healthy young adults provides another example (Figure 1). It presents the acrophases (s) of a limited number of physiological functions. The peak time locations are not randomly distributed over 24 h, but correspond to the human needs related to diurnal activity and nocturnal rest. Here, there is a causal phase relationship between the of blood pressure and that of variables known to be involved in its control. The s of renin activity, aldosterone, cortisol, and catecholamines precede in phase the blood pressure . Likewise, the s of aldosterone and cortisol precede the s of the urinary excretion of sodium and potassium. A similar temporal organization can be observed in the rat (Sprague-Dawley [SD]), with a phase shift of 12 h with regard to humans (these rodents are nocturnally active). Lemmer et al43 used transgenic SD rats, in which the mouse renin gene REN-2 had been inserted into the SD rat genome (TGR(mREN-2)). The transgenic rats developed hypertension and their blood pressure, renin, and aldosterone rhythms were phase shifted with regard to the heart rate rhythm, in comparison to the normal temporal organization control of SD rats.43 This indicates that a physiological function, eg, cardiovascular function, involves a set of rhythms, some of which are independent of each other and some of which exhibit strong interactions (or coupling). Consequently, temporal organization should generally be regarded as a multifactor rhythm system.
The functional advantage of human temporal organization

We have seen that the sequential array of rhythms over 24 h constructs temporal organization. The rhythm phase of each variable can be identified by location of its . Another characteristic of rhythm is the ratio A/M, which indicates the strength of the rhythm to shifting signals. Thus, to examine the question of whether temporal organization is structured to endow the organism with a functional advantage, three parameters must be assessed: Time-dependent distribution of the s of the variables rhythms. Time distribution of variables rhythms according to function. Time distribution of the A/M ratio.
Ticher et al24 conducted such a study by computing these parameters for 168 circadian rhythms of diurnally active (7 AM 30 min to 11 PM 60 min) young human subjects. The analysis showed that the distribution of the s over 24 h exhibits a strong time dependence (Figure 2). The s are unevenly distributed over 24 h and no was detected between 5 AM and 7 AM. This time zone corresponds to the overall greatest vulnerability of the human organism, eg, the circadian of the human mortality rhythm, including all-cause mortality.25,26,44 The number of s per hour was then clustered according to function. Seven groups were formed 37 physiological rhythms (body temperature, blood pressure, bronchial patency, etc). 32 rhythms for cognitive function. 27 rhythms for endocrine function. 14 rhythms for metabolites. 25 rhythms for organic molecules. 18 rhythms for cellular components. 15 rhythms for enzymatic activity. A correlation matrix of the pattern of distribution of the s between each of the 7 groups served as a basis for cluster analysis. The greater the coefficient r, the stronger the similarity in the distribution of the s. An dendrogram (H in Figure 2) can be constructed to visualize the similiarities. The level of correlation is shown by the distance between each group. It can be seen that the correlation is very strong between physiological variables and cognitive function rhythms with s clustering in the late afternoon. The correlation between cognitive function and hormone rhythms remains strong. Organic and inorganic substance rhythms exhibit rather strong similarities with s clustering around 1 PM. Rhythms in cellular features and enzymatic activities also show a rather strong similarity with a cluster around midnight. The time distribution of A/M ratio also exhibited a significant time dependence with modes: at preawaking time; postawaking time and morning meal; time of midday meal; time of evening meal; and around midnight (time of falling asleep). This suggests that stronger rhythms are clustered around the times where the human is confronted with the domineering exogenous signals. These types of analyses enable us to explore the possible adaptive value of the human temporal organization, which allows variables of each function to reach their peak time in phase with predictable environmental changes, such as night and day, in alternation with other synchronizing signals.
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The synchronization of human circadian rhythms
The major environmental signals that trigger biological clocks in most animals in nature and in laboratory rodents are related to the L:D alternation and photic signals.7,13,21 Human circadian rhythms can also be synchronized by photic signals,30,31,45,46 but are mainly determined by social signals, like those involving the senses of sight, sound, smell, or touch (or even other signals like roosters, which signaled the beginning of daily activity in the time before clocks).47 The importance of nonphotic signals can be demonstrated by free-running experiments, in which a group of subjects is isolated from known time clues and cues. When each subject is isolated separately from the others, the circadian rhythm differs from 24 h, and it differs also from subject to subject (range 24.3 to 25.4 h).5,13,48 In group isolation, the rhythm (eg, sleep/wake) differs from 24 h, but is identical for all the subjects in the group (eg, =24.8 h),49,50 ie, social interaction synchronizes the rhythms of subjects living closely in a group. Another nonphotic signal that triggers circadian rhythms, including those of human subjects, is physical activity.51-53 For example, nocturnal activity (15 min/h on ergometric bicycle) induced a phase shift of body temperature rhythms in two-thirds of subjects.51 In crewmembers of a transmeridian flight, diurnal outdoor exercise speeds up the resynchronization of the urinary 17-hydroxycorticosteroid circadian rhythm, compared with those without exercise.52 Czeisler and Wright46 proposed a constant routine protocol, where the masking influences of ambient light, temperature, noise, food consumption, and activity level are carefully controlled. Subjects stayed awake in recliners for 24 to 48 h in dim light. In this condition, the unmasked rhythms of, for example, body temperature, exhibited a curve close to a cosine function. This type of experiment suggests that, in the real world, masking effects may alter the curve of many circadian rhythms. However, it should be noted that the constant routine protocol, which involves sleep deprivation, might alter the circadian period of a set of variables and its adequacy for this study will be discussed in another section of this paper.
Quantification of rhythm parameters with special reference to

In circadian rhythm studies, the critical parameter to be quantified is . In most investigations, it is assumed that =24 h (as a mean) when subjects are synchronized with a diurnal activity and nocturnal rest with stable and regular times (eg, awakening [lights on] at 7 AM and retiring [lights off] at 11 PM). Using this procedure, a set of rhythms can be documented in subjects with a sampling interval of, for example, 4 h over a 24- or 48-h period. Using this transverse sampling, other circadian parameters can be computed, such as , A, and 24-h M, provided the parameters exhibit statistically significant rhythms. However, with a transverse sampling of this kind, 24-h rhythm is computed, but not the circadian . This can only be obtained by longitudinal sampling over at least 7 days. With these requirements, inter- and intraindividual changes can be taken into account, which is mandatory to document human rhythms in certain circumstances. Prominent with the largest A, as well as other periods (with lower As) are quantified from time series by relevant methods including power spectra.5,6,16,26,28,44 The precise quantification of is critical to problems such as one versus several biological clocks, as well as few versus many clock genes.
Masking effects
The advantage of a rhythm with the shape of a cosine function was discussed above. However, the patterns of many circadian rhythms deviate from that of an optimal cosine function. In many cases, a secondary peak or shoulder is observed in the 24-h pattern. This shoulder may indicate the presence of additional period component (eg, with <20 h), and the rhythm may be defined as a compound rhythm. However, the change may be due to masking effect. Masking is the result of a direct influence of one variable on another, or a direct influence of an external stimulus on a variable, without reference to a rhythmic process.48 In natural settings and habitual life conditions, the body temperature rhythm curve is trapezoidal rather than close to a cosine curve. Mills et al53 and
One versus several biological clocks in primates

Experiments in rodents yielded a widely accepted model for the control of biological rhythms. According to this model, the SCN functions as a master (central) clock
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from which slave (peripheral) clocks, or subordinate structures, receive their rhythm characteristics such as the circadian , A, and .13,18,21,22,54 According to Moore and Silver22: ... all of the available data support the view that the SCN is the circadian pacemaker responsible for providing a temporal organization of behavioral, physiological, and endocrine functions. As pacemaker, the SCN sets the phase of oscillators of many physiological and endocrine rhythms in the body. Transplantation of SCN in hamster tau mutants was associated with a rhythm of activity with the same as the donor rather than the host.55 Genetic and molecular studies in rodents support this model.18,22,56,57 Is this model valid for other mammalian species? In longitudinal studies, Jouvet et al42 assessed hourly the distribution of PS in cats kept in isolation chambers under continuous light (L:L). Under these conditions, a robust circadian rhythm of PS was detected in all normal cats, and in 4 out of 6 pontine cats (where all neural structures rostral to the pons were removed), as well as in cats without SCN or without hypothalamus. This result is evidence for the presence of a multioscillatory circadian system in this species. The squirrel monkey, a primate, has a prominent and stable body temperature circadian rhythm.13 After total bilateral SCN lesions, feeding and drinking behaviors lose their circadian rhythms, but the rhythm in body temperature was found to persist when studied over 1 year postlesion.13 Presumably, in primates, there are other biological clocks outside the SCN, which are responsible for generating a rhythm for temperature, and other variables, such as cortisol rhythms in the rhesus monkey.58 There is no doubt that the SCN plays an important role because it is the only anatomical structure in which a circadian pacemaker has been identified and it is reset by photic triggers. However, it seems that in cats and primates (and presumably in many other species), other major pacemakers are present.
Desynchronization of human circadian rhythms

Aschoff and Wever recorded rhythms in human subjects individually isolated from known zeitgebers in long-term (>3 weeks) longitudinal experiments.48,59 They observed that, after a fortnight, 28% of women and 23% of men,
exhibited 25 h for body temperature rhythm and =13 to 36 h for sleep/wake rhythm. Thus, the phase relation between rhythms was distorted compared with the structure of the normal temporal order in the isolated state. On this basis, it was suggested that the two documented rhythms were driven by different biological clocks, a phenomenon called internal desynchronization.60 External desynchronization corresponds to a condition in which the phase relation of rhythms are changed by manipulating external synchronizers. This category refers, for example, to a phase shift of at least 5 h due to transmeridian flight or shift work (even if the rhythm was not changed) and/or an induced change in , becoming longer or shorter than 24 h. The term desynchronization was used thereafter, to report the experimental fact that, for a set of variables, the (endogenous) circadian s can differ from one another and from 24 h in the same subject during longitudinal studies, even in the presence of natural zeitgebers. This was documented for circadian rhythms such as activity/rest, body temperature, heart rate, grip strength of both hands, and cognitive performance.48,61-73 The of the circadian rhythm for hand grip strength may even differ between the right and left hands, as well as from 24 h. This was documented in a set of studies involving both Caucasian and Asian shift workers,63,68,70 healthy volunteers involved in placebo studies,64 geographers sojourning in the high Arctic summer,65 and saber fencers of the French Olympic team.66 Apart from the night shifts (about 4 nights out of 20) of shift workers,63,68,70 all subjects were synchronized with diurnal activity and nocturnal rest. Test times were similar for both hands, eg, 4 to 6 times a day during a 8- to 21-day span. With regard to the grip strength circadian rhythm, 67 healthy adult males and 24 adult women were investigated. The circadian of the dominant hand (DH) differed from 24 h and/or from that of the other hand in 49.2% of male subjects (33/67) and 50% of female subjects (12/24). The circadian period of the nondominant hand (NDH) differed from 24 h and/or from that of the DH in 62.6% of male subjects (33/67) and 62.5% of female subjects (15/24). It should be stressed that the activity/rest rhythm , which is presumably controlled by the SCN, was equal to 24 h in 95.6% of the subjects (87/91) involved in the studies. The finding of a circadian that differs among investigated physiological variables has been confirmed by Motohashi,67,68 in a Japanese population and by Chandrawanshi and Pati,69 in an Indian population.
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Thus, generalization of the laboratory rodent model to human beings is inadequate, and the hypothesis has to be modified by stating that: apart from the SCN or in addition to it, circadian rhythms of the human organism may be driven by several clocks, which may differ from each other in their respective values.63-69 Biological clocks are present in right and left hemispheres of the human cortices. Functional differences in prominent performance rhythm are task-loadrelated, and the NDH side is more sensitive than the DH. The aim of another study73 was to assess the influence of age and gender on the difference in for RT of the DH and NDH, in comparison to the grip strength rhythm. Healthy subjects of both genders were involved (9 adolescents [10 to 16 years old] and 15 adults [18 to 67 years old]).They were active between 8 AM 1 h and 11 PM 1 h; wrist actigraphs were used to assess the activity/rest rhythm, as well as sleep logs. Data were gathered longitudinally at home and work four to seven times daily for 11 to 20 days. In almost all cases, a 24-h sleep/wake rhythm was detected. For the SRT in adults, a prominent =24 h was documented for both DH and NDH, whereas for the CRT a prominent =24 h was detected for DH, but <24 h for the NDH. This phenomenon was not genderrelated, but was age-related since it was seldom observed in adolescent subjects. Hand-side differences in grip strength rhythms in the same individuals were detected: was ultradian rather than circadian in adolescent subjects, while frequently differed from that of the rhythm in CRT in mature subjects. These findings further support the hypothesis that functional biological clocks with varying periodicities exist in the left and the right hemispheres of the human cortex.
Functional circadian clocks in the human cortex

One avenue to explore to help understand multibiological clock systems is the difference in the s for the circadian rhythms of the DH and NDH.The term functional is used here because these clocks do not necessarily have an elective anatomical location, though they are undoubtedly controlled by brain activity. It has been suggested that each of the brain cortex hemispheres has its own biological clock, and differences in the of grip strength rhythm may be used to explore the presence of these different clocks. Longitudinal circadian rhythms in reaction time (RT) to light and other signals were documented in two studies, to test the hypothesis that the prominent rhythm varies between the DH and the NDH when performing tasks of different complexity. These studies were carried in close cooperation between workers71 at Tel Aviv University and a group investigators72 at the Fondation Adolphe de Rothschild in Paris. The French study72 assessed performance of easy single reaction time (SRT) tests involving a series of 32 yellow light signals following simple and nonvarying instructions; it also assessed the performance of a complex and difficult task, a choice reaction time (CRT) test, involving a series of 96 yellow, red, or green signals following different instructions from test to test, including which hand to use. The Israeli study71 explored DH and NDH RTs of men with an aviation background who were expert in the use of the pilot evaluation system, a flight simulator designed as a modern cockpit with hands on throttle and stick instrumentation to test performance under 7 scenarios of varying levels of complexity, from easy to very difficult. Despite differences in methods, subjects, and data gathering, the two studies yielded similar results. When the task is easy (ie, SRT), the prominent period RT rhythm has =24 h for both DH and NDH. When the task is complex and tricky (ie, CRT), the DH maintains a prominent =24 h in performance, while the NDH shows a prominent rhythm with 24 h, eg, =8 h, 6 h, or 12 h. These findings suggest that:
Allochronism versus dyschronism

There is evidence of interest in human biological rhythms and their implications for health and disease in ancient Chinese cultures, since the time of the mythical emperor Chennong (3000 to 4000 years ago). Sickness was related to an alteration of the yin-yang cycles, ie, when they are not in harmony with those of the universe.47 In 1797, Lavoisier and Seguin74 were the first to report a rhythm of about 24 h in human body weight. They were so impressed by the regularity of this cyclic phenomenon that they suggested an association of circadian rhythm alterations with states of pain and disease. However, the question of how to handle our biological rhythms to live to a ripe old age and in good health remains unanswered.75 As stated in the introduction, the stable structure of temporal order is highly advantageous for the organism. We have also presented evidence63-73 that desynchonization
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of a set of human circadian rhythms is rather frequent. Does this mean that a subject with an alteration of temporal organization is a sick (or potentially a sick) person? In the late 1970s, the answer to this question would have been yes because the prevailing assumption at that time was that irregularity in a rhythm and/or changes in the temporal organization corresponded to a pathological state, or at least to ... a statistically significant higher (P<0.05) chance of progression toward overt disease.76 The values of the computed rhythm parameters were averaged from population studies without focusing on interindividual variability. Dyschronism, a term coined by Halberg et al76 was defined as a time structure (including rhythm) alteration associated with demonstrable physical, physiological, or mental deficit, if not disease. The definition also states: Dyschronism is not necessarily a determinant of overt or occult disease. To illustrate this definition, one can regard the clinical intolerance to shift work as dyschronism, from the point of view of medical chronobiology.77,78 Intolerance to shift work was defined by the following symptoms63,78,79: Sleep alterations, like poor sleep quality, difficulty falling asleep when retiring, frequent awakenings. Persistent fatigue that does not disappear after sleep, weekends, days off, and vacations. Changes in behavior, consisting of unusual irritability, tantrums, malaise, and feeling of inadequate performance. Digestive problems (which seem to be less frequent than 20 years ago). The regular use of sleeping pills (barbiturates, benzodiazepines, phenothiazines, tranquillizers, antidepressants, etc), especially when sleep cannot be controlled or even improved by these medications or others. Sleep alterations, persistent fatigue, and regular use of sleeping pills (an almost pathognomonic indicator of intolerance to shift work) are present in any intolerant subject. The intensity and number of symptoms vary from subject to subject. The occurrence of intolerance to shift work unrelated to age, duration of shift work, type of industry, or type of rotation, including night work. This battery of symptoms was used to clinically validate intolerance to shift work in a set of prospective studies involving more than 140 shift workers.63,67,68,77-79 A good tolerance amounted to 56% and poor tolerance to 46% of this population. Dyschronism has been documented in male shift workers (age range: 25-58 years) in various types of industry
(oil refinery, steel industry, chemical engineering). Four groups were considered: 9 former nontolerant shift workers with diurnal work resumed for at least 18 months; 14 shift workers with good tolerance; 17 shift workers with poor and very poor tolerance (for the latter, symptoms were so severe that a clinical decision was made to transfer them from shift work). For at least 15 days, including 1 or 2 night shifts, circadian rhythms of sleep/wake, oral temperature, and grip strength of both hands were selfrecorded 4 to 5 times per 24 h during the activity span. Prominent circadian s were plotted in hours (Figure 3) with regard to both variables and tolerance to shift work.63 The of the sleep/wake rhythm (not shown) was 24 h for 38 out of 40 subjects. For the group as a whole, only one variable, oral temperature, yielded statistically significant (P<0.029) probability that desynchronization from 24 h is related to intolerance to shift work. With regard to interindividual differences, it is clear that desynchronization is frequent and associated with symptoms quoted above in subjects intolerant to shift work, while desynchronization can be present without clinical complaint in tolerant or former shift workers. In many healthy subjects, one or several desynchronized circadian rhythms can be seen (eg, body temperature, grip strength of both hands, or heart rate) without any decrease in performance or any symptom of shift work intolerance or affective disorder.62,64-66,78 With the acquisition of new experimental data, it is becoming clear that time-structure variability (presumably genetically controlled) is very common, as are environmentally induced changes without clinical symptoms. The general practitioner may be bewildered by the inherited variability, the flexibility of the system, and the changes induced.We should therefore distinguish between a normal variability from abnormal (pathological) changes of the temporal organization. In order to achieve this, at least from a conceptual point of view, the idea of allochronism versus dyschronism was introduced.26 We assigned the term allochronism (allo = different) to designate a variant form of alteration in the human temporal organization with no pathological implications. We restrict the term dyschronism (dys = alteration, perturbation) to changes or alterations in the temporal organization associated with a set of symptoms similar to those observed in subjects intolerant to shift work. Terms like dyschronsis, dyschrony, jet lag, and jet lag syndrome have been used to name transient subjective phenomena that may follow transmeridian flights,38,80,81 in
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which the primary consequence of these time zone changes is fatigue.82 The major effect of a transmeridian flight (>5 time zones) is a shift (phase shift) for the circadian rhythm of most variables.5,6,13,25,44,78,80 The speed (or duration) of adjustment varies among the variables for a given individual, as well among individuals for a given variable. This phenomenon is named transient desynchronization, since in most subjects the changes in the temporal organization will disappear as the subject becomes adjusted to the new local time. Transient desynchronization occurs in all subjects. However, some passengersabout 50% according to Winget et al80suffer from the so-called jet lag symptoms until their adjustment is achieved. Using shift work and jet lag as our experimental models, we focused on the zeitgeber manipulations mainly involved in allochronism and dyschronism. However, other factors are capable of inducing allochronism with a change in the temporal organization without manipulation of zeitgebers. This is the case for age (eg, newborns or the elderly), work load, complexity of task, unusual environment, odd psychological conditions such as that of placebo effect,64 and intake of certain drugs (eg, lithium, -blockers, or oral contraceptives).25,26,37,83 We do not yet have a practical diagnostic tool to distinguish between allochronism and dyschronism. There is no doubt that such a tool would be extremely valuable for assigning people to various work tasks and conditions. Dyschronism cannot be applied to all cases in which there is a change in the temporal order, but to individuals who complain of persisting fatigue, sleep, and mood disorders (and other related clinical symptoms); who take sleeping pills or other medications; in whom no direct clinical cause can be documented; and in whom desyn-
Former shift workers

27
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Shift workers with tolerance: Poor Very poor
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Prominent circadian period (h)
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Figure 3. Prominent circadian period resulting from power spectra analyses of longitudinal time series for 39 subjects. Prominent s for all of the variables and subjects were plotted for each of the four groups and their tolerance to shift work. Gray circles, oral temperature; blue triangles, right-hand grip strength; gray triangles, left-hand grip strength.
Reproduced from reference 63: Reinberg A, Motohashi Y, Bourdeleau P, Andlauer P, Lvi F, Bicakova-Rocher A. Alteration of period and amplitude of circadian rhythms in shift workers with special reference to temperature, right and left hand grip strength. Eur J Appl Physiol. 1988;57:15-25.Copyright 1988, Springer-Verlag.
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chronization of rhythms can be observed. Furthermore, the critical indicative parameter is a change in (changes in other rhythm parameters are secondary). Clinical conditions that mimick those of dyschronism in shift workers In many diseases and syndromes, patients may be chronically deprived of night sleep. This may be because the patients condition prevents sleep, rather than because of a sleep disorder per se.40,84 As even one or two sleepdeprived nights may deeply alter rhythms in body temperature, heart rate, self-rated vigilance, and mood in healthy young subjects,85 this chronically induced sleep deprivation mimics that which occurs in a night worker. In clinical practice, chronic deprivation of night sleep is a rather frequent condition and, as in the case of nontolerant shift workers, it may lead to dyschronism. Using actigraphic recordings, it is possible to evaluate sleep deprivation related to various conditions, for example, sleep deprivation due to pain.86,87 Nocturnal exacerbation of pain is rather frequent in rheumatology and there are large interindividual differences.87-89 Following oral or head/neck surgery, changes in temporal organization were also observed associated with restless and/or fragmented sleep.90 Likewise, in cancer patients, Mormont et al91 showed that nocturnal sleep disruption is associated with statistically significant alteration in rhythms of melatonin, cortisol, and circulating lymphocytes. Although the conventional explanations for the observed alterations are the effects of factors like tumor type or growth rate, or the toxic effects of chemotherapy, the alteration of temporal order due to deprivation of night sleep should not be excluded in this condition. Thus, dyschronism may be involved in a rather large variety of circumstances, including chronic pain syndrome, nocturnal asthma, persisting anxiety and stress, prostate adenoma, or fibroma with nocturnal urinary voiding.26 Affective disorders and dyschronism Possible interference and interactions between psychiatric disorders and biological rhythms have been discussed widely.92-95 Special attention has been paid to affective disorders, for which the occurrence of phase shifts or drifts in some circadian rhythms (though not always linked to changes in the circadian ) have been reported.
The aim was to clarify to what extent rhythm alteration participates in the psychiatric problem. It has been hypothesized that depression occurs when circadian oscillators are phase advanced relative to environmental zeitgebers.92-94 If this is correct, depression may occur when certain s are phase shifted with respect to one another, as is the case during shift work. In this approach, emphasis is placed upon shifts or drifts in one or several variables, namely phase instability. Changes in rhythm and period instability have also been considered. Pflug96 documented alteration in for body temperature rhythm of depressed patients. Likewise, Bicakova-Rocher et al97 recorded the body temperature of patients hospitalized for major affective disorders for several days and found that in half of the cases that the temperature was shorter than 24 h, while the sleep/wake rhythm remained at 24 h. Moreover, improvement in these patients (treated by antidepressant or electroshock therapy) was associated with the reoccurrence of a body temperature rhythm with =24 h. However, not all cases of affective disorders can be classified as dyschronism, because, unlike the intolerance to shift work, which is always accompanied by changes in rhythm , in depression (even major affective disorder), only half of all patients present a change in temperature .97 Furthermore, in shift workers, dyschronism disappears (both the symptoms and the desynchronization) when the subject returns to regular lifestyle, and medications are ineffective in the treatment of intolerance to shift work. We can thus conclude that there is a strong link between changes in rhythm values and clinical symptoms in dyschronism, whereas such a link is not present or else very weak in depressive states and can be evidenced in only a fraction of cases. Consequently, depression and dyschronism presumably represent two different nosological entities. Putative mechanisms involved in allochronism and dyschronism In a discussion on depression, Kripke95,98 raised the idea that it is the individual sensitivity to desynchronization, rather than the desynchronization itself, that tips the scale between the occurrence and nonoccurrence of clinical symptoms. This idea can be extended to interindividual differences in the occurrence of symptoms resulting from intolerance to jet lag, shift work, and disease-related chronic deprivation of night sleep.
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Temporal organization variability has been known for many years. Its association with clinical and pathological conditions has also been documented. However, there has been no attempt to array the temporal organization variants and, consequently, no experimental data are available with regard to the mechanisms that underlie this variability. We will offer here some hypotheses and models for possible putative mechanisms involved in allochronism (temporal organization variants without clinical symptoms) and dyschronism (temporal organization variants with clinical symptoms). Hypothesis A rather large variety of environmental factors serve as signals that may affect the human temporal organization. Let us assume that two groups, A and B, are exposed to any of these signals. In group A, no changes in the time structure are detected (nonreactors), while in group B, changes are detected (reactors). Group B can then divided to two subgroups: group B1, in whom no clinical symptoms or complaints are encountered; and group B2, in whom clinical symptoms and complaints are found.According to our terminology, group B1 should be categorized as having allochronism and group B2 dyschronism. The presence of interindividual variability (with genderrelated differences) and variability in the propensity of human subjects to exhibit a change (even temporary, ie, reversible),48,64 suggests the involvement of genetic factors. However, while the mere presence of variability can be explained by simple models of genetic polymorphism, more complicated control mechanisms are needed to explain why some people are more prone to change their temporal organization than others, even if natural zeitgebers are present, and suggest how these changes can be reversed. Temporal organization variability: a genetic model for allochronism While evaluating the effects of external signals, some authors forwarded the idea that certain zeitgebers are strong, while others are weak.13,48 We propose that reference to the strength or weakness of a zeitgeber will not relate to the environmental signal itself, but to the susceptibility of the subject to that zeitgeber. These differences in the level of susceptibility should be channeled to describe differences among the internal oscillators that govern the biological clocks. Hence, strong (stable) oscillators will be defined as those less prone to be affected by changes in external signals, and weak (fragile) oscillators as those which can more readily be affected by any change in external signals. Our proposal gauges the strength of an oscillator by its capacity to maintain =24 h when exposed to many challenging circumstances. As an example of a strong oscillator, we would like to suggest the sleep/wake oscillator. This suggestion is based on the fact that, in our time series analyses, the of this rhythm seldom differed from 24 h. Body temperature rhythm can serve as an example of a weak oscillator since documentation has revealed that its frequently differs from 24 h.63,64,67,70,85,99,100
Distribution of s
30
Number of AJ subjects
8 7 6 5 4 3 2 1 0
16 .0 16 .8 17 .6 18 .4 19 .2 20 .0 20 .8 21 .6 22 .4 23 .2 24 .0 24 .8 25 .6 26 .4 27 .2 28 .0
(hours)
51
Number of CF subjects
8 7 6 5 4 3 2 1 0
17 .6 18 .4 19 .2 20 .0 20 .8 21 .6 22 .4 23 .2 24 .0 24 .8 25 .6 26 .4 27 .2 28 .0
(hours)
Figure 4. Periods of oral temperature rhythm: frequency distribution in Caucasian-French (CF) and Asiatic-Japanese (AJ) subjects. The CF distribution includes the frequency distribution of 78 individuals was extracted from data of Ashkenazi et al.16 In both CF and AJ populations, the 0.8 h deviation unit was found to reach a higher degree of statistical significance, with P<0.02 to P<0.0004 according to tests.
Reproduced from reference 68: Motohashi Y, Reinberg AE, Ashkenazi IE, Bikcakova-Rocher A. Genetic aspects of circadian dyschronism: comparison between Asiatic-Japanese and Caucasian-French populations. Chronobiol Int. 1995;12:324-332. Copyright 1995, Marcel Dekker.
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However, within one population, there are interindividual differences with regard to the susceptibility levels of the same oscillator. It seems that the strength or weakness of oscillators does not exhibit a fixed level, but rather a range of levels.To find an explanation for this polymorphic phenomenon, we analyzed individual time series for 69 male Caucasian-French (CF) shift workers16 and 42 male AsianJapanese (AJ) shift workers.67,68 In 30% of both populations, a change in temporal organization between sleep/wake and oral temperature rhythms was observed. The of the sleep/wake rhythm seldom differed from 24 h (in only 4 subjects of the AJ group and none of the CF group), while in 30% of both populations the of the temperature rhythm exhibited deviation from 24 h, which arrayed as a symmetrical distribution around the 24-h value (Figure 4). In both groups, the interval of the deviations from the predominantly 24-h level clustered in multiples of +0.8 h and -0.8 h (eg, 24+n[0.8 h] yielding =24.8 h, 25.6 h, 26.4 h, 27.2 h, 28.0 h, etc; and 24-n[0.8 h], yielding =23.2 h, 22.4 h, 21.6 h, 20.8 h, 20.0 h, etc; Figure 4). The analyses of these findings resulted in the dian-circadian model, which integrates the function of a constitutive (essential) gene that produces an exact =24 h (the dian domain) with a set of polygenes, the alleles of which can add or subtract identical time entities (n[0.8 h]) to the 24h period.16 Such an assembly of genes creates periods ranging from 20 to 28 h in the circadian domain. Further elaboration of this genetic model suggests that these polygenes are usually repressed when natural zeitgebers are present. Induction of these genes will occur under conditions that distort or weaken the perception of the zeitgeber signals. The system will not behave like a flip-flop control, but the intensity of its output will depend on the individually related strength of zeitgebers (eg, the time taken for a susceptible individual to exhibit a change in temporal organization in a given situation).This model allows free running to be seen as a special case in which the entities of 0.8 h (or multiplications thereof) are always induced. This model differs from conventional models based on attributing changes in to the effects of a single mutation. Although the possible presence of a multiple allele system can explain the range of deviation, it will still not be adequate to explain the change and restoration of the period. The polygene system with the inducible-repressible mod-
ification seems more appropriate to account for the various changes and dynamics found in rhythm periods. It is interesting to note that a year after the dian-circadian genetic model was presented, similar thoughts were also presented for rhythm behavior in another species. Emery et al27 were examining a 24-h true-breeding strain of Drosophila melanogaster and reported that period, phase, definition [the degree to which a rhythmic signal is obscured by noise], and rhythm waveform were all found to vary continuously among the strains, although within each strain the rhythm phenotype was remarkably consistent. This continuous variation contrasts with the discrete period of the mutant phenotype reported by Konopka and Benzer.101 This is not cited to compare the results of the two studies in humans16 and Drosophila,27 but to stress that even in Drosophila the oversimplified genetic model does not fit well with the natural genetic variability of the circadian system of this insect species. The advantages of the dian-circadian model reside in: Providing a better understanding of observed phenomena related to changes in temporal organization and interindividual differences, as well as the effects of jet lag and shift work. Consideration of the fact that the characteristics of circadian rhythms cannot be reduced to the presence of only one phenotype, but instead relate to predictable phenotypic variability (polymorphisms).102
Conclusion
The present review did not attempt to cover all the conceptsestablished or contradictorythat prevail in chronobiology. Its aim was to present phenomena that are mainly characteristic and unique to human chronobiology and which cannot be fully explained by concepts and model drawn from laboratory experiments with plants, insects, and rodents. Attention was given to nonphotic signals that play a major role in affecting human biological rhythms, and the range of interindividual variability (with an attempt to offer a genetic model). Special emphasis was placed on distinguishing between states of human health and disease that are connected to changes in temporal organization, and a conceptual classification was suggested for these situations.
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State of the art

Conceptos en ritmos biolgicos humanos
Los ritmos biolgicos y su organizacin temporal son fenmenos de adaptacin a las variaciones peridicas del ambiente relacionadas con la rotacin de la tierra sobre su eje y alrededor del sol. Los datos experimentales provenientes de los reinos vegetal y animal han dado origen a muchos modelos y conceptos relacionados con relojes biolgicos que ayudan a describir y comprender los mecanismos de estos cambios. Muchos de los conceptos comunes se aplican a todos los organismos, pero la mayora de los datos experimentales son insuficientes para explicar la dinmica de los relojes biolgicos humanos. Esta revisin presenta los fenmenos que caracterizan la cronobiologa humana de manera nica y que no pueden ser totalmente explicados a travs de conceptos y modelos propuestos a partir de experimentos de laboratorio. Ella est centrada en las ventajas funcionales de la organizacin temporal humana y el problema de la desincronizacin, con especial atencin al perodo () del ritmo circadiano y su variabilidad interindividual e intraindividual. Tambin se describen las diferencias entre los ritmos de los diestros y los zurdos, lo que sugiere la existencia de diferentes relojes biolgicos en las cortezas derecha e izquierda. La desincronizacin de los ritmos es un fenmeno relativamente frecuente (por ejemplo, el trabajo con turnos nocturnos). En algunos sujetos la desincronizacin no se acompaa de ningn sntoma, por lo que se propone el concepto de alosincrona (alo = diferente), para designar una variedad de la organizacin temporal humana que no tiene repercusiones patolgicas. Se reserva el trmino discrona (dis = alteracin, perturbacin) para cambios o alteraciones asociadas con un conjunto de sntomas similares a los observados en sujetos que no toleran los trabajos con turnos, como fatiga persistente y trastornos del nimo y del sueo. Muchas enfermedades incluyen una privacin crnica del sueo nocturno y originan una sintomatologa similar a la de los trabajadores con turnos nocturnos que no toleran la desincronizacin. Tambin se presenta un modelo gentico (dian circadiano) para explicar las diferencias interindividuales en el perodo de los ritmos biolgicos en determinadas condiciones.
Concepts dans les rythmes biologiques humains

Les rythmes biologiques et leur organisation temporelle sont des phnomnes dadaptation aux variations priodiques de lenvironnement lies aux rotations de la terre sur son axe et autour du soleil. Des donnes exprimentales issues des rgnes vgtal et animal ont fourni de nombreux modles et concepts concernant les horloges biologiques. Ils permettent de dcrire et de mieux comprendre les mcanismes de ces variations. Plusieurs des concepts majeurs sappliquent tous les organismes mais ces donnes exprimentales ne suffisent pas expliquer la dynamique des horloges biologiques humaines. Cette revue prsente des phnomnes qui caractrisent la chronobiologie humaine de manire unique et qui ne peuvent tre entirement expliqus par les concepts et les modles exprimentaux. Elle est centre sur lavantage fonctionnel de lorganisation temporelle humaine et les problmes de dsynchronisation, la rfrence critique tant la priode des rythmes circadiens et sa variabilit intra- et interindividuelle. Ainsi, nous avons dcrit des diffrences entre les rythmes des mains droite et gauche qui donnent penser que des horloges biologiques fonctionnelles diffrentes existent dans les cortex droit et gauche. La dsynchronisation des rythmes est un phnomne relativement frquent (par exemple : le travail post). Chez certains sujets la dsynchronisation ne saccompagne daucun symptme, ce qui conduit au concept d allosynchronisme (allo = diffrent) qui dsigne une variante de lorganisation temporelle humaine, sans implication pathologique. Nous rservons le terme dyschronisme (dys = altration, perturbation) aux changements ou aux altrations de lorganisation temporelle associs des symptmes sobservant chez les sujets qui ne tolrent pas le travail post : fatigue persistante, troubles de lhumeur et du sommeil. De nombreuses maladies induisent une privation chronique du sommeil nocturne et sont lorigine dune symptomatologie similaire celle des travailleurs posts intolrants la dsynchronisation. Nous prsentons galement un modle gntique dien-circadien pour expliquer les diffrences interindividuelles de priodes de rythmes biologiques dans certaines circonstances.
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Regulation of Sleep and Circadian Rhythms. New York, NY: Marcel Dekker; 1999. 85. Benoit O, Foret J, Merle B, Reinberg A. Circadian rhythms (temperature, heart rate, vigilance, mood) of short and long sleepers: effects of sleep deprivation. Chronobiologia. 1981;8:341-350. 86. Sadeh A, Hauri PJ, Kripke F, Lavie P. The role of actigraphy in the evaluation of sleep disorders. Sleep. 1995;18:288-302. 87. Labrecque G, Karzazi M, Vanier MC. Biological rhythms in pain and analgesia. In: Redfern PH, Lemmer B, eds. Physiology and Pharmacology of Biological Rhythms. Berlin, Germany: Springer-Verlag; 1997:619-650. 88. Hermann D, Chan W, Smolensky MH Twenty-four-hour wrist actigraphy for evaluation of nocturnal sleep of pain patients. 6th International Conference on Chronopharmacology. Amelia Island, Fla. 1994. Abstract XIII-2. 89. Lavie P, Lorber M, Tzischinsky O, Epstein R, Sharf Y. Wrist actigraphic measurements in patients with rheumatoid arthritis: a novel method to assess drug efficacy. Drug Invest. 1992;(suppl 2):15-21. 90. Farr LA, Todero CM, Boen LM. Advancement of circadian rhythms reduces disruption and improves recovery from surgery. 6th International Conference on Chronopharmacology. Amelia Island, Fla. 1994. Abstract XV-4. 91. Mormont MC, Claustrat B, Waterhouse JM, et al. Clinical relevance of circadian rhythm assessment in cancer patients. In: Touitou Y, ed. Biological Clocks: Mechanisms and Applications. Amsterdam, The Netherlands: Elsevier; 1998:497-505. 92. Wehr TA, Goodwin FK, eds. Biological Rhythms in Psychiatry. Pacific Grove, Calif: Boxwood Press; 1983. 93. Halaris A, ed. Chronobiology and Psychiatric Disorders. New York, NY: Elsevier Science; 1987. 94. Taillard J, Lemoine P, Boule P, Drogue M, Mouret J. Sleep and heart rate circadian rhythm in depression: the necessity to separate. Chronobiol Int. 1993;10:63-72. 95. Kripke DF. Phase-advance theory for affective illnesses. In: Wehr TA, Goodwin FK, eds. Biological Rhythms in Psychiatry. Pacific Grove, Calif: Boxwood Press; 1983:41-69. 96. Pflug B. Circadian rhythms in depression. In: Rensing L, der Heiden U, Mackey MC, eds. Temporal Disorders in Human Oscillatory System. Berlin, Germany: Springer-Verlag; 1987:194-201. 97. Bicakova-Rocher A, Gorceix A, Reinberg A, Ashkenazi IA, Ticher A. Temperature rhythms of patients with major affective disorders: reduced circadian period length. Chronobiol Int. 1996;13:47-57. 98. Kripke DF, Mullaney DJ, Savides TJ, Gillin JC. Phototherapy for nonseasonal major depressive disorders. In: Rosenthal NE, Blehar MC, eds. Seasonal Affective Disorders and Phototherapy. New York, NY: Gilford Press; 1989:342-356. 99. Johnson A, Engelman W, Pflug B, Klemke W. Influence of lithium ions on human circadian rhythms. Z Naturforsch (C). 1980;35:503-507. 100. Reinberg A, Smolensky M. Chronobiology and thermoregulation. In: Schnbaum E, Lomax P, eds. Thermoregulation Physiology and Biochemistry. New York, NY: Pergamon Press; 1990:61-100. 101. Konopka RJ, Benzer R. Clock mutant of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1971;58:2112-2116. 102. Brok-Simoni F, Ashkenazi IE, Ramot B, Holtzman F. The diurnal rhythm of enzymes in human red blood cells: in vivo studies. Br J Haematol. 1976;32:601-605.
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Melatonin in animal models
Paul Pvet, PhD
Melatonin is a hormone synthesized and secreted during the night by the pineal gland. Its production is mainly driven by the circadian clock, which, in mammals, is situated in the suprachiasmatic nucleus of the hypothalamus. The melatonin production and release displays characteristic daily (nocturnal) and seasonal patterns (changes in duration proportional to the length of the night) of secretion. These rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes. In mammals, the role of melatonin in the control of seasonality is well documented, and the sites and mechanisms of action involved are beginning to be identified. The exact role of the hormone in the diurnal (circadian) timing system remains to be determined. However, exogenous melatonin has been shown to affect the circadian clock. The molecular and cellular mechanisms involved in this well-characterized chronobiotic effect have also begun to be characterized. The circadian clock itself appears to be an important site for the entrainment effect of melatonin and the presence of melatonin receptors appears to be a prerequisite. A better understanding of such chronobiotic effects of melatonin will allow clarification of the role of endogenous melatonin in circadian organization.
he Earths rotation on its axis, the orbit of the Earth around the Sun, and the orbit of the Moon around the Earth induce rhythmic geophysical phenomena. Organisms are thus affected by daily and seasonal variations of many physical factors of their environment. The ability to adapt to this changing environment is an essential survival mechanism. As a result, life has evolved to adapt to periodically changing environmental demands, and to anticipate them according to their predictability. Circadian and seasonal rhythms in biochemical, metabolic, endocrine, physiological, and behavioral processes are a fundamental feature of all living organisms, reflecting the need to ensure that biological functions occur at a given time of the day or year. The most obvious example is the fact that many animals are active only during the light period (diurnal species; human belong to this group) or in the dark period (nocturnal species), and are inactive during the other part of the day (sleep/wake cycle). Other rhythms, such as reproduction, diapause, hibernation, fur color changes, and migration, can also be given as examples. Precise timing is required at all levels from behavior to gene expression, and its dysregulation causes malfunction. Since the beginning of time, mankind has been fascinated by the sun and the invariably changing seasons, and ancient medical scripts include considerations on the variation of disease through the seasons. Disorders of rhythmicity are characteristic ofand may underliea variety
Keywords: melatonin; animal model; seasonal function; circadian function; chronobiotic effect Author affiliations: Laboratoire de Neurobiologie des Rythmes, UMR 7518 CNRS-Universit Louis Pasteur, Strasbourg, France Address for correspondence: Laboratoire de Neurobiologie des Rythmes, UMR 7518 CNRS-Universit Louis Pasteur, 12 rue de lUniversit, 67000 Strasbourg, France (e-mail: pevet@neurochem.u-strasbg.fr)
Copyright 2003 LLS SAS. All rights reserved
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DMH LD LH PT SCN SP dorsomedial hypothalamus light/dark luteinizing hormone pars tuberalis suprachiasmatic nucleus short photoperiod the most important reaching the pineal gland. This endocrine structure synthesizes and releases melatonin.* Melatonin is synthesized and secreted during the dark period of the LD cycle, independent of whether the animal is diurnally or nocturnally active, and the duration of the nocturnal production is proportional to the length of the night.8,9 Melatonin is thus an important efferent hormonal signal from the clock and its pattern of secretion provides both a daily and seasonal endocrine message to any structure or organ that can read it. It is now well established, as will be discussed below, that these messages are directly involved in the regulation of both circadian and seasonal rhythms in mammals. Before we start the description of current knowledge, it should be mentioned that, at high doses, exogenously administered melatonin has been reported to be a potent free radical scavenger.10,11 This effect can be explained through direct scavenging of free radicals or through interactions of enzyme that improve total antioxidative defense capacity. Even though the physiological nature of such an effect could be questioned, it should not be neglected when assessing the therapeutic potential of the hormone,12 especially because the binding of melatonin to quinone reductase (QR2), an enzyme with wellknown oxidoreductive properties, has recently been demonstrated.13
of medical and behavioral disorders. For example, sleep and circadian rhythms are often disrupted in neurological disorders and there is increasing evidence that alterations in the sleep/wake cycle accompany many types of neurological disorders. Moreover, in our modern human society, there is an increasing incidence of circadian misalignment caused by behaviors that perturb the relationship between light-mediated and activity-related input to the circadian system (eg, delayed resynchronization to local time [jet lag] or shift work rotation associated with general malaise [especially insomnia] and decrements in work productivity and increases in accidents).1 Additionally, in our aging society, there is a high incidence of circadian disorders, particularly disturbed sleep patterns, which reduce the quality of life. Moreover clinical responses to drug therapies, including those for cancer,2 can crucially depend on the state of the patients circadian system. The challenge for scientists is to understand the functional mechanisms involved and develop strategies to control or treat these disorders, which have important economic and health consequences. The functional mechanism used for the daily or seasonal organization of functions is far from well understood. We now know that, in mammals, these adaptive processes are organized within a circadian network comprising an endogenous self-sustained oscillator, synchronizing clock inputs, and various clock outputs. The major circadian oscillator is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and the decoding of its genetic background is underway. Photic and nonphotic inputs act directly or indirectly on the rhythms of clock gene expression to synchronize the circadian oscillations to exactly 24 h.3 The most efficient synchronizer is the daily light/dark (LD) cycle, but other factors, such as food restriction, locomotor activity, and chronobiotic drugs, are well-defined clock synchronizers as well.4 The circadian oscillator outputs allow the internal synchronization and temporal organization of physiological, endocrine, and behavioral functions. From the hypothalamic clock, various efferent pathways have been described, one of
Melatonin and seasonal function

The duration of the peak of melatonin secretion is positively correlated with the length of the night period. Experimentally, it has been demonstrated that the brain is able to integrate photoperiodic information through these changes in duration of melatonin synthesis. This explains the current use of this hormone in farming to control seasonal functions (eg, fur growth, reproduction, and milk production). This also opens therapeutic perspectives if we consider the hypothesis of Wehr14 that the photoperiod-induced changes in the duration of melatonin secretion drive the annual cycle that occurs in
*Although the pineal gland is the major source of melatonin, other sources do exist. The retina is one such extrapineal source.5,6 However, and contrary to what happens in some nonmammalian vertebrates, mammalian retinal melatonin does not contribute to circulating melatonin. The Harderian and lachrymal glands, gastrointestinal tract, red blood cells, platelets, and mononuclear cells have also been identified as sites of melatonin synthesis. Melatonin does not appear to be released into the general circulation from these tissues, at least under normal physiological conditions.7 Moreover, the synthesis of melatonin in these tissues does not appear to be rhythmic.
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Melatonin in animal models - Pvet
seasonal affective disorders. The exact mechanism of action of melatonin is unclear. The duration of nocturnal melatonin production is the key signal,8 but the existence within this signal of a melatonin-driven circadian rhythm of sensitivity to melatonin has been proposed to explain the photoperiodic response.15 In fact, our understanding of melatonins physiological functions depends on the understanding of how and where its action is exerted. Considering the lipophilic nature of the hormone, interactions with specific intracellular proteins16,17 or nuclear receptors cannot be excluded; however, melatonin seems to exert its effects principally throughout high-affinity G-proteincoupled receptors. The introduction of 2-[125I]iodomelatonin (125I-Mel)18 heralded the development of the melatonin receptor field. The cloning of the first high-affinity melatonin receptor in 1994 by Ebisawa et al19 then led to the subsequent identification of three types of vertebrate melatonin receptors (MT1, MT2, and Mel1c), and this very probably is only the beginning of a long list. Considering the photoperiodic responses, the melatonin receptors involved most probably are of the MT1 subtype. Indeed, the gene of the only other melatonin receptor subtype found in mammals, MT2, is nonfunctional in two highly photoperiodic species, Siberian and Syrian hamsters (Weaver and Reppert, unpublished data cited in reference 20). The target sites mediating melatonin control of photoperiod-dependent seasonal functions and especially the annual sexual cycle have not yet been totally determined. Contrary to what is generally claimed, melatonin receptors are present in a large number of structures in mammals (more than 110 brain structures have been identified, among them the internal granular layer and the external plexiform layer of the olfactory bulb, lateral septum, septohippocampal nucleus, caudate putamen, bed nucleus of the stria terminalis, SCN, mediobasal hypothalamic nuclei, paraventricular nuclei of the hypothalamus, paraventricular nuclei of the thalamus, intergeniculate leaflet, central and medial amygdaloid nucleus, inferior colliculus, fasciculus retroflexus, substantia nigra, and frontal, orbitofrontal and parietal cortex; numerous peripheral organs also contain melatonin receptors21-25). However, a great variability has been noted in the number and location of structures among the species, as well as large differences in receptor density between structures and in the same structures between species. Few structures are common, even among species from the same family,21 and very probably this should be correlated to either the numer-
ous photoperiodic responses, which are different from one species to another, or the many different effects described for melatonin. One structure, however, the pars tuberalis (PT) of the pituitary, which contains a very high density of melatonin receptors in all mammals studied, is thought to be of primary importance in photoperiodic response. Its density of melatonin receptors exhibits clear seasonal changes in photoperiodic species, but not in nonphotoperiodic mammals,26,27 and its implication in the control of seasonal secretion of prolactin has been demonstrated.28-31 The PT is thus a good model to delineate the melatonins signal transduction pathways32,33 and to study how the cellular response can distinguish between long- and short-duration melatonin signals. The cyclic adenosine monophosphate (cAMP)-mediated pathways appear to be central to the melatonin readout. Pretreatment with melatonin has been demonstrated to induce a sensitization of adenylate cyclase, and a potentiated cAMP response to forskolin stimulation.34,35 Melatonin pretreatment that is effective in potentiating cAMP accumulation in the PT is duration-dependent (between 0-16 h) and corresponds well with the duration of the nocturnal melatonin signal.34 The nocturnal melatonin signal is also crucial for the rhythmic expression in the PT of several cAMP-responsive genes, including the transcriptional inhibitorinducible cAMP early repressor (ICER), and of several clock genes.36,37 Indeed, two components of the molecular clock, namely Per1 and Cry1, are rhythmically expressed in the PT. Furthermore, other components of the clock like Timeless, Clock, and Per2 (Pvet P et al, unpublished observations) are also expressed in the PT, at least in the PT of some rodents, raising the possibility that the PT might contain a complete set of clock genes.33,36,38-41 However, the clock gene expression in the PT differs from what is observed in the SCN or other peripheral tissues (peripheral oscillators) because it appears to be directly driven by melatonin. Removal of the pineal gland abolishes rhythmic PT gene expression, and extension of the dark phase of the LD cycle dampens the amplitude of the Per1 in PT cells.39 Cry1 is rapidly and very strongly induced by melatonin administration. In nontreated animals, a peak of expression occurs during the dark phase (ie, at a time when melatonin is present in the bloodstream). This indicates that melatonin may gate the expression of Cry1 in the PT, suggesting that these clock genes are involved in the melatonin readout mechanism. Cry1 expression appears
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to be anchored to the onset of melatonin secretion. It acts as a sensor of melatonin onset, rather than a marker of the duration of the melatonin signal. Per1 mRNA peaks early in the day, when blood plasma melatonin levels are back to low levels. Per1 expression thus appears to be linked to the offset of melatonin secretion. This dual effect of melatonin together with its photoperiod-dependent pattern in plasma levels may provide the basis of a time measurement mechanism. This model may help understand how the PT is involved in the seasonal control of prolactin secretion by the PT. The validation of such a model will, however, require further experiments and the complete understanding of the melatonin and photoperiodic readout requires a link with identified downstream response in the PT. This is still difficult. It is through the production of a prolactin-releasing (or release inhibitor) factor that the photoperiodic and melatonin information to lactotroph cells in the pituitary are relayed. This factor, termed tuberalin,30,42 has not yet been identified. Photoperiod-induced changes in prolactin secretion, however, are not enough to explain the seasonal sexual cycle. This implies that in order to mediate photoperiodic information melatonin must act on other target sites. This view is supported by the fact that Syrian hamsters bearing lesions to the dorsomedial hypothalamus (DMH) and infused with melatonin to mimic short photoperiod (SP), display differential responses in terms of prolactin and luteinizing hormone (LH).43 While the prolactin response remains intact, the LH response in blocked by the DMH lesion.43 Moreover, in sheep, melatonin implants in the mediobasal hypothalamus block the effects of SP on LH but not on prolactin, while implants close to the PT inhibit prolactin secretion.44 Interestingly, melatonin binding sites have been detected in the DMH in the Syrian hamster, although with a very low density, and their density depends on the photoperiod (Pvet P et al, unpublished data). The hypothesis of a parallel and concomitant action of melatonin on different structures to transduce the photoperiodic message is attractive. The photoperiod is known, through changes in duration of melatonin secretion, to control not only the reproductive annual cycle, but also a large number of other seasonal functions (eg, body weight, hibernation, daily torpor, fur color changes, and migration). Furthermore, not all seasonal functions are expressed in every species and different control mechanisms may be involved. For example, SP induces an activation of the sexual axis in sheep, but inhibition in Syrian and Siberian hamsters; and hibernation in the Syrian hamster is directly dependent on photoperiod, while in the European hamster it is dependent on a circannual clock entrained by photoperiod. It thus seems likely that melatonin acts at different structures according to the species and the function. This concept would account for the large interspecies differences observed in mammals in the distribution of structures containing melatonin receptors. Interestingly, and in support of this concept, a pharmacological dissociation of photoperiodic-controlled seasonal functions has been reported. S 22153, a melatonin antagonist of MT1 and MT2 melatonin receptor subtypes, caused a decrease in the duration of hibernation in Syrian hamsters under SP and low temperature, but did not affect SP-induced gonadal atrophy.45
Melatonin and circadian function

In most nonmammalian vertebrates, the rhythmic synthesis and secretion of melatonin is the direct output of circadian clock, and the rhythmic changes in the concentration of circulating melatonin are fundamental to circadian rhythmicity.46 In mammals, despite the presence of melatonin receptors in the SCN of most species indicating hormonal feedback on the clock, the consensus has been that melatonin has only a limited role in circadian organization. This view has arisen, in part, since pinealectomy has little effect on circadian organization.47 Melatonin rhythm, however, is only one of the outputs of the clock and it is probable that, for the organization of circadian activities, a number of different output signals from the clock are involved in the distribution of circadian information to target tissues.48,49 This does not preclude an important role for melatonin in circadian organization.36 After pinealectomy, for example, subtle desynchrony of several physiological functions has been described,50 and the reentrainment of the rat locomotor activity rhythm is modified after a phase shift of the LD cycle.51 One week after pinealectomy, the firing rate rhythm of SCN neurons in vitro is altered, as well as the daily rhythm of responsiveness to melatonin.52 It is also known that melatonin interferes with metabolic activity (glucose utilization and protein synthesis) in the SCN.53 The SCN may use the daily melatonin signal to convey the circadian message to any system that can read it, ie, to any structure or organ possessing melatonin receptors, either in the central nervous system or at the periphery.9,54
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This concept helps explain numerous results in the literature: the melatonin inhibition of spontaneous and light evoked activity of cells in the intergeniculate leaflet55; melatonin-enhancing splenic lymphocyte proliferation56,57; melatonin-induced inhibition of leukocyte rolling and adhesion to rat microcirculation58; melatonin-induced vasoconstriction of cerebral and tail arteries59; and melatonin regulation of emotional behavior.60 What could be the mechanism involved? Clock genes are expressed widely in mammalian tissues. It appears that cyclical expression of these genes in the periphery is driven by the SCN. The role of melatonin in regulating rhythmic clock gene expression in peripheral tissues as described in the PT (see above) may be one of the mechanisms for tissue-specific regulation of the phase of rhythmicity. Interestingly, it has been demonstrated that the circadian rhythm of melatonin receptor density in rat PT is suppressed after pinealectomy and melatonin drives this rhythm directly.61,62 Even if the role of endogenous melatonin on clock functioning is not yet defined, the presence of melatonin receptors within the SCN indicates that exogenous melatonin affects circadian regulation, which is of potential therapeutic value. Exogenous melatonin and circadian rhythms Exogenous melatonin is known to be able to influence, directly or indirectly, the phase and/or the period of the circadian clock. In terms of treatments, this means that exogenous melatonin (or any agonist) can be used as a pharmacological tool to manipulate sleep-wake cycle and other circadian rhythms (chronobiotic properties63). It has long been known that administration of melatonin can entrain free-running activity rhythms in rodents.20,64 Entrainment means that the period of the observed rhythm must adjust to, and equal, the synchronizer (zeitgeber) cycle (T), and a stable phase relation must be established between the rhythm and the zeitgeber cycle. This synchronization process occurs through daily phase shifts. Administering melatonin for a series of T values, 24 h, 23 h 50 min, 23 h 45 min, 23 h 35 min, and 23 h 25 min65 has led to the definition of the limiting phase advance value to which the rat activity rhythm entrains to melatonin at 35 min. The entrainment limits found in this study correspond quite well to the maximum daily phase shift values defined by the melatonin phase response curve,66 and the magnitude of phase shift responses to a single melatonin injection67 (range 15-52
min). Daily acute melatonin administration in the rat thus causes true entrainment as defined by Enright et al.68 Interestingly, when melatonin is administered by daily infusion, the phase angle difference between the entrained rhythm and the zeitgeber (melatonin) depends upon the duration of the infusion period. A negative phase angle is observed and its value increases with the duration of the infusion period.69 Moreover, with long infusion times (8 h and, more especially, with 16 h), melatonin induces a change in the free-running period in the first days, suggesting that melatonin delays the pacemaker each day until entrainment occurs. In other words, with a long duration of infusion, entrainment occurs earlier than predicted by the model based on acute melatonin administration. The magnitude of the change in period increases significantly with the duration of infusion. These observations suggest that, beside its chronobiotic properties, melatonin affects the circadian clock properties (effect on the period ?). This conclusion is supported by the results obtained after a skeleton infusion. Under these conditions, melatonin induced entrainment after a time during which circadian periods were either lengthened (in a fraction of the animals) or shortened (in the others).69 This finding suggests that, to achieve entrainment, melatonin has to induce either a phase delay (when the period is shortened) or a phase advance (when the period is lengthened). Such a dual effect of melatonin has also been reported in other studies. For example, when rats received a 5 h phase advance of the dark onset in LD conditions, those injected melatonin daily at the new dark onset reentrained with decreased latency; some of the animals did so by phase delays, whereas others did so by phase advances.66 Melatonin has been reported to entrain hamsters and Arvicanthis ansorgei, a diurnal rodent, by inducing phase advances when the free-running period is longer than 24 h and phase delays when the period is shorter than 24 h.70-72 All these observations strongly suggest that the effects of exogenous melatonin are complex and depend on the period before entrainment. Another potential effect of exogenous melatonin should be considered. A single application of melatonin within the SCN, in vivo, induced a long-lasting increase in the amplitude of the nocturnal melatonin secretion.73 This effect demonstrates that exogenous melatonin is able to sustain the oscillation of the clock and suggests a possible role for endogenous melatonin in mammals.
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Sites of action for the effects of exogenous melatonin on the circadian activities In the experiments reported above, responsiveness to melatonin is restricted to a narrow window of sensitivity, which is generally late in the subjective afternoon, but depends upon the duration of the melatonin signal as well as the previous free-running period. The finding that pinealectomized rats entrain to daily melatonin administration67,69 indicates that endogenous melatonin is not necessary for the entrainment effect of exogenous melatonin, for example, by entraining a window of sensitivity to melatonin.15 Nocturnal melatonin production is a direct output of the SCN circadian clock. Exogenous melatonin is effective at a time when endogenous melatonin is not produced. Consequently, the effects of melatonin administration in vivo appear not to be related to the role of endogenous melatonin on circadian function. This conclusion is reinforced by the observation that to obtain entrainment of the circadian activity rhythm of rodents kept under constant darkness (DD), high doses of melatonin have to be used, independently of the mode of administration.69,74,75 These doses of melatonin produce peak serum levels 100- to 1000-fold higher than the endogenous melatonin nighttime levels. The necessity of such a high dose of melatonin is unlikely to be a consequence of its rapid metabolism. Appropriate photoperiodic response is indeed obtained when melatonin is administered via a similar subcutaneous infusion system with a dose that mimics the endogenous secretion profile.15,76 Most likely, this high dose of melatonin is needed because it is an integral part of the response observed. In vitro administration of melatonin can phase shift the firing rate of SCN neuron brain slices (rat and mouse).77,78 It is principally for this reason that it is generally believed that melatonin mediates these effects through the highaffinity melatonin receptors located within the SCN.61,79 The high correlation between the density of melatonin receptors within the SCN and the ability of daily melatonin administration to entrain the free-running activity rhythm in mammals supports this view. In contrast to the rat, mouse, and Djungarian hamster (rodents that can be entrained by daily melatonin administration and in which a high density of melatonin receptors is observed within the SCN), the mink (Mustela vison) does not appear to have specific melatonin receptors (at least 2-iodomelatonin binding sites) within the SCN. This animal does not entrain to melatonin.80 Newborn Syrian hamsters express melatonin receptors in the SCN, but the receptor number decreases shortly after birth.81,82 Young hamsters are entrainable by daily acute melatonin administration, while, in the adult, melatonin is unable to entrain83,84 or synchronize, except under particular experimental conditions (eg, long-term infusions which affect the ).70,72 Since SCN-lesioned hamsters whose rhythmicity had been restored with fetal hypothalamic graft are entrained by daily melatonin injection, it is evident that the chronobiotic effect of exogenous melatonin is the consequence of an action on the clock. This conclusion is supported by the observation that in vivo a melatonin receptor antagonist (S 22153) blocks the phase-advancing effect of melatonin.85 Which receptor subtypes are involved? Siberian hamsters without a functional MT2 receptor show circadian responses to melatonin.86 Similarly, the most robust entraining response to melatonin, synchronization of developing circadian pacemakers in Syrian hamsters by melatonin injections, occurs in the absence of a functional MT2 receptor within the SCN.87 This strongly suggests the implication of MT1 receptors. In in vitro experiments in animal models that possess both subtypes, the mechanisms involved appear to be more complex. An acute inhibitory effect on neuronal firing and a phase-shifting effect in the rhythm in electrical activity have been described.88 In mice with a targeted deletion of the MT1 receptor, the acute inhibitory effect of melatonin was abolished, while the phase-shifting effect remained intact.88 However, this phase shift disappears when the MT2 antagonist 4-phenylpropionamidotetraline (4P-PDOT) is added.89 This suggests that either a low density of MT2 receptors is still capable of producing a phase shift or that an as yet unidentified melatonin receptor subtype is involved. In contrast to previous studies, van den Top et al90 have recently demonstrated the absence of a specific window of sensitivity for melatonin to inhibit SCN neuronal activity. This lack of a window of sensitivity contrasts with the phase-shifting effect of melatonin, and indicates that the cellular mechanisms involved in the acute inhibitory effect and in the phase-shifting effect of melatonin are distinct. This may be related to the two types of effects observed in vivo after daily 8 or 16 h melatonin perfusions69 described above. The presence of MT1 and/or MT2 melatonin receptors appears to be a necessary condition for the chronobiotic effect of melatonin. However, if these high-affinity melatonin receptors were the only mechanism involved, it
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would be difficult to explain why a pharmacological dose of melatonin is needed. This implies that other neural mechanisms may be involved.Although a strong modulatory role of exogenous melatonin on serotonin (5-hydroxytryptamine) 5-HT receptormediated responses has been reported, the 5-HT system does not appear to be crucial to the effects of melatonin on circadian rhythms.91
Conclusions and perspectives

Melatonin is produced nocturnally by the pineal gland, in a pattern that reflects the phase and duration of the night. The physiological roles of the hormone directly relate to the temporal information it conveys. In fact, nocturnal melatonin secretion is a hormonal output signal of the circadian clock able to convey photoperiodic as well as circadian signals to multiple structures and organs possessing melatonin receptors, within the brain or at the periphery. This explains why melatonin appears to act in so many different systems. The use of melatonin to control seasonally expressed traits of economic importance (milk and wood produc-
tion, etc) in farm animals is now well documented, and the sites and mechanisms of action involved are beginning to be identified. The exact role of the hormone in the circadian timing system remains to be determined. However, due to the presence of melatonin receptors within the SCN itself, exogenous melatonin has been shown to affect the circadian clock in animal models (chronobiotic effect). The observations that, in humans, melatonin improves some circadian-based disorders refer to such properties and will lead to strategies to treat, prevent, or delay such disturbances. Melatonin, as explained above, acts through several mechanisms. The hormones physiological functionsand thereby its therapeutic potentialwill depend on our knowledge of its mechanism of action. Today, the pathways through which temporal information encoded in the melatonin signal is decoded in target tissues, and the phenotypic nature of those target tissues, are not completely understood. Experimental work in animal models is still needed to define exactly the therapeutic value of the hormone (for more perspectives with the use of pharmacological tools based on melatonin receptors and -antagonists see reviews in references 63 and 92).
REFERENCES
1. Rajaratnam SM, Arendt J. Health in a 24-h society. Lancet. 2001;358:9991005. 2. Fu L, Lee CC. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer. 2003;3:350-361. 3. Challet E, Caldelas I, Graff C, Pvet P. Synchronization of the molecular clockwork by light- and food-related cues in mammals. Biol Chem. 2003;384:711-719. 4. Challet E, Pvet P. Interactions between photic and nonphotic stimuli to synchronize the master circadian clock in mammals. Front Biosci. 2003;8:s246-s257. 5. Pvet P, Balemans MGM, Bary FAM, Noodergraef EM. The pineal of the mole (Talpa europeae L.). V. Activity of hydroxyindole-O-methyltryptophol in the eyes and the pineal gland. Ann Biol Amin Biochem Biophys. 1978;18:259-264. 6. Tosini G, Menaker M. Circadian rhythms in cultured mammalian retina. Science. 1996;272:419-421. 7. Djeridane Y, Pitrosky B, Vivien-Roels B, Pvet P. Long-term melatonin infusion induces large and stable increase in N-acetyltransferase activity, hydroxyindole-O-methyltransferase activity and melatonin content in the Harderian gland and eye of pinealectomized male Siberian hamster (Phodopus sungorus). J Pineal Res. 2000;29:65-73. 8. Bartness T, Bittman EL, Hastings MH, Powers JB, Goldman B. Timed melatonin infusion paradigm for melatonin delivery: what has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses? J Pineal Res. 1993;15:161-190. 9. Pvet P. Mlatonine et rythmes biologiques. Thrapie. 1998;53:411-420. 10. Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci. 2000;7:444-458. 11. Reiter RJ. Melatonin: clinical relevance. Best Pract Res Clin Endocrinol Metab. 2003;17:273-285.
12. Husson I, Mesples B, Bac P, Vamecq J, Evrard P, Gressens P. Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge. Ann Neurol. 2002;51:82-92. 13. Nosjean O, Ferro M, Coge F, et al. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem. 2000;275:3131131317. 14. Wehr TA. Photoperiodism in humans and other primates: evidence and implications. J Biol Rhythms. 2001;16:348-364. 15. Pitrosky B, Kirsch R, Vivien-Roels B, Georg-Bentz I, Canguilhem B, Pvet P. The photoperiodic response in Syrian hamster depends upon a melatonin-driven circadian rhythm of sensitivity to melatonin. J Neuroendocrinol. 1995;7:889-895. 16. Cardinali DP. Molecular biology of melatonin: assessment of the microtubule hypothesis of melatonin action. In: Birau N, Schloot W, eds. Melatonin Current Status and Perspectives. Oxford, UK: Pergamon; 1980:247-256. 17. Benitez-King G, Rios A, Martinez A, Anton-Tay F. In vitro inhibition of Ca2+/calmodulin-dependent kinase II activity by melatonin. Biochim Biophys Acta. 1996;1290:191-196. 18. Vakkuri O, Lamsa E, Rahkamaa E, Ruotsalainen H, Leppaluoto J. Iodinated melatonin: preparation and characterization of the molecular structure by mass and 1H NMR spectrometry. Anal Biochem. 1984;142:284-289. 19. Ebisawa T, Karne S, Lerner MR, Reppert SM. Expression cloning of a high affinity melatonin receptor from Xenopus dermal melanophores. Proc Natl Acad Sci U S A. 1994;91:6133-6137. 20. Weaver DR. Melatonin and circadian rhythmicity in vertebrates: physiological roles and pharmacological effects. In: Turek FW, Zee PC, eds. Regulation of Sleep and Circadian Rhythms. New York, NY: Marcel Dekker; 1999:197-262. 21. Masson-Pvet M, George D, Kalsbeek A, Saboureau M, Lakhdar-Ghazal N, Pvet P. An attempt to correlate brain areas containing melatoninbinding sites with rhythmic functions: a study in five hibernator species. Cell Tissue Res. 1994;278:97-106.
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Melatonina en modelos animales
La melatonina es una hormona que es sintetizada y secretada durante la noche por la glndula pineal. Su produccin es controlada principalmente por el reloj circadiano, el cual en los mamferos est situado en el ncleo supraquiasmtico del hipotlamo. La produccin y liberacin de melatonina tiene perfiles de secrecin caractersticos tanto diarios (nocturnos) como estacionales (cambios en la duracin proporcionales a la duracin de la noche). Estos ritmos en la melatonina circulante son fuertes sincronizadores para la expresin de numerosos procesos fisiolgicos. En los mamferos, el papel de la melatonina en el control de la estacionalidad est bien documentado, y los sitios y mecanismos de accin involucrados se estn comenzando a identificar. El papel exacto de la hormona en el sistema de ritmo diurno (circadiano) debe ser determinado. Sin embargo, se ha observado que la melatonina exgena afecta el reloj circadiano. Los mecanismos moleculares y celulares que participan en este efecto cronobitico bien caracterizado tambin han comenzado a ser identificados. El reloj circadiano en s mismo parece ser un sitio importante para el efecto de arrastre de melatonina y la presencia de receptores de melatonina parece ser un prerrequisito. Una mejor comprensin de tales efectos cronobiticos de la melatonina permitir aclarar el papel de la melatonina endgena en la organizacin circadiana.
22. Stankov B, Capsoni S, Lucini V. Autoradiographic localization of putative melatonin receptor in the brain of two old world primates, Cercopithecus aethiops and Papio ursinus. Neuroscience. 1993;52:459-468. 23. Stankov B, Cozzi B, Lucini V, Fumagalli P, Scaglione F, Fraschini F. Characterization and mapping of melatonin receptors in the brain of three mammalian species: rabbit, horse and sheep. A comparative in vitro binding study. Neuroendocrinology. 1991;53:214-221. 24. Morgan PJ, Barrett P, Howell HE, Helliwell R. Melatonin receptors: localization, molecular pharmacology and physiological significance. Neurochem Int. 1994;24:101-146. 25. Poirel VJ, Cailotto C, Streicher D, Pvet P, Masson-Pvet M, Gauer F. MT1 melatonin receptor mRNA tissular-localization by PCR amplification. Neuroendocrinol Lett. 2003;24:33-38. 26. Gauer F, Masson-Pvet M, Pvet P. Seasonal regulation of melatonin receptors in rodents pars tuberalis: correlation to reproductive state. J Neural Transm. 1994;96:187-195. 27. Masson-Pvet M, Gauer F. Seasonality and melatonin receptors in the pars tuberalis in some long day breeder. In: Brown GM, Pvet P, Pang SF, eds. Melatonin Binding Sites in Endocrine and Immune system. Biological Signals. Basel, Switzerland: Karger; 1994;3:63-70. 28. Lincoln GA, Clarke IJ. Photoperiodically induced cycles in secretion of prolactin in hypothalamo-pituitary disconnected ram: evidence for translation of the melatonin signal in the pituitary gland. J Neuroendocrinol. 1994;6:251-260.
Mlatonine et modles animaux

La mlatonine est une hormone synthtise et scrte par la glande pinale. Cette synthse est sous le contrle de lhorloge circadienne localise chez les mammifres dans les noyaux suprachiasmatiques de lhypothalamus. La scrtion de mlatonine est nocturne (caractre journalier) et la dure de cette scrtion est proportionnelle la dure de la nuit (caractre saisonnier). Ces variations rythmiques de la scrtion de mlatonine permettent de distribuer lorganisme un message journalier et saisonnier. Chez les mammifres, le rle de la mlatonine dans le contrle des fonctions saisonnires est maintenant bien dmontr et les sites et mcanismes daction commencent tre bien identifis. Le rle exact de la mlatonine dans lorganisation journalire des fonctions reste dterminer. Toutefois des administrations de mlatonine exogne sont connues pour agir sur le systme circadien. Les mcanismes molculaire et cellulaire impliqus dans cet effet chronobiotique de lhormone commencent tre identifis. Lhorloge circadienne elle-mme semble tre la cible principale et la prsence de rcepteurs la mlatonine est ncessaire. Dterminer ces mcanismes daction permettra de clarifier le rle de la mlatonine endogne dans lorganisation circadienne des fonctions.
29. Graham ES, Webster CA, Hazlerigg DG, Morgan PJ. Evidence for the biosynthesis of a prolactin-releasing factor from the ovine pars tuberalis, which is distinct from thyrotropin-releasing hormone. J Neuroendocrinol. 2002;14:945-954. 30. Morgan PJ. The pars tuberalis: the missing link in the photoperiodic regulation of prolactin secretion? J Neuroendocrinol. 2000;12:287-295. 31. Hazlerigg DG, Morgan PJ, Messager S. Decoding photoperiodic time and melatonin in mammals: what can we learn from the pars tuberalis? J Biol Rhythms. 2001;16:326-335. 32. Von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res. 2002;309:151162. 33. Von Gall C. Rhythmic clock gene expression in the hypophyseal pars tuberalis is regulated by melatonin. Ann Anat. 2003;185:301-302. 34. Hazlerigg DG, Gonzalez-Brito A, Lawson W, Hastings MH, Morgan PJ. Prolonged exposure to melatonin leads to time-dependent sensitization of adenylate cyclase and down-regulates melatonin receptors in pars tuberalis cells from ovine pituitary. Endocrinology. 1993;132:285-292. 35. Hazlerigg DG, Hastings MH, Morgan PJ. The recovery of ovine pars tuberalis cells from melatonin-induced sensitization is a slow, protein synthesis-dependent phenomenon. J Endocrinol. 1994;142:127-138. 36. Von Gall C, Garabette ML, Kell CA, et al. Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin. Nat Neurosci. 2002;5:234-238.
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37. Korf HW, Von Gall C, Stehle J. The circadian system and melatonin: lessons from rats and mice. Chronobiol Int. 2003;20:697-710. 38. Messager S, Hazlerigg DG, Mercer JG, Morgan PJ. Photoperiod differentially regulates the expression of Per1 and ICER in the pars tuberalis and the suprachiasmatic nucleus of the Siberian hamster. Eur J Neurosci. 2000;12:2865-2870. 39. Messager S, Garabette ML, Hastings MH, Hazlerigg DG. Tissue-specific abolition of Per1 expression in the pars tuberalis by pinealectomy in the Syrian hamster. Neuroreport. 2001;12:1-4. 40. Lincoln GA, Andersson H, Hazlerigg D. Clock genes and the long-term regulation of prolactin secretion: evidence for a photoperiod/circannual timer in the pars tuberalis. J Neuroendocrinol. 2003;15:390-397. 41. Dardente H, Menet JS, Poirel VJ, et al. Melatonin induces Cry1 expression in the pars tuberalis of the rat. Brain Res Mol Brain Res. 2003;114:101-106. 42. Hazlerigg DG, Hastings MH, Morgan PJ. Production of a prolactin-releasing factor by the ovine pars tuberalis. J Neurendocrinol. 1996;8:489-492. 43. Maywood ES, Bittman EL, Hastings MH. Lesions of the melatonin- and androgen-responsive tissue of the dorsomedial nucleus of the hypothalamus block the gonadal response of male Syrian hamsters to programmed infusions of melatonin. Biol Reprod. 1996;54:470-477. 44. Malpaux B, Migaud M, Tricoire H, Chemineau P. Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin. J Biol Rhythms. 2001;16:336-347. 45. Pitrosky B, Delagrange P, Rettori MC, Pvet P. S 22153, a melatonin antagonist, dissociates different aspects of photoperiodic responses in Syrian hamsters. Behav Brain Res. 2002;138:145-152. 46. Cassone VM. Melatonins role in vertebrate circadian rhythms. Chronobiol Int. 1998;15:457-473. 47. Underwood H, Goldman BD. Vertebrate circadian and photoperiodic systems: role of the pineal gland and melatonin. J Biol Rhythms. 1987;2:279315. 48. Buijs RM, Kalsbeek A. Hypothalamic integration of central and peripheral clocks. Nat Rev Neurosci. 2001;2:521-526. 49. Kramer A, Yang FC, Snodgrass P, et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science. 2001;294:2511-2515. 50. Lima FB, Machado UF, Bartol I, et al. Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats. Am J Physiol. 1998;275:E934-E941. 51. Armstrong SM. Melatonin: the interval Zeitgeber of mammals. In: Reiter RJ, ed. Pineal Research Review. Vol 7. New York, NY: Liss; 1989:157202. 52. Rusak B, Yu GD. Regulation of melatonin-sensitivity and firing-rate rhythms of hamster suprachiasmatic nucleus neurons: pinealectomy effects. Brain Res. 1993;602:200-204. 53. Cassone VM, Roberts MH, Moore RY. Effects of melatonin on 2-deoxy[1-14C]glucose uptake within rat suprachiasmatic nucleus. Am J Physiol. 1988;255:R332-R337. 54. Cardinali DP, Pvet P. Basic aspects of melatonin action. Sleep Med Rev. 1998;2:175-190. 55. Ying SW, Zhang DX, Rusak B. Effects of serotonin agonists and melatonin on photic responses of hamster intergeniculate leaflet neurons. Brain Res. 1993;628:8-16. 56. Drazen DL, Bilu D, Bilbo SD, Nelson RJ. Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1476-R1482. 57. Drazen DL, Nelson RJ. Melatonin receptor subtype MT2 (Mel 1b) and not mt1 (Mel 1a) is associated with melatonin-induced enhancement of cell mediated and humoral immunity. Neuroendocrinology. 2001;74:178-184. 58. Lotufo CM, Lopes C, Dubocovich ML, Farsky SH, Markus RP. Melatonin and N-acetylserotonin inhibit leukocyte rolling and adhesion to rat microcirculation. Eur J Pharmacol. 2001;430:351-357. 59. Regrigny O, Delagrange P, Scalbert E, Atkinson J, Chillon JM. Melatonin increases pial artery tone and decreases the lower limit of cerebral blood flow autoregulation. Fund Clin Pharmacol. 2001;15:233-238. 60. Kopp C, Vogel E, Rettori MC, et al. Regulation of emotional behaviour by day length in mice: implication of melatonin. Behav Pharmacol. 1999;10:747-752.
61. Gauer F, Masson-Pvet M, Skene DJ, Vivien-Roels B, Pvet P. Daily rhythms of melatonin binding sites in the rat pars tuberalis and suprachiasmatic nuclei; evidence for a regulation of melatonin receptors by melatonin itself. Neuroendocrinology. 1993;57:120-126. 62. Gauer F, Masson-Pvet M, Stehle J, Pvet P. Daily variations in melatonin receptor density of rat pars tuberalis and suprachiasmatic nuclei are distinctly regulated. Brain Res. 1994;641:92-98. 63. Pvet P. Melatonin. Dialogues Clin Neurosci. 2002;4:57-72. 64. Redman J, Armstrong S, Ng KT. Free-running activity rhythms in the rat: entrainment by melatonin. Science. 1983;219:1089-1091. 65. Slotten HA, Pitrosky B, Pvet P. Entrainment of circadian activity rhythms in rats to melatonin administered at T cycles different from 24 hours. Neurosignals. 2002;11:73-80. 66. Redman JR, Armstrong SM. Reentrainment of rat circadian activity rhythms: effects of melatonin. J Pineal Res. 1988;5:203-215. 67. Warren WS, Hodges DB, Cassone VM. Pinealectomized rats entrain and phase-shift to melatonin injections in a dose-dependent manner. J Biol Rhythms. 1993;8:233-245. 68. Enright JT. Methodology. In: Aschoff J, ed. Handbook of Behavioral Neurobiology. Vol 4. New York, NY: Plenum Press; 1981;11-19. 69. Pitrosky B, Kirsch R, Malan A, Mocaer E, Pvet P. Organization of rat circadian rhythms during daily infusion of melatonin or S 20098, a melatonin agonist. Am J Physiol. 1999;277:R812-R828. 70. Kirsch R, Belgnaoui S, Gourmelen S, Pvet P. Daily melatonin infusion entrains free-running activity in Syrian and Siberian hamsters. In: Wettenberg L, ed. Light and Biological Rhythm in Man. New York, NY: Pergamon; 1993:107-120. 71. Slotten HA, Krekling S, Sicard B, Pvet P. Daily administration of melatonin entrains circadian activity rhythms in the diurnal rodent Arvicanthis ensorgei. Behav Brain Res. 2002;133:11-19. 72. Schuhler S, Pitrosky B, Kirsch R, Pvet P. Entrainment of locomotor activity rhythm in pinealectomized Syrian hamster by daily melatonin infusion under different conditions. Behav Brain Res. 2002;133:343-350. 73. Bothorel B, Barassin S, Saboureau M, Malan A, Pvet P. In the rat exogenous melatonin increases the amplitude of pineal melatonin secretion by a direct action on the circadian clock. Eur J Neurosci. 2002;16:1090-1098. 74. Cassone VM, Chesworth MJ, Armstrong SM. Dose-dependent entrainment of rat circadian rhythms by daily injection of melatonin. J Biol Rhythms. 1986;1:219-229. 75. Slotten HA, Pitrosky B, Pvet P. Influence of the mode of daily melatonin administration on entrainment of rat circadian rhythms. J Biol Rhythms. 1999;14:347-353. 76. Pitrosky B, Masson-Pvet M, Kirsch R, Vivien-Roels B, Canguilhem B, Pvet P. Effects of different doses and durations of melatonin infusions on plasma melatonin concentrations in pinealectomized Syrian hamsters: consequences at the level of sexual activity. J Pineal Res. 1991;11:149-155. 77. McArthur AJ, Hunt AE, Gillette MU. Melatonin action and signal transduction in the rat suprachiasmatic circadian clock: activation of protein kinase C at dusk and dawn. Endocrinology. 1997;138:627-634. 78. Gillette MU, McArthur AJ. Circadian actions of melatonin at the suprachiasmatic nucleus. Behav Brain Res. 1996;73:135-139. 79. Vanecek J, Pavlik A, Illnerova H. Hypothalamic melatonin receptor sites revealed by autoradiography. Brain Res. 1987;435:359-362. 80. Bonnefond C, Monnerie R, Richard JP, Martinet L. Melatonin and the circadian clock in mink: effects of daily injections of melatonin on circadian rhythm of locomotor activity and autoradiographic localization of melatonin binding sites. J Neuroendocrinol. 1993;5:241-246. 81. Gauer F, Schuster C, Poirel VJ, Pvet P, Masson-Pvet M. Cloning experiments and developmental expression of both melatonin receptor Mel1A mRNA and melatonin binding sites in the Syrian hamster suprachiasmatic nuclei. Mol Brain Res. 1998;60:193-202. 82. Maywood ES, Bittman EL, Ebling FJ, Barrett P, Morgan P, Hastings MH. Regional distribution of iodomelatonin binding sites within the suprachiasmatic nucleus of the Syrian hamster and the Siberian hamster. J Neuroendocrinol. 1995;7:215-223. 83. Grosse J, Velickovic A, Davis FC. Entrainment of Syrian hamster circadian activity rhythms by neonatal melatonin injections. Am J Physiol. 1996;270:R533-R540.
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84. Hastings MH, Mead SM, Vindlacheruvu RR, Ebling FJ, Maywood ES, Grosse J. Non-photic phase shifting of the circadian activity rhythm of Syrian hamsters: the relative potency of arousal and melatonin. Brain Res. 1992;591:20-26. 85. Weibel L, Rettori MC, Lesieur D, Delagrange P, Renard P, Van Reeth O. A single oral dose of S 22153, a melatonin antagonist, blocks the phaseadvancing effects of melatonin in C3H mice. Brain Res. 1999;829:160-166. 86. Weaver DR, Liu C, Reppert SM. Natures knockout: the Mel1b receptor is not necessary for circadian or reproductive responses in Siberian hamsters. Mol Endocrinol. 1996;10:1478-1487. 87. Viswanathan N, Davis FC. Single prenatal injections of melatonin or the D1-dopamine agonist SKF 38393 to pregnant hamsters sets the offsprings circadian rhythms to phases. 180 degrees apart. J Comp Physiol A. 1997;180:339-346. 88. Liu C, Weaver DR, Jin X, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 1997;19:91-102. 89. Hunt AE, Al-Ghoul WM, Gillette MU, Dubocovich ML. Activation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am J Physiol. 2001;280:C110-C118. 90. van den Top M, Buijs RM, Ruijter M, Delagrange P, Spanswick D, Hermes MLHJ. Melatonin generates an outward potassium current in rat suprachiasmatic nucleus neurons in vitro independent of their circadian rhythm. Neuroscience. 2001;107:99-108. 91. Slotten HA, Pitrosky B, Pvet P. Entrainment of rat circadian rhythms by melatonin does not depend on the serotonergic afferents to the suprachiasmatic nuclei. Brain Res. 2000;876:10-16. 92. Pvet P, Bothorel B, Slotten H, Saboureau M. The chronobiotic properties of melatonin. Cell Tissue Res. 2002;309:183-191.
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Light treatment of mood disorders
Barbara L. Parry, MD; Eva L. Maurer, BS
Initial studies
In 1981, seven patients with nonseasonal depression were treated with bright white light. In 1982, bright artificial light was used to treat a manic-depressive patient with a seasonal mood cycle. In the last 20 years, a plethora of studies have further defined the depressive populations, who are responsive to light treatment; the optimal timing, intensity, spectral frequency, and duration of treatment; its comparison with other pharmacological interventions; predictors of response; side-effect profiles; viable placebo-control conditions; alternative devices and forms of administration; potential mechanisms and anatomical pathways mediating lights physiological effects; and its application to other disorders and subsyndromal states. These studies have been conducted across multiple countries with surprisingly consistent results. Further work is needed, as highlighted in this review, to clarify the specific mechanism of action in subtypes of depressive disorders and differential age and gender effects. Although the majority of work in this area is relatively new, it behooves the reader to remember that Solomon, almost 3000 years ago, wrote in Ecclesiastes: Truly the light is sweet and a pleasant thing it is for the eyes to behold the sun (11:7).
Keywords: light treatment; phototherapy; mood disorder; depression; seasonal affective disorder Author affiliations: Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, Calif, USA Address for correspondence: Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA (e-mail: bparry@ucsd.edu) Copyright 2003 LLS SAS. All rights reserved
n 1981, Kripke1 exposed seven nonseasonally depressed patients to bright white light shortly before their usual time of arising. Depression scores were reduced on the following day. In a subsequent study,2 5 new subjects were added, for a total of 12 subjects, including 11 males with major depressive disorder (MDD) (3 with bipolar illness) according to research diagnostic criteria (RDC),3 who were on an inpatient psychiatric research ward. In counterbalanced order, the investigators administered either bright white light (1000 to 2000 lux) or dim red light (less than 25 lux) for 1 h, 2 h before the subjects usual time of arising. The bright white light treatment produced significantly lower depression scores on both the Hamilton4 and Beck5 ratings as compared with baseline. A follow-up pilot experiment of 12 depressed inpatients6 showed that there was no indication that 1 h awakening with exposure to dim red light (25 lux) had any antidepressant effect. After demonstrating that sunlight and bright artificial light could suppress human melatonin secretion, Lewy et al7 reported on a patient with a bipolar II seasonal mood cycle whose winter depression remitted when his hours of daylight were lengthened with bright fluorescent light (Vital-Lite) of 2000 lux between his time of awakening (6.00 AM) and 9.00 AM, and between 4.00 PM and 7.00 PM, thereby extending his daylength (photoperiod) to 13 h (a spring photoperiod). During light exposure, melatonin levels declined by 88% between 1.00 and 5.00 AM. Winter depression has been found to improve when patients are exposed to bright full-spectrum light before dawn and after dusk, thereby extending the photoperiod.8,9 Bright light consisted of 2500 lux of full-spectrum light; dim light was 300 lux. Light was administered from 5.00 AM to 8.00 AM, and 5.30 PM to 8.30 PM every day. Bright light had a marked antidepressant effect, whereas
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dim light did not. The response could not be attributed to sleep deprivation. Thus, the initial studies of light treatment appeared promising, but many questions remained concerning the optimal timing and intensity of treatment intervention. increased response rates in SAD after 2 weeks rather than 1 week of light treatment: 15% of nonresponders at week 1 responded after week 2 of treatment. Byerley et al22 found that, in 3 patients with SAD treated with 2 h of morning light exposure, remission of symptoms within 2 to 5 days was sustained during the 2-month treatment period. With regard to daily duration of treatment, 2 h, but not 0.5 h, morning white light was an effective treatment for SAD.23 Doghramji et al24 reported that 2 h of evening light was as effective as 4 h in SAD. As WirzJustice et al25 commented, in patients who may be supersensitive to light, 1 h of 2500 lux may be the minimum light exposure necessary to maintain an antidepressant effect in SAD. Spectral frequency Oren et al26 compared green light and red light, and found that green light induced greater antidepressant effects than red light. Stewart et al,27 however, observed that white light was more effective than green light in reducing endogenous symptoms, but not the atypical symptoms characteristic of winter depression. Other workers28 reported that ultraviolet (UV) light reduced depressive symptoms, but that UV-blocked light reduced only atypical depressive symptoms. Bielski et al29 reported that both broad-spectrum fluorescent light and cool white light were equally effective in reducing SAD symptoms of depression. Brainard et al30 found that white light had greater benefit than red or blue light in SAD. Levitt et al31 studied dim versus bright red (light-emitting diode) light, and found there was no significant difference in response rates between the two different illuminances of red light for SAD. Alternative techniques: dawn simulation Bright (1700 lux) dawn simulation (4.00-6.00 AM) was not effective in reducing depression scores in seven patients with winter depression compared with a standard bright (1700 lux) morning (6.00-8.00 AM) light treatment and contributed to early morning awakening (EMA).32 In comparing a gradual dawn signal with a hypothesized placebo condition, a rapid dawn signal, Avery et al33 found that improvement was similar for both treatments, but that EMA was more common with the gradual dawn condition. In a follow-up study34 of 22 patients with winter depression, 1 week of treatment with 2-h dawn simu-
Methodological issues
Morning versus evening light Wehr et al10 found that time of day and suppression of melatonin were not critical for antidepressant effects of phototherapy, indicating that photoperiodic mechanisms were not mediating the efficacy of therapeutic response. A review of efficacy using a pooled clustering technique for light therapy of seasonal affective disorder (SAD)11 reported that 2500-lux intensity light exposure for 2 h daily for 1 week resulted in significantly more remissions when administered in the early morning (53%) than in the evening (38%) or at midday (32%). All three times were significantly more effective than dim light controls (11%). Exposure to morning plus evening light provided no benefit over morning light alone. In support of the phase-shift hypothesis for winter depression, two groups12,13 found that morning bright light phaseadvanced the dim-light melatonin onset (DLMO) and was more antidepressant than evening light, which phasedelayed it. The DLMO generally was delayed in the patients with winter depression compared with the healthy control subjects. Avery et al14 also found that improvement was significantly greater with morning light than with evening light in 7 patients with winter depression treated with 7 days of bright light for 2 h daily. Other workers,15-17 however, found that either morning or evening light therapy improved depressive symptoms in patients with SAD, suggesting that more practical and flexible schedules for light therapy are appropriate for SAD, since time of day is not crucial. As Wirz-Justice and Anderson noted,18 prior morning light treatment may prevent an evening light response, and it may potentiate responses to subsequent morning light. Duration of response and treatment The efficacy of treatment of patients with SAD lasts longer after withdrawal with bright light (>2000 lux) than with dim light (<300 lux).19,20 Labbate et al21 reported
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Light treatment of mood disorders - Parry and Maurer
lation peaking at 250 lux resulted in significantly lower depression scores than 1 week of treatment with a 30-min dawn simulation peaking at 0.2 lux. Norden and Avery35 also demonstrated that a slow dawn (a gradually increasing illuminance over 45 min peaking at 100 lux) was better than a rapid dawn (light rapidly increasing over a 4-s period to 100 lux) in 16 patients with subsyndromal winter depression. In a second controlled study of dawn simulation of winter depression, Avery et al36 showed that 1.5 h of 250 lux dawn simulation with while light resulted in lower depression scores than 1.5 h of a 2 lux, red dawn signal. Linjaerde et al37 found that symptoms of winter depression improved 57% with lightbox treatment of 1500 to 2500 lux for 2 h in the morning for 6 days compared with 40% for dawn simulation of 60 to 90 min with 100 to 300 lux for 2 weeks. A controlled study of 95 subjects with SAD38 found that dawn simulation (1.5-h dawn signal from 4.30-6.00 AM peaking at 250 lux), but not bright light treatment (10 000 lux for 30 min from 6.006.30 AM), was associated with greater remission rates than placebo (dim red light, 1.5-h dawn signal from 4.306.00 AM peaking at 0.5 lux). Light visor Stewart et al39 reported that a portable, head-mounted unit (HMU) was as efficacious as a standard lightbox for the treatment of winter depression. In a study of 105 subjects across five centers,40 three intensities of a light visor (60, 600, and 3500 lux) for 2 weeks had equal antidepressant efficacy in SAD. Teicher et al41 found no significant differences in therapeutic response between patients with SAD who were treated with a dim (30 lux) red light or a bright (600 lux) white light visor. In a controlled comparison of a lightbox and a HMU in SAD,42 there was no significant difference in response rates between patients with SAD who received 2 weeks of light versus patients who received no visible light by an HMU, or between patients who received the lightbox versus the HMU. Summary The majority of studies support the beneficial effects of particularly morning light in SAD for 2 h with at least 2500 lux. UV light is not required for response. Dawn stimulation is an effective alternative, although the light visor is not.
Clinical phenomenology
Effects of latitude In Iceland, Magnusson and Kristbjarnarson43 found that 10 000-lux white light was more effective than 400-lux red light for 40 min for 8 days for treatment of SAD: patients who improved most on phototherapy also improved most during summer. In Norway, Lingjaerde et al44 reported that patients with SAD, after treatment with 1500-lux white full-spectrum light for 2 h in the morning for 6 days, had a 48% reduction in symptoms compared with a 56% reduction of patients receiving light and drug treatment. Improvement at 1 week was maintained for the rest of the season. In a follow-up study of SAD in Switzerland, Graw et al45 observed that 2 to 5 years after participation in a light therapy trial, 64% of the patients had a reduction in the incidence and severity of depressive episodes and the use of antidepressant drugs. In a study of light therapy for SAD in adolescents in Iceland,46 light therapy mildly improved the ability to concentrate and wake up in the morning in some students, but did not improve school attendance. Predictors of response Lam47 reported that hypersomnia, hyperphagia, and younger age predicted morning light therapy response in winter depression. Terman et al48 observed that, in 103 subjects with winter depression given light treatment, responders were characterized by atypical symptoms, especially hypersomnia, afternoon or evening slump, reverse diurnal variation (evening worse), and carbohydrate craving. Nonresponders were characterized mainly by melancholic symptoms. A follow-up study of 59 patients with winter SAD at the National Institute of Mental Health49 found that 42% remained purely seasonal. The occurrence of nonseasonal depression in 44% of patients was associated with greater severity of illness and less responsiveness to light treatment. There is a greater improvement in mood in summer than with light treatment in winter in patients with SAD.50 In metaanalysis of dose-response relationships of phototherapy for SAD,51 no significant effects between strong, medium, and dim light in reducing atypical symptoms of depression were found, but light intensity varied positively with the antidepressant effects for typical symp-
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toms. Levitt et al52 found that response rates were similar in SAD and subsyndromal SAD with morning bright light therapy of 5000 lux for 3 weeks. Longer exposure of 45 to 60 min daily tended to be associated with better outcome. In examining the effects of light therapy on suicidal ideation, Lam et al53 found that 67% of patients with winter depression were clinical responders: 45% of patients showed a reduction in the suicide item score on the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders Version (SIGH-SAD).54 Prevention Meesters et al55,56 observed that administration of light treatment at the first signs of a winter depression prevented it from developing into a full-blown depression. When light exposure was administered at a symptomfree period at the beginning of autumn, however, it was not successful in preventing the development of winter depression.57 Partonen and Lonnqvist,58 in contrast, did find that bright light given well in advance of the emerging symptoms of winter SAD prevented a depressive episode. Effects on hypersomnia Hypersomnia has been associated with a superior response to morning light.59 In an open study design, Lam et al60 found that patients with winter depression who had hypersomnia had greater improvement, particularly in atypical depression symptoms than patients with insomnia. Evening subjective sleepiness improves with morning light, even a short 15-min exposure, in patients with winter depression.61 Comparison with antidepressant medication Wirz-Justice et al62 described a woman with SAD who, after remitting within a week in each of 6 separate trials of light therapy, remitted within 2 weeks of initiating citalopram, despite the delayed sleep and intermittent awakening induced with citalopram, but not with light therapy. Ruhrmann et al63 found that 70% of 40 SAD patients treated with bright light (3000 lux 2 h daily) were responders compared with 65% treated with fluoxetine (20 mg daily for 5 weeks). Light treatment improved depression scores faster, while fluoxetine had a faster effect on atypical symptoms. In 13 SAD patients, Ghadirian et al64 compared light therapy for 2 weeks or tryptophan for 4 weeks in an open repeated-measures design. Tryptophan was equally effective to light therapy in treating SAD, but relapse after withdrawal of tryptophan occurred more slowly. Improvement of atypical depressive symptoms after 1 h of light therapy positively correlated with improvement after 2 weeks of therapy.65 Comparison with natural light Eastman66 documented that the perceived sunlight exposure in SAD patients in Chicago was twice as much in summer than in winter: the perceived daylength was 4 to 5 h longer in summer than in winter, with a later perceived dusk contributing more to the lengthening than an earlier perceived dawn. Wirz-Justice et al67 observed that 50% of patients with SAD remitted after a daily 1-h morning walk outdoors in natural light, which phase-advanced the onset and/or offset of salivary melatonin secretion, and decreased morning cortisol compared with low-dose artificial light, which did not modify depression self-ratings, or melatonin or cortisol patterns. The effects of bright light treatment (2500 lux) on subsyndromal SAD in the workplace have been studied,68 and both morning and afternoon exposure resulted in similar levels of improvement in mood, energy, alertness, and productivity. Side effects Terman et al69 reviewed the ocular effects of particularly the more recent treatment approach of using approximately 10 000 lux light exposure for 30 min. Although ophthamological examinations have thus far revealed no induced abnormalities, precaution is warranted with use of photosensitizing antidepressant drugs that may enhance UV and visible-lightinduced lesions. Bauer et al70 observed the induction of hypomania in winter depressives treated with 4 weeks of light treatment. Seasonalitybut not diagnosis of major depression, bipolar disorder with seasonal pattern, or control subjectpredicted the emergence of manic symptoms. The influence of comorbid and other disorders Stewart et al71 questioned whether SAD and atypical depression might be subtypes of the same disorder.
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Bright artificial light (2500 lux, 6.00-8.00 AM and 6.008.00 PM), however, was less effective in treating patients with atypical depression than with SAD, suggesting that the two disorders are separate with a different underlying pathophysiology. Partonen and Lonnqvist72 observed that in patients with comorbid personality disorder, the remission rate with light treatment was similar to that of patients with recurrent winter depression, although there was a more variable course and an increased risk of an earlier onset of a depressive episode. A controlled trial in 28 children (aged 7-17 years)73 investigated the efficacy of light therapy for the treatment of pediatric SAD. In a primary care setting,74 patients with SAD improved after light therapy, but bright white versus dim red light was not associated with greater improvement. Response to placebo Eastman et al75 observed that 32 patients with SAD responded equally to 1 h of morning light (7000 lux) and 1 h of morning placebo treatment (a deactivated negative ion generator). Richter et al,76 comparing exposure to real bright light and placebo bright light perceived through hypnosis, concluded that the findings did not support the hypothesis that the long-term results of light treatment in SAD were merely placebo effects. Terman and Terman77 reported that 58% of patients with SAD responded to high-density negative ionizer treatment, whereas 15% responded to low-density ion generator treatment. A placebo-controlled trial of bright (6000 lux) morning light, bright evening light, or morning placebo (a sham negative ion generator) for 1.5 h daily for 4 weeks,78 found that by using strict response criteria from the SIGH-SAD54 (50% decrease of baseline and 8), 61% of SAD patients responded to morning light, 50% to evening light, and 32% to placebo; however, there was no significant benefit on mean Hamilton depression rating scores. A controlled trial of timed bright light and negative air ionization (6 groups) in 158 patients with winter depression,79 reported that low-density ion response was inferior to all other groups, that evening light response was reduced when preceded by treatment with morning light, and when stringent remission criteria were used, a higher response rate to morning than evening light. In summary, SAD patients, in particular, are responsive to light treatment. Carbohydrate craving and hyper-
somnia are predictors of response. Acute intervention is more efficacious than prophylactic treatment. Light administration is as effective as antidepressant treatment or natural light exposure. Side effects are minimal, with the exception of the induction of mania in bipolar patients, and there may be significant placebo effects.
Light treatment of nonseasonal mood disorders

Major depressive disorder In an open trial with unmatched patient groups, Yerevanian et al80 found that 1 to 2 weeks of light treatment with 2000 lux was effective in reducing depressive symptoms in seasonal, but not nonseasonal patients, whose functioning was more impaired (by unpaired t tests). Although the patient groups were unmatched, in a comparison of bright white light (2500 lux) and dim light (50 lux) from approximately 7.00 to 9.00 AM for 7 days in up to 42 patients who met RDC for nonseasonal MDD, other workers81-83 observed a significant reduction in depressive symptomatology in all patients, but the difference between bright and dim light was not significant. In a 10-day study of morning (6.00-8.00 AM) or evening (6.00-8.00 PM) bright (1500 lux) light room treatment of 90 patients with either seasonal or nonseasonal MDD,84 patients with seasonal pattern improved significantly more than those with a nonseasonal pattern, irrespective of time of treatment, atypical symptoms, or carbohydrate craving. Yamada et al85 administered bright or dim light in the morning or evening to 27 unmedicated patients with nonseasonal depression by Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R)86 criteria and found that bright, but not dim, light significantly improved clinical symptoms of depression, independent of the time of treatment. The circadian rhythm of body temperature was more sensitive to the entraining effects of bright light in depressed versus normal control subjects, but was not related to clinical improvement. In a reassessment of the speed, efficacy, and combined treatment effects for nonseasonal depression, Kripke87 observed that light treatment produced net benefits in the range of 12% to 35% often within a week, and that the effects for nonseasonal and seasonal depression were comparable and produced faster antidepressant benefits than psychopharmacological treatment.
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Inpatient studies In the setting of a psychiatric hospital, Wirz-Justice et al88 reported that 61% of 37 nonmedicated patients with major depression responded to light treatment in a 10day open trial using ceiling lights of 3000 lux either for 8 h (5.00-9.00 AM and 4.00-8.00 PM) or 4 h only (5.00-9.00 AM). Results of pilot data using 2 h of 10 000 lux light also suggested that further controlled trials were warranted in this population. In a controlled trial of hospitalized veterans with nonseasonal MDD or depressed forms of bipolar disorder, Kripke et al89 found that the 25 patients treated with bright white light (2000-3000 lux) improved in measures of depression compared with the 26 patients randomized to dim red light placebo-control treatment. Two patients treated with bright white light became hypomanic. Partial relapse appeared within 2 days. Patients treated in winter responded as well as those treated in summer. Beauchemin and Hays90 observed that in a psychiatric inpatient unit, depressed patients in sunny rooms had a significantly shorter hospital stay than those in dull rooms. In a follow-up study,91 they randomly assigned depressed inpatients to high and low levels of artificial light and found that both unipolar and bipolar depressed patients responded more to bright than dim light when used as an adjunct to pharmacotherapy. Benedetti et al92 also found that length of hospitalization for 415 unipolar and 187 bipolar depressed inpatients was reduced in bipolar patients in eastern rooms exposed to direct sunlight in the morning compared with western rooms. No effect was found in unipolar inpatients. In a placebo-controlled, crossover study of bright light treatment of depression in institutionalized older adults, Sumaya et al93 found that 50% of patients were no longer in the depressed range after 1 week treatment with 10 000 lux, but their depression scores were unchanged after placebo (300 lux) or control (no treatment) conditions. Patients with higher depression scores, associated with longer duration of institutionalization, experienced the greatest improvement with the 10 000 lux treatment. Interaction with medication and other antidepressant treatment Levitt et al94 administered a 2-week course of bright light therapy to 10 patients who presented during the winter months with major depression and who had failed an adequate trial of antidepressants, or who had relapsed following a successful course of antidepressants and found that augmentation with bright lights resulted in substantial improvement in 7 of the 10 patients. Holsboer-Trachsler et al95 reported that adjunctive treatment with bright light or sleep deprivation did not hasten the onset of antidepressant action of the antidepressant trimipramine, but the groups were not balanced on baseline prognostic factors. Neumeister et al96 administered bright (3000 lux) or dim (100 lux) light for 6 days to depressed patients from the morning after they underwent partial sleep deprivation (PSD) treatment. In responders to PSD, bright light therapy prevented the relapse after the next night of sleep and significantly prolonged the antidepressant effects of PSD up to 7 days. Patients treated with dim light relapsed after a recovery night of sleep and showed no further improvement of their depressive symptoms after 1 week of dim light treatment. PSD nonresponders did not benefit from light treatment. Muller et al97 found that the side effects of adjunct bright light therapy as compared with antidepressant (trimipramine) monotherapy included aggravated sedation, restlessness, sleep disturbance, decreased appetite, and vertigo. Prasko et al98 treated inpatients with recurrent nonseasonal depression with (i) bright light (5000 lux from 6.00-8.00 AM) and impramine 150 mg/day; (ii) bright light and placebo; or (iii) dim red light (500 lux from 6.00-8.00 AM) and imipramine 150 mg/day. Patients in all 3 groups improved significantly, but the improvement of patients with bright light plus placebo was nonsignificantly superior to the other two groups. Loving et al99 found that in 13 patients with MDD who underwent a half night of home wake therapy (sleep deprivation), those who subsequently received 10 000 lux bright white light for 30 min between 6.00 and 9.00 AM improved 27% in 1 week, compared with those receiving dim red (placebo) light at a comparable time. Bipolar illness The effects of 2 weeks of bright light and 1 week of dim light were investigated in patients with bipolar II SAD versus controls100 and bright light was found to reduce or eliminate all group differences and variability in behavioral engagement, a mood dimension specifically associated with depression. Papatheodorou and Kutcher101 treated persistent depressive symptoms in adolescentonset bipolar disorder with adjunctive light therapy (10
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000 lux twice per day): out of 7 patients, 3 showed a marked (70%) decrease in symptoms, 2 had a moderate (40%) decrease, and 2 had mild to no response. In 2 patients with bipolar disorder and 1 with recurrent MDD, Praschak-Rieder et al102 observed that within the first week after beginning bright light therapy, 2 subjects attempted suicide and the third patient developed suicidal thoughts that were so acute and overwhelming that the light therapy had to be discontinued. In a patient with rapid-cycling bipolar illness, Wirz-Justice et al103 found that extending the dark/rest period to 14 h (plus a 1-h midday nap) immediately stopped the rapid cycling and when midday, then morning light therapy was added, depression gradually improved achieving neareuthymia. In 115 bipolar depressed inpatients treated with total sleep deprivation,104 morning light therapy (150 or 2500 lux) and ongoing lithium treatment significantly enhanced and sustained the effects of total sleep deprivation on mood, with no additional benefit when the two treatments were combined. Womens mood disorders The efficacy of light treatment has been studied in women with premenstrual (late luteal phase) dysphoric disorder.105-108 In an open trial of morning light therapy for treatment of antepartum depression, Oren et al109 observed that, after 3 weeks of treatment, mean depression ratings improved by 49%. Benefits were seen through 5 weeks of treatment and there was no evidence of adverse effects of light therapy on pregnancy. In two patients with postpartum depression,110 there was a 75% reduction in depressive symptoms with light therapy. In summary, the emerging evidence suggests the potential efficacy of light treatment in MDD, in inpatients and outpatients, and in womens mood disorders. Light treatment may also enhance the efficacy of other antidepressant modalities.
tiated by early-morning administration in circadian time, optimally about 8.5 h after melatonin onset or 2.5 h after the sleep midpoint, suggesting the importance of phase relationships in treatment response. Melatonin Terman et al113 proposed that early morning and evening light exposure impacted a photosensitive interval in SAD patients, in which melatonin secretion overshoots its normal nocturnal phase. Despite equal suppression of plasma melatonin levels, altered timing of light treatments has differential effects on mood.114 Danilenko et al115 found that daytime (12 noon and 4.00 PM) serum melatonin levels were higher in women with SAD compared with controls in winter; this difference disappeared in the summer and after light treatment in the winter. Light treatment and change in season also resulted in a phase-advance shift of melatonin in the SAD patients, associated with a decline in symptoms of hyperphagia and carbohydrate craving. Partonen116 hypothesized that the induction of arousing stimuli mediated by effects of melatonin and the blockade of serotonin uptake mechanisms in the suprachiasmatic nucleus is necessary for the antidepressant effects of light in SAD. In patients with SAD who underwent light treatment with full-spectrum or cool white light,117 both treatments reduced depression scores, advanced the timing of the salivary melatonin rhythm (in both responders and nonresponders), and increased its concentration. In light treatment of patients with seasonal and nonseasonal depression, melatonin amplitude was decreased by light and its phase position was advanced by morning light and delayed by evening light, but therapeutic outcome was not related to baseline melatonin phase position, the degree of light suppression of melatonin or the rebound effect of serum melatonin levels following bright light exposure.118 Serotonin A study of patients with nonseasonal depression and healthy subjects119,120 found that both bright as well as dim light augmented blood serotonin throughout the day. The influence of light was more pronounced on serotonin than on melatonin metabolism. Mellerup et al121 examined platelet paroxetine binding as an indirect measure of the effect of light therapy on serotonin
Proposed mechanisms
Circadian timing Lewy et al111 proposed that the timing of bright light is critical for its antidepressant effect in SAD: the mechanism was related to a phase-advance of circadian rhythms that corrected a pathogenic phase-delay. Terman et al112 found that the antidepressant effect of light in SAD was poten-
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uptake capacity in patients with winter depression. They found that in responders, but not in nonresponders, platelet serotonin transporters decreased significantly following treatment. An extended study of the serotonergic agent meta-chlorophenylpiperazine (m-CPP)122 replicated the finding that m-CPPinduced activationeuphoria responses in untreated depressed patients with SAD, reflecting a state marker for the illness. This study also showed blunted corticotropin and norepinephrine responses to m-CPP, suggesting trait abnormalities. Mood improvement after light treatment was associated with lowering of nocturnal core temperatures, compatible with deficient serotonin transmission during winter depression. In a study of platelet serotonergic functions in SAD, Stain-Malmgren et al123 found that responders to light therapy had higher Km and lower Bmax for paroxetine binding than nonresponders, suggesting abnormalities in the serotonin uptake mechanism with enhanced serotonin 5-HT2 receptor density that may reflect an upregulation. Effects of tryptophan depletion Rapid tryptophan depletion reverses the antidepressant effect of bright light therapy in patients with SAD,124,125 suggesting that the therapeutic effects of bright light in this disorder may involve a serotonergic mechanism. Neumeister et al126 also demonstrated that catecholamine depletion reversed the beneficial effects of light therapy, suggesting that brain catecholaminergic systems may also be involved. Other neurotransmitters In studies of platelet [3H]imipramine binding in patients with or without SAD, and healthy controls, Szadoczky et al127,128 observed that, after incandescent light treatment, Bmax values increased in SAD patients parallel with clinical improvement. In patients with SAD, light therapy produced a decrease in the urinary output of norepinephrine and its metabolites in association with significant decreases in depression ratings.129 In contrast, Rudorfer et al130 measured cerebrospinal fluid concentrations of the principal metabolites of norepinephrine, serotonin, and dopamine and did not find differences between SAD and healthy controls. Neither the transmitter measures nor their interrelatedness was affected by phototherapy. Endocrine function On the basis of observed low serum prolactin concentration in women with winter depression that was independent of season and bright light treatment, Partonen131 hypothesized a role for estrogen and serotonergic function in SAD. Normal thyroid function in SAD does not alter with light treatment.132 Serum cortisol does not differ between SAD and non-SAD patients, and no significant changes were seen as a result of light treatment, although melatonin appears to serve as a coordinating hormone transducing light information for the phase position of cortisol.133 Partonen134 also hypothesized that bright light, by normalizing increased corticotropin-releasing factor (CRF) activity in the evening in SAD, might thereby normalize subjective sleepiness via its effects on neurons of the paraventricular nucleus of the hypothalamus. In studies of growth hormone (GH),Yatham et al135 reported that GH responses to sumatriptan (a 5-HT1D receptor agonist) were significantly blunted during winter depression in SAD patients compared with healthy controls and were normalized following light treatment.These findings suggest a role for the serotonergic system in the mechanism of action of light therapy. In contrast, Shiah et al136 found that GH response to the -aminobutyric acid (GABA)B receptor agonist, baclofen, was not altered in SAD or by light therapy. On the basis of evidence that heme moieties and bile pigments in plants and animals mediate some of the nonvisual influences of light on biological rhythms, Oren137 hypothesized that bilirubin, which is a proposed photoreceptor given its similarity to the chromophore of phytochrome (a primary time-setting plant molecule), plays an evolutionary role in the regulation of rapid-eye movement (REM) sleep and in mediating some of the antidepressant effects of light. He and his colleagues138 found that nocturnal bilirubin levels were lower in patients with winter depression compared with controls, and that levels increased in both groups during the night and increased in patients after 2 weeks of morning light treatment that improved mood. Sleep, hemispheric, and EEG changes Bright light shortens sleep onset, decreases number of awakenings, increases REM latency, attenuates REM length, and improves morning alertness in patients with MDD.139 In SAD patients, Partonen et al140 found no sleep electroencephalographic (EEG) changes after
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treatment with bright light, although morning sleepiness was reduced. SAD patients have the expected pattern of EEG frontal asymmetry when depressed and following light-induced remission, although right hemisphere coherence is a state-dependent indicator of seasonal depression.141 Winter depression is associated with a shift of laterality from the left to the right that was normalized by bright light treatment.142 Brunner et al143 documented normal homeostatic sleep regulation in SAD; although sleep EEG spectra in SAD, but not controls, showed modifications resembling those of recovery sleep after light treatment (perhaps reflecting sleep curtailment), the authors concluded that the effects of light treatment in SAD were unlikely to be mediated by changes in sleep. A positive response to total sleep deprivation in major depression is predictive of a beneficial outcome of subsequent light therapy.144 Temperature regulation In a review of the neurobiological effects of artificial bright light, Dilsaver145 reported that, based on measures of core temperature, bright light subsensitizes muscarinic and nicotinic mechanisms. Although temperature curves between SAD and controls were similar, light treatment enhanced the amplitude of the core body temperature rhythm in SAD patients during winter.146 There were no abnormalities in the baseline phase or amplitude of the temperature rhythm in SAD patients versus controls,147 and antidepressant responses to light treatment were unrelated to changes in the temperature rhythm. In constant routine conditions, Avery et al148 documented a phase-delay of temperature and cortisol rhythms in hypersomnic winter depression that phase-advanced with bright light treatment. Schwartz et al149 observed that core temperature minima were lower during the extended photoperiod of summer compared with winter in SAD patients, but not controls. In studying the oscillations of facial skin and core temperatures in relation to slowwave activity during sleep, Schwartz et al150 found that brain cooling activity, which oscillates in an ultradian manner during sleep, is reduced during winter depression, providing support for the hypothesis that brain temperatures are elevated during winter depression.
Functional anatomic and retinal sensitivity factors Seggie et al151 observed that antidepressant medication (sinuequan) reversed the increased sensitivity to light in depression. Terman and Terman152 reported heightened retinal sensitivity with increased light exposure and supersensitivity of SAD patients relative to controls in winter. UVA-spectrum light did not increase the antidepressant response153 and illumination applied in the upper visual field was most effective.154 An increase in cerebral blood flow is associated with recovery following light treatment for SAD.155 Other Patients with non-SAD major depression show a more pronounced light-associated increment of parasympathetically controlled cardiac functions compared with other depressed patients and controls.156 Light therapy normalizes transducin (G1 protein) levels observed to be reduced in winter depression.157 No effects of light therapy were noted on basal glucagon levels in SAD and comparison subjects.158 Immune-inflammatory markers are increased in SAD patients but are not altered by successful light therapy.159 In summary, the proposed mechanisms for light treatment primarily involve effects on the circadian timing system, melatonin, serotonin, and temperature regulation.
Conclusions
Light treatment is efficacious for SAD (winter-type) and an increasing database suggests that it has beneficial effects in nonseasonal depression as well. In toto, bright light (>2500 lux) results in greater improvement than dim light; morning light of at least 3 to 4 days duration results in more responders than evening light in SAD; UV-spectrum wavelengths are not required for antidepressant effects; and dawn-stimulation is an effective alternative. Light visors, in contrast, are not efficacious. Carbohydrate craving is a predictor of response and there are minimal side effects with the exception of the risk of inducing mania in bipolar patients. Further investigation is warranted with respect to light treatments mechanism of action.
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Fototerapia de los trastornos afectivos
En 1981 siete pacientes con depresin no estacional fueron tratados con luz blanca brillante. En 1982 se utiliz luz artificial brillante para tratar a un paciente manaco-depresivo con un ciclo de nimo estacional. En los ltimos 20 aos gran cantidad de estudios han permitido definir con mayor precisin, adems de las poblaciones de pacientes depresivos que responden a la fototerapia, el momento ptimo de la aplicacin, la intensidad, la frecuencia del espectro y la duracin del tratamiento. Tambin se la ha comparado con otras intervenciones farmacolgicas, se han estudiado los predictores de respuesta, el perfil de efectos colaterales, el uso de placebos adecuados a estos estudios, diversos aparatos y formas de administracin, potenciales mecanismos y vas anatmicas que median los efectos farmacolgicos de la luz y su aplicacin a otros trastornos y estados subsindromticos. Estos estudios se han realizado en varios pases con resultados sorprendentemente constantes. Se requiere de futuros trabajos, como se destaca en esta revisin, para aclarar el mecanismo de accin especfico en subtipos de trastornos depresivos y diferenciar efectos segn edad y sexo. Aunque la mayor parte del trabajo en esta rea es relativamente nuevo, le corresponde al lector recordar que Salomn, hace casi 3000 aos, escribi en el Eclesiasts (11:7) Verdaderamente la luz es dulce y es algo placentero para los ojos contemplar el sol.
Luminothrapie des troubles de lhumeur

En 1981, sept patients atteints de dpression non saisonnire ont t traits par lumire blanche intense. En 1982, la lumire artificielle intense a t utilise pour traiter un patient maniacodpressif souffrant dun trouble cyclothymique saisonnier. Durant ces 20 dernires annes, une plthore dtudes ont mieux identifi les populations dpressives sensibles la luminothrapie ; le rythme optimal du traitement, son intensit, sa frquence spectrale et sa dure ; sa comparaison avec dautres types de traitement ; les facteurs prdictifs de rponse ; les effets secondaires ; les conditions placebo/tmoin adaptes ; les techniques alternatives et les diffrentes mthodes dadministration ; les voies anatomiques et les mcanismes potentiels vhiculant les effets physiologiques de la lumire ; et ses applications aux autres troubles et tats sous-syndromiques. Ces tudes ont t conduites dans de nombreux pays, la concordance des rsultats tant tout fait surprenante. Comme le souligne cet article, dautres travaux sont ncessaires afin de clarifier les mcanismes daction spcifiques dans les sous-types de troubles dpressifs et linfluence de lge et du sexe. Bien que la majorit des travaux dans ce domaine soit relativement rcente, il incombe au lecteur de se souvenir de ce que Salomon, il y a presque 3 000 ans, crivit dans lEcclsiaste (XI, 7) : Douce est la lumire et il plat aux yeux de voir le soleil .
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Posters & images in neuroscience

Sleep deprivation and antidepressant treatment
The mood-improving effect of sleep deprivation (SD) in depression is even today still not fully understood. Despite the fact that mood and cognitive functions are lowered by prolonged sleep loss and despite convincing data that insomnia is a strong risk factor for subsequent depression,1 acute SD for one night or even partial SD in the second half of the night improves mood in about 60% of depressed patients the day after.2,3 In this respect, among all types of antidepressant treatments, SD elicits the fastest results, faster even than electroconvulsive therapy. Many authors correlate the likelihood of responding to SD with clinical variables. A summary of predictors is listed in Table I.
The main limitation is the transient nature of the effect, since the majoritybut not allof the improved patients experience a relapse after the next night of sleep.2 Despite the rapid effects and low risk of relevant side effects (Table I),2-9 the method has remained an orphan drug or orphan method. This may be explained not only by the effort and motivation needed by the patient
Predictive High level of arousal4 High variability of mood swings5 Diurnal and day-to-day mood variations6 Endogenous and melancholic subtype2,3 Bipolar subtype7 Not predictive2,3 Age Sex Severity of depression Duration of depressive episode Duration of illness Earlier treatments Expectation of patients Side effects of SD in depression* Tiredness, fatigue Switch to hypomania or mania in bipolar patients8 Exacerbation of psychotic symptoms in psychotically depressed patients9 Lowering of seizure threshold Table I. Clinical predictors of an antidepressant response to sleep deprivation (SD) in depressed subjects and side effects. *Not based on systematic documentation.
Copyright 2003 LLS SAS. All rights reserved
and by the frequent relapses after the next night of sleep, but also by the lack of funding for nonpharmacological and nonneurochemical research. Nevertheless, some progress has been made within the last few years. A variety of studies have focused on the problem of how to avoid relapses occurring after the next night of sleep and additionally treated the patients with light therapy, lithium, or other drugs. Lower relapse rates after SD were found when SD was combined with one of these therapeutic options (Table II).10-20 A further strategy has been to advance the sleep period to an unphysiological time. Several uncontrolled studies in small numbers of patients have indicated that this phase advance procedure per se acts as an antidepressant. More recent studies have combined SD with a subsequent phase advance of the sleep period, over the course of either six or three nights and consistently found that a phase advance of the sleep period stabilizes the antidepressant effect of SD in about 60% of those patients who responded positively to SD.17-20 Only one study also included a control group which participated in a phase-delay protocol after SD instead of a phaseadvance protocol.18 Significantly more patients relapsed in the phase-delay protocol compared with the phase advance protocol (Figure 1). This indicates that the high
Antidepressants (clomipramine)10 Lithium11-13 Pindolol14 Light therapy15,16 Sleep phase advance over 3 to 6 nights17-20 Table II. Therapeutic strategies to avoid relapses after successful sleep deprivation in depression (selected papers).
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Poster by: Ulrich Voderholzer, MD, PhD Department of Psychiatry and Psychotherapy, Klinikum of the Albert-Ludwig-University, Hauptstrasse 5, 79104 Freiburg, Germany (Ulrich_Voderholzer@psyallg.ukl.uni-freiburg.de)
response rate after SD and phase advance cannot be explained by a placebo phenomenon alone and supports the hypothesis that, in depressed subjects, sleeping at certain phases of the circadian rhythm, ie, especially late in the night and in the morning, has depressogenic effects. Unfortunately, one major issue has been almost completely neglected by researchers: does SD produce any lasting effects after 4 to 6 weeks, which is the typical period for measuring the effects of antidepressants? There is only one controlled study using such a design.21 Twenty-four patients received amitriptyline without additional SD, whereas 27 patients received amitriptyline plus a series of 6 partial SDs. Observer ratings, but not patient ratings, demonstrated superiority of the combined treatment after 4 weeks. By the standards of evidence-based medicine, there is little evidence to date that SD therapy has lasting effects over the course of several weeks.
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Neurobiology of SD in depression
There is no generally accepted hypothesis concerning the mechanism of action of SD, nor an explanation for the observation that subsequent sleep after SD leads to relapses. A variety of neurobiological effects point toward potential mechanisms of action of the procedure (Table III).22-32 Based on the observations that hyperarousal and a high level of activation predict a favorable SD response,4 the antidepressant effect was explained using the two-process model of sleep regulation (Figure 2).33 In this model, depressed patients have a deficiency of process S (ie, sleep need) with process C (circadian rhythm) remaining unaffected. Depression is characterized by a deficient build-up of process S (Figure 2). SD transiently leads to an increase in process S to normal, whereas relapse occurs after recovery sleep due to a return to low levels of S. Several brain imaging studies have tried to correlate the SD response with metabolic states of certain brain areas. Two early studies using single photon emission computed tomography (SPECT)22 and positron emission tomography (PET),23 respectively, found higher metabolic rates in limbic areas in responders compared with nonresponders. A more recent study24 confirmed these earlier findings: responders to SD had higher relative metabolic rates in the ventral anterior cingulate and in the medial prefrontal cortex (Figure 3), as well as in the posterior subcallosal gyrus at baseline than depressed patients who did not respond to SD and normal volunteers. After SD,
Figure 1. Antidepressant effects of total sleep deprivation (TSD) in one night with a consecutive phase advance of the sleep period (blue circles) in comparison with a phase delay of the sleep period (gray circles). In the phase-advance group, the antidepressant effect of SD (between day 0 and day 1) was stabilized until day 8, whereas in the phase-delay group mood worsened again (mood was measured by a short version of the Hamilton Depression Rating Scale [HDRS], containing 6 items). This scale is suitable for frequent ratings, whereas the 21-item HDRS would not have been adequate within the study design.18 Decrease in limbic hypermetabolism22-24 Increase in dopamine turnover25 Increase in peripheral cytokines26,27 Increase in cortisol28-30 Increase in growth hormone secretion (recovery sleep)30 Increase in thyroid hormones31,32 Table III. Neurobiological effects of sleep deprivation. In humans some of the studies were performed in depressed patients, while other studies were in healthy subjects or in depressed patients and healthy subjects.
significant decreases in metabolic rates occurred in the medial prefrontal cortex and frontal pole in the patients who responded positively to SD. The brain imaging studies convincingly demonstrated that acute antidepressant SD is able to change metabolic states of brain areas that are involved in mood regulation. Many studies have assessed endocrine parameters before and after SD. The results have been inconsistent, which may be partially explained by methodological shortcomings. Several authors favor the hypothesis that the hypothalamo-pituitary-thyroid (HPT) axis plays a key role in mediating the antidepressant effects of SD.31,32
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Posters & images in neuroscience

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Another issue is the impact of SD on the hypothalamopituitary-adrenal (HPA) axis. Increased activity of this axis is one of the most consistent abnormalities in depression and normalization of this hyperactivity is a correlate of clinical remission and has been suggested as the mechanism of action of antidepressant treatment.34 In healthy humans, acute SD increases cortisol secretion.28,29 In a study that we conducted ourselves, we found a significant stimulatory effect of acute SD on nighttime cortisol in a group of unmedicated depressed subjects, which was not related to treatment response.30 However, during the first
Figure 2. Two-process model of sleep deprivation (SD) and depression . This model can explain the antidepressant effect of SD by assuming that an insufficient build-up of process S (S stands for sleep need), SD transiently increases the level of process S, thus, leading to the antidepressant effect. Recovery sleep decreases process S to baseline levels leading to relapse into the depressed state. This model fits well with clinical observations that depressed patients have hyperarousal, which has been shown to be a positive predictor of the SD response.4
Reproduced from reference 33: Borbly AA, Wirz-Justice A. Sleep, sleep deprivation and depression. Hum Neurobiol. 1982;1:205-210. Copyright 1982, Springer Verlag. 13. Szuba MP, Baxter LR Jr, Altshuler LL, et al. Lithium sustains the acute antidepressant effects of sleep deprivation: preliminary findings from a controlled study. Psychiatry Res. 1994;51:283-295. 14. Smeraldi E, Benedetti F, Barbini B, Campori E, Colombo C. Sustained antidepressant effect of sleep deprivation combined with pindolol in bipolar depression. A placebo-controlled trial. Neuropsychopharmacology. 1999;20:380-385. 15. Neumeister A, Goessler R, Lucht M, Kapitany T, Bamas C, Kasper S. Bright light therapy stabilizes the antidepressant effect of partial sleep deprivation. Biol Psychiatry. 1996;39:16-21. 16. Colombo C, Lucca A, Benedetti F, Barbini B, Campori E, Smeraldi E. Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: replication of main effects and interaction. Psychiatry Res. 2000;95:43-53. 17. Berger M, Vollmann J, Hohagen F, et al. Sleep deprivation combined with consecutive sleep phase advance as a fast-acting therapy in depression: an open pilot trial in medicated and unmedicated patients. Am J Psychiatry. 1997;154:870-872. 18. Riemann D, Knig A, Hohagen F, et al. How to preserve the antidepressant effect of sleep deprivation: a comparison of sleep phase advance and sleep phase delay. Eur Arch Psychiatry Clin Neurosci. 1999;249:231-237. 19. Benedetti F, Barbini B, Campori E, Fulgosi MC, Pontiggia A, Colombo C. Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model? J Psychiatr Res. 2001;35:323-329. 20. Voderholzer U, Valerius G, Schaerer L, et al. Is the antidepressive effect of sleep deprivation stabilized by a three day phase advance of the sleep period? A pilot study. Eur Arch Psychiatry Clin Neurosci. 2003;253:68-72. 21. Kuhs H, Frber D, Borgstdt S, Mrosek S, Tlle R. Amitriptyline in combination with repeated late sleep deprivation versus amitriptyline alone in major depression. A randomised study. J Affect Disord. 1996;37:31-41. 22. Ebert D, Feistel H, Barocka A. Effects of sleep deprivation on the limbic system and the frontal lobes in affective disorders: a study with Tc-99mHMPAO SPECT. Psychiatry Res. 1991;40:247-251. 23. Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr. Effect of sleep deprivation on brain metabolism of depressed patients. Am J Psychiatry. 1992;149:538-543.
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REFERENCES
1. Riemann D, Voderholzer U. Primary insomnia: a risk factor to develop depression? J Affect Disord. 2003;76:247-251. 2. Wu JC, Bunney WE. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry. 1990;147:14-21. 3. Van den Hoofdakker RH. Total sleep deprivation: clinical and theoretical aspects. In: Honig A, van Praag HM, eds. Depression: Neurobiological, Psychopathological and Therapeutic Advances. Chichester, UK: John Wiley & Sons Ltd; 1997:563-589. 4. Bouhuys AL, van den Burg W, van den Hoofdakker RH. The relationship between tiredness prior to sleep deprivation and the antidepressant response to sleep deprivation in depression. Biol Psychiatry. 1995;37:457-461. 5. Gordijn MC, Beersma DG, Bouhuys AL, Reinink E, Van den Hoofdakker RH. A longitudinal study of diurnal mood variation in depression; characteristics and significance. J Affect Disord. 1994;31:261-273. 6. Reinink E, Bouhuys N, Wirz-Justice A, van den Hoofdakker R. Prediction of the antidepressant response to total sleep deprivation by diurnal variation of mood. Psychiatry Res. 1990;32:113-124. 7. Barbini B, Colombo C, Benedetti F, Campori E, Bellodi L, Smeraldi E. The unipolar-bipolar dichotomy and the response to sleep deprivation. Psychiatry Res. 1998;79:43-50. 8. Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E. Rate of switch from depression into mania after therapeutic sleep deprivation in bipolar depression. Psychiatry Res. 1999;86:267-270. 9. Benedetti F, Zanardi R, Colombo C, Smeraldi E. Worsening of delusional depression after sleep deprivation: case reports. J Psychiatr Res. 1999;33:69-72. 10. Elsenga S, van den Hoofdakker RH. Clinical effects of sleep deprivation and clomipramine in endogenous depression. J Psychiatr Res. 1982/83;17:361-74. 11. Baxter LR Jr, Liston EH, Schwartz JM, et al. Prolongation of the antidepressant response to partial sleep deprivation by lithium. Psychiatry Res. 1986;19:17-23. 12. Grube M, Hartwich P. Maintenance of antidepressant effect of sleep deprivation with the help of lithium. Eur Arch Psychiat Neurol Sci. 1990;240:60-61.
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half of the day after the night, SD responders in contrast to nonresponders had higher cortisol concentrations compared with the day before SD. This finding does not necessarily contradict the above relationship between depression and HPA axis hyperactivity for two reasons. First, the acute effects of antidepressant treatments on the HPA axis may differ from the chronic effects. It has been shown that electroconvulsive treatment and antidepressants also initially stimulate the HPA axis. Second, two studies demonstrated acute antidepressant effects of cortisol infusion compared with placebo.35,36 Another theory that possibly provides a link to the HPA effects of SD focuses on the psychostimulant effects. Earlier studies reported an increase in dopamine, norepinephrine, and serotonin after SD, ie, similar neurobiological effects as after the intake of psychostimulants like amphetamines (see reference 25 for an overview). Support for a psycho-stimulant theory also comes from brain imaging data, demonstrating effects of psychostimulants such as amphetamines on metabolic rates similar to those observed in SD.37 Since there is a functional coupling of psychostimulant effects and the HPA axis,38 a cortisol increase following SD might therefore mediate psychostimulant-like actions of increased aminergic neurotransmitter release.
Z: -4.00 mm Percent difference +20.00 +13.33 +6.67 0.00 -6.67 -13.33 -20.00 % X -6 -3 0 +3 +6 -9.0 cm -6.0 0.0 -3.0 Y 6.0 3.0
Figure 3. Positron emission tomography (PET) scan of depressed patients who respond to total sleep deprivation (SD) in one night.24 At baseline, responders to SD had higher metabolic rates in the ventral anterior cingulate and in the medial prefrontal cortex. The study confirmed earlier findings demonstrating an association between high metabolic rates in limbic areas and the likelihood to respond to SD.22,23
Adapted from reference 24: Wu J, Buchsbaum MS, Gillin JC, et al. Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry. 1999;156:1149-1158. Copyright 1999, American Psychiatry Association.
In summary, the SD response in depressive patients remains a highly interesting issue for depression research, since, contrary to all antidepressant drugs, it may significantly ameliorate mood within one day. Understanding this effect and optimizing the duration of the effect, ie, preventing relapse after the response, might improve our ability to treat depression.
24. Wu J, Buchsbaum MS, Gillin JC, et al. Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry. 1999;156:1149-1158. 25. Ebert D, Berger M. Neurobiological similarities in antidepressant sleep deprivation and psychostimulant use: a psychostimulant theory of antidepressant sleep deprivation. Psychopharmacology. 1998;40:1-10. 26. Dinges DF, Douglas SD, Hamarman S, Zaugg L, Kapoor S. Sleep deprivation and human immune function. Adv Neuroimmunol. 1995;5:97-110. 27. Voderholzer U, Hohagen F, Herr A, et al. Effects of sleep deprivation on cytokines in healthy and depressed subjects. In: Sperner-Unterweger B, Fleischhacker WW, Kaschka WP, eds. Psychoneuroimmunology. Hypotheses and Current Research. Advances in Biological Psychiatry. Basel, Switzerland: Karger; 2001;20:98-109. 28. Leproult R, Copinschi G, Buxton O, Van-Cauter E. Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 1997;20:865-870. 29. Spiegel K, Leproult R, Van-Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354:1435-1439. 30. Voderholzer U, Weske G, Klein T, et al. Endocrine studies during sleep, sleep deprivation, and recovery sleep in depressed patients. Neuropsychopharmacology. 2000;23(suppl 2):S82-S83. 31. Parekh PI, Ketter TA, Altshuler L, et al. Relationships between thyroid hormone and antidepressant responses to total sleep deprivation in mood disorder patients. Biol Psychiatry. 1998;43:392-394. 32. Orth DN, Shelton RC, Nicholson WE, et al. Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression. Arch Gen Psychiatry. 2001;58:77-83. 33. Borbly AA, Wirz-Justice A. Sleep, sleep deprivation and depression. Hum Neurobiol. 1982;1:205-210. 34. Holsboer F, Barden N. Antidepressants and hypothalamic-pituitaryadrenocortical regulation. Endocr Rev. 1996;17:187-205. 35. Goodwin GM, Muir WJ, Seckl JR, et al. The effects of cortisol infusion upon hormone secretion from the anterior pituitary and subjective mood in depressive illness and in controls. J Affect Disord. 1992;26:73-83. 36. DeBattista C, Posener JA, Kalehzan BM, Schatzberg AF. Acute antidepressant effects of intravenous hydrocortisone and CRH in depressed patients: a double-blind, placebo-controlled study. Am J Psychiatry. 2000;157:1334-1337. 37. Volkow ND, Wang GJ, Fowler JS, et al. Gender differences in cerebellar metabolism: text-retest reproducibility. Am J Psychiatry. 1997;154:50-55. 38. Marinelli M, Rouge-Pont F, Deroche V, et al. Glucocorticoids and behavioral effects of psychostimulants. I: Locomotor response to cocaine depends on basal levels of glucocorticoids. J Pharmacol Exp Ther. 1997;281:1392-1400.
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Clinical research
Diagnosis and treatment of sleep disorders: a brief review for clinicians
Vivien C. Abad, MD, MBA; Christian Guilleminault, MD
orty million Americans are afflicted with chronic disorders of sleep and wakefulness, which interfere with work, driving, and social activities. Sleep disorders cause 38 000 cardiovascular deaths and cost over $16 billion annually.1 Indirect costs of accidents, property destruction, litigation, hospitalization, and death add another $50 to $100 billion.1 The most common sleep disorders include insomnia, sleep apnea, restless legs syndrome, and narcolepsy.1-3 Sleep disorders encompass a wide spectrum of diseases with significant individual health consequences and high economic costs to society. To facilitate the diagnosis and treatment of sleep disorders, this review provides a framework using the International Classification of Sleep Disorders. Primary and secondary insomnia are differentiated, and pharmacological and nonpharmacological treatments are discussed. Common circadian rhythm disorders are described in conjunction with interventions, including chronotherapy and light therapy. The diagnosis and treatment of restless legs syndrome/periodic limb movement disorder is addressed. Attention is focused on obstructive sleep apnea and upper airway resistance syndrome, and their treatment. The constellation of symptoms and findings in narcolepsy are reviewed together with diagnostic testing and therapy. Parasomnias, including sleep terrors, somnambulism, and rapid eye movement (REM) behavior sleep disorders are described, together with associated laboratory testing results and treatment.
Classification of sleep disorders

The International Classification of Sleep Disorders diagnostic and coding manual 2000 lists four major categories of sleep disorders: dyssomnias; parasomnias; sleep disorders associated with mental, neurologic, or other medical disorders; and proposed sleep disorders (Table I).4-7 Dyssomnias are disorders characterized by either excessive sleepiness or difficulty initiating or maintaining sleep.4 On the basis of pathophysiological mechanisms, they can be subdivided into intrinsic, extrinsic, and circadian rhythm sleep disorders.4-9 Intrinsic sleep disorders are disorders that originate or develop within the body or that arise from causes within the body. Common intrinsic sleep disorders include idiopathic and psychophysiological insomnia, narcolepsy, obstructive sleep apnea syndrome (OSAS), periodic limb movement disorder (PLMD), and restless legs syndrome (RLS).4-7 Sleep disorders caused by external factors are termed extrinsic sleep disorders and include inadequate sleep hygiene, environmental sleep disorder, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association
Address for correspondence: Christian Guilleminault, MD, Professor of Psychiatry and Behavioral Sciences and Director of Training, Stanford Sleep Disorders Center, 401 Quarry Road, Suite 3301, Stanford, CA 94305, USA (e-mail: cguil@stanford.edu)
Keywords: diagnosis; treatment; sleep disorder; insomnia; circadian rhythm disorder; excessive somnolence; parasomnia Author affiliations: Stanford University Sleep Disorders Clinic and Research Center, Stanford University, School of Medicine, Stanford, Calif, USA Copyright 2003 LLS SAS. All rights reserved
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Clinical research
AHI BIPAP CPAP EDS EMG EOG MSLT MWT NPT NREM OSAS PLMD PMR PSG RBD RDI REM RLS SOL SWS UARS WASO apnea-hypopnea index bilevel positive airway pressure continuous positive airway pressure excessive daytime somnolence electromyogram electro-oculogram mean sleep latency test maintenance of wakefulness test nocturnal penile tumescence nonrapid eye movement obstructive sleep apnea syndrome periodic limb movement disorder progressive muscle relaxation polysomnogram REM behavior sleep disorder respiratory disturbance index rapid eye movement restless legs syndrome sleep-onset latency slow-wave sleep upper airway resistance syndrome wake after sleep onset Proposed sleep disorders include short sleeper, long sleeper, subwakefulness syndrome, fragmentary myoclonus, sleep hyperhidrosis, menstrual-associated sleep disorder, pregnancy-associated sleep disorder, terrifying hypnagogic hallucinations, sleep-related neurogenic tachypnea, sleep-related laryngospasm, and sleep choking syndrome.4
Approach to sleep disorders

History and physical examination An accurate and detailed history from the patient, bed partner, or family member combined with a sleep questionnaire can elicit critical information. Most sleep complaints fall into three categories: insomnia (sleep onset, maintenance, or early morning awakening); excessive sleepiness; or abnormal behaviors during sleep. The procedure is as follows. Inquire into the chief complaint, when symptom(s) started, the pattern since onset, and associated factors (medical, environmental, occupational, psychological/stress, lifestyle choices) that may have predisposed to or precipitated the illness, perpetuated the condition, and improved or worsened symptoms.7 Assess the impact of the sleep complaint on the patients life, and inquire about meal and sleep schedules, sleep hygiene, restless legs sensation, snoring, witnessed apneic episodes, sweating, coughing, gasping/ choking/snorting, dryness of the mouth, bruxism, excessive movements during sleep, periodic limb movements, any abnormal behaviors during sleep, daytime sleepiness, presence of cataplexy, sleep paralysis, and hypnagogic or hypnapompic hallucinations. Ask about caffeine intake, alcohol and nicotine use, as well as use of illicit drugs. Review the pertinent medical/surgical/psychiatric history and past treatments, and their efficacy or lack thereof. Determine if there is any family history of sleep disorders (snoring, OSAS, narcolepsy, RLS). A completed 2-week sleep log or sleep diary can be utilized to compute sleep efficiency, total sleep time, and number of awakenings during the night, and can be used to diagnose sleep disorders and monitor efficacy of treatment. On the basis of the information from questionnaires and sleep diary, the chief complaint, and the history, a working diagnosis is outlined.
disorder, and hypnotic-, stimulant-, or alcohol-dependent sleep disorder.4-7 Circadian rhythm sleep disorders share a common chronophysiological basis whereby there is a discordance between the patients sleep pattern and the desired or societal sleep norm.4-9 Examples of circadian rhythm sleep disorders include shift work sleep disorder, delayed sleep phase syndrome, and advanced sleep phase syndrome. Parasomnias are characterized by undesirable behavioral and physical phenomena that occur predominantly during sleep.4-7 They include disorders of arousal, partial arousal, and sleep-stage transition. Sleep disorders can also be associated with mental disorders, such as psychoses, mood disorders, anxiety disorders, panic disorders, and alcoholism. Neurological conditions associated with sleep disorders include cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, and sleep-related headaches.4,10 Sleep disorders can occur with medical disorders, such as sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleeprelated gastroesophageal reflux, peptic ulcer disease, irritable bowel syndrome and fibromyalgia.4,11-14
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Diagnosis and treatment of sleep disorders - Abad and Guilleminault
Dyssomnias
Parasomnias
Sleep disorders associated with mental,neurological, or other medical disorders Associated with mental disorders - Psychoses - Mood disorders - Anxiety disorders - Panic disorders - Alcoholism Associated with neurological disorders - Cerebral degenerative disorders - Dementia - Parkinsonism - Fatal familial insomnia - Sleep-related epilepsy - Electrical status epilepticus of sleep - Sleep-related headaches Associated with other medical disorders - Chronic obstructive pulmonary disease - Sleep-related asthma - Sleep-related gastroesophageal reflux - Peptic ulcer disease - Fibromyalgia
Proposed sleep disorders
Intrinsic sleep disorders - Psychophysiological insomnia - Sleep state misperception - Idiopathic insomnia - Narcolepsy - Recurrent hypersomnia - Idiopathic hypersomnia - Posttraumatic hypersomnia - Central alveolar hypoventilation syndrome - Periodic limb movement disorder - Restless legs syndrome - Intrinsic sleep disorder NOS Extrinsic sleep disorders - Inadequate sleep hygiene - Environmental sleep disorder - Altitude insomnia - Adjustment sleep disorder - Insufficient sleep syndrome - Limit-setting sleep disorder - Sleep-onset association disorder - Food allergy insomnia - Nocturnal eating (drinking) syndrome - Hypnotic-dependent sleep disorder - Stimulant-dependent sleep disorder - Toxin-induced sleep disorder - Extrinsic sleep disorder NOS Circadian rhythm sleep disorders - Jet lag syndrome - Shift work sleep disorder - Irregular sleep-wake pattern - Delayed sleep-phase syndrome - Advanced sleep-phase syndrome - Non24-h sleep-wake disorder - Circadian rhythm sleep disorder NOS
Arousal disorders - Confusional arousals - Sleepwalking - Sleep terrors Sleep-wake transition disorders - Rhythmic starts - Sleep starts - Sleep talking - Nocturnal leg cramps Parasomnias usually associated with REM sleep - Nightmares - Sleep paralysis - Impaired sleep-related penile erections - REM sleep-related sinus arrest - REM sleep behavior disorder Other parasomnias - Sleep bruxism - Sleep enuresis - Sleep-related abnormal swallowing syndrome - Nocturnal paroxysmal dystonia - Sudden unexplained nocturnal death syndrome - Primary snoring - Infant sleep apnea - Congenital central hypoventilation syndrome - Sudden infant death syndrome - Benign neonatal sleep myoclonus - Other parasomnias NOS
- Short sleeper - Long sleeper - Subwakefulness syndrome - Fragmentary myoclonus - Sleep hyperhidrosis - Menstrual-associated sleep disorder - Pregnancy-associated sleep disorder - Terrifying hypnagogic hallucinations - Sleep-related neurogenic tachypnea - Sleep-related laryngospasm - Sleep-choking syndrome
Table I. Classification of sleep disorders.4 NOS, not otherwise specified; REM, rapid eye movement.
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Clinical research
Laboratory studies Laboratory tests that are performed to assess and therefore treat sleep disorders include the polysomnogram (PSG), multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT), actigraphy, video-PSG, nocturnal penile tumescence monitoring (NPT), and electroencephalography (EEG), including 24-h ambulatory EEG. PSG is a complete, nocturnal, laboratory-based monitoring, which simultaneously records numerous variables during sleep. It includes sleep staging (EEG), electro-oculogram (EOG), submental electromyogram (EMG), nasal or oral airflow, respiratory effort, oximetry, electrocardiogram (ECG), anterior tibialis EMG, and position monitoring. Depending upon the clinical diagnosis, additional parameters may be added: transcutaneous CO2 monitoring or end-tidal gas analysis; extremity muscle activity; motor activity movement; extended video-EEG; penile tumescence; esophageal pressure; gastroesophageal reflux; snoring; and continuous blood pressure recording.15-17 Modified forms of PSG include daytime nap PSG, splitnight studies, and portable recording studies.18-21 Daytime PSG is reported to have a high negative predictive value (95% when the apnea-hypopnea index [AHI] 10) for OSAS, but results are inconsistent.18 Split-night studies may save time and money, but it is still controversial whether diagnosis and treatment are adequately established.21,22 The American Academy of Sleep Medicine (AASM) has formulated guidelines for the use of PSGs, split-night studies, and portable recordings.15,16,19 The MSLT is used to confirm the diagnosis of narcolepsy; to assess complaints of moderate to severe sleepiness in patients with mild to moderate OSAS, idiopathic hypersomnia, PLMD, some circadian rhythm disorders, and unknown causes of excessive sleepiness; to evaluate the complaint of insomnia when moderate to severe excessive daytime sleepiness is suspected; and to assess response to treatment following therapy for disorders that cause sleepiness when an additional sleep disorder that produces sleepiness is suspected.23,24 The MWT is used less commonly than the MSLT mainly to assess improved alertness following therapeutic interventions.23-25 Actigraphy uses a small portable device that senses physical motion and stores the resulting information. Actigraphic studies need to be conducted for a minimum of three consecutive 24-h periods.26,27 The AASM Standards of Practice Committee recently updated practice parameters which state that actigraphy is not indicated for the routine diagnosis, assessment of severity, or management of any of the sleep disorders.28 However, it may be a useful adjunct that provides objective demonstration of multiday rest/activity patterns, which can be used to assist in the diagnosis, treatment, and/or assessment of treatment effects in various sleep disorders, including insomnia, circadian rhythm disorders, RLS/PLMD, and disorders of excessive sleepiness.26 Video-PSG may be helpful in the diagnosis of patients with arousal disorders or other sleep disruptions that are believed to be seizure-related.15,16 NPT for sleep-related erections (SRE) is an adjunct in the diagnosis of impotence.29 It usually requires 2 nights of PSG, although 1 night is sufficient if SRE is normal. Twenty-four hours of EEG is monitored for patients with suspected epilepsy.
Description of common sleep disorders

It is beyond the scope of this review to describe the entire gamut of sleep disorders. We will focus on the following common or severe sleep disorders: insomnia, circadian rhythm disorders, disorders of excessive somnolence (sleep apnea, narcolepsy, RLS/PLMD), and parasomnias. Insomnia Insomnia refers to almost nightly complaints of insufficient amounts of sleep or not feeling rested after the habitual sleep episode. As the most common sleepwakerelated disorder, it is more common in women and has a prevalence ranging from 10% to 30%.2,3 It can be classified based on severity (mild, moderate, severe) or duration (acute, subacute, chronic).4 Transient insomnia can occur in adjustment sleep disorders triggered by acute stress, travel, or sleeping in an unfamiliar environment.7 Symptoms usually resolve once the stress is reduced or removed, or the individuals adaptation to the stressor increases. For transient insomnia, treatment consists of education and advice about healthy sleep practices. If these are insufficient, short-term treatment with hypnotics can be undertaken. Chronic insomnia may be primary, or secondary to circadian rhythm, environmental, behavioral, medical, neurological, and psychiatric disorders. Vgontzas et al and Rodenback and Hajak reported nyctohemeral activation of the hypothalamic-pituitary-adrenal axis (HPA) in patients with chronic insomnia consistent with the arousal theory of insomnia.30,31 Vgontzas et al demon-
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strated a shift in interleukin-6 (IL-6) and tumor necrosis factor (TNF) secretion from nighttime to daytime in chronic insomniacs, and postulated that these could explain the daytime fatigue and performance decrements associated with insomnia.32,33 The diagnosis of primary insomnia requires exclusion of the direct physiological effects of a substance or general medical condition. It does not occur exclusively during the course of a mental disorder or other sleep disorder. Among the primary insomnias, idiopathic insomnia represents a lifelong sleep disturbance associated with reduction in daytime alertness and performance, increased sleep latency, and decreased sleep efficiency on PSG.4 Other primary insomnias include psychophysiological insomnia and sleep-state misperception. Psychophysiological insomnia refers to maladaptive sleep-preventing behaviors, which perpetuate the sleep disturbance. Typically, these patients sleep better in any place other than their own bedroom. PSG shows increased sleep latency, increased number of awakenings, and poor sleep efficiency. Sleep-state misperception refers to complaints of sleep difficulties with no PSG evidence of significant sleep disturbance; the sleep latency, quality, and architecture are normal. Inadequate sleep hygiene and behavioral disorders can also produce chronic insomnia.4 Limit-setting disorder occurs in 5% to 10% of children and is characterized by refusal to go to sleep when asked to do so and delaying bedtime; the PSG is normal.4,7 Secondary insomnia can result from medical, neurological, environmental, drugs, or psychiatric causes. Medical causes include pain, thyroid disease, acid reflux, coronary artery disease, pulmonary disease (chronic obstructive pulmonary disease, asthma, sleep apnea, central alveolar hypoventilation syndrome), chronic renal insufficiency, eating disorders, thyroid dysfunction, fibromyalgia, menstrual-associated sleep disorder, and pregnancy.34-36 Neurological causes of insomnia include headaches, Parkinsons disease, and sleep-related movement disorders (nocturnal myoclonus, RLS). Environmental sleep disorders can be triggered by excessive noise, noxious odors, bright light, or extremes of ambient temperature. Alcohol-, hypnotic-, and stimulant-dependent sleep disorders also contribute to chronic insomnia. Psychiatric disorders are characterized by sleep-onset difficulties, frequent arousals, sleep fragmentation, shortened total sleep time, and decreased sleep efficiency. These disorders include alcoholism, anxiety disorders, mood disorders, panic disorders, and psychoses. Preliminary data indi-
cate that chronic insomnia may precede depressive episodes by several years, and the question of systematic treatment of chronic insomnia as a means of avoiding depression is being studied. Stressful life events can precipitate chronic insomnia in predisposed individuals with neurotic depression, rumination, chronic anxiety, inhibition of emotions, and inability to express anger.36 PSG in anxiety disorders shows increased sleep latency, decreased rapid eye movement (REM) sleep, and reduced sleep efficiency, while PSG in mood disorders demonstrates frequent arousals and awakenings, decreased slow-wave sleep (SWS), decreased REM latency, increased first REM period duration, and increased REM density.34 Insomnia assessment tools can utilize self-reporting methods (sleep diary and Pittsburgh Sleep Quality Index) and objective methods include actigraphy and PSG.26,37 Treatment for insomnia can be categorized into pharmacological and nonpharmacological treatments. Pharmacological strategies must achieve a balance between hypnotic and adverse effects. Hypnotics are indicated in psychophysiological insomnia for occasional intermittent use or short-term (2 weeks) administration. Benzodiazepine usage can result in impaired sleep quality, residual sedation, memory or functional impairment the day following drug administration, or rebound insomnia. Other problems may include increased rates of falls, drowsiness, dizziness, cognitive impairment, and automobile accidents.35,38-40 Nonbenzodiazepine hypnotics, type I selective -aminobutyric acid (GABA) receptor agents, such as zolpidem (t1/2=2.4 h), zopiclone (t1/2=5 h), and zaleplon (t1/2=1 h), have hypnosedative action similar to the benzodiazepines and interact preferentially with 1 receptors.41 Nonbenzodiazepines preserve psychomotor tasks and memory capacities better than benzodiazepines and do not possess respiratory depressive side effects.35 Petit and colleagues suggest that pharmacological therapy be limited to 4 weeks.35 Nonpharmacological treatments for chronic insomnia include stimulus control therapy, sleep restriction, sleep hygiene education, cognitive therapy, paradoxical intention, relaxation therapy and multicomponent therapy.34,35,42-48 Stimulus control therapy is based on the premise that insomnia is a conditioned response to temporal (bedtime) and environmental (bed/bedroom cues) that are typically associated with sleep.34 Interventions result in reduction of sleep-onset latency (SOL) and wake after sleep onset (WASO) to 30 min or less, with total sleep time increased by 30 to 40 min.
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Sleep restriction creates a mild state of sleep deprivation, decreases sleep latency, and promotes more efficient sleep, with less internight variability.34 Interventions curtail the amount of time spent in bed to match sleep efficiency as determined through sleep diaries or actigraphy, with a caveat of a minimum of 5 h in bed. Adjustments are made weekly until optimal sleep duration is achieved. Sleep hygiene education promotes better sleep through awareness of environmental factors (light, noise, temperature, and mattress) and health practices (diet, exercise, and substance use) that may be beneficial or detrimental to sleep. Poor sleep hygiene complicates insomnia and hinders progress in therapy. Guilleminault et al reported statistically significant improvement at the end of 4 weeks in insomnia patients treated with sleep hygiene and light treatment.48 Cognitive therapy identifies patient-specific dysfunctional sleep cognition, challenges their validity, and replaces them with more adaptive substitutes using attention shifting, decatastrophizing, reappraisal, reattribution testing, and hypotheses testing.34,37,42,44,46 Paradoxical intention is a form of cognitive restructuring to alleviate performance anxiety and is based on the premise that performance anxiety hinders sleep onset.34 It is a method that consists of persuading a patient to engage in his most feared behavior, ie, staying awake. Relaxation treatments include progressive muscle relaxation (PMR), imagery training, meditation, and biofeedback. Meta-analyses of PMR trials have demonstrated reduced SOL and WASO by an average of 20 to 30 min from baseline to posttreatment with equivalent increases in total sleep time in addition to enhanced perception of sleep quality.34,35 Studies on imagery training have yielded variable results.34,35 Three studies on meditation demonstrated significant improvements in SOL or WASO.34 Biofeedback training reduced SOL with improvement rates similar to those obtained with standard relaxation procedures.35 Various nonpharmacological treatments may be combined as multicomponent therapy. Table II lists a combination of interventions derived from stimulus control therapy, sleep restriction therapy, sleep hygiene, and light therapy.
Reduce and limit intake of caffeine, tobacco, and other stimulants to the earlier part of the day. Discontinue nicotine and caffeine at least 4 to 6 h before bedtime Avoid alcohol as a sleeping aid Regularize sleep-wake schedule, meal times, and exercise time Exercise daily, but not closer than 3 h before bedtime If racing thoughts predominate during bedtime, set aside 15- to 20-min worry time earlier during the day. Use this to think about or list worries, problems, concerns, etc Avoid work-related or strenuous activities close to bedtime Engage in relaxing, pleasant activities 1 to 2 h before bedtime to wind down from the stresses of the day. Focus on positive thoughts at bedtime Minimize noise, light, and excessive temperature during sleep. If needed, use earplugs, eye shades, or an electric blanket/air conditioner Go to bed only when sleepy If sleep restriction is chosen as a treatment option, determine average estimated sleep time. Restrict the time in bed to the average estimated sleep time and continue with the weekly sleep diary. Using the sleep diary, determine the sleep efficiency (total sleep time/time in bed x100%) each week. Increase time in bed by 15 to 20 min when sleep efficiency >90%. Decrease time in bed by 15 to 20 min when sleep efficiency <80%. Maintain time in bed if sleep efficiency is 80% to 90%. Adjust the time in bed each week until the ideal sleep duration is obtained. The minimum time in bed is 5 h per night Use the bedroom only for sleep and sex. Do not read or watch TV in bed Get out of bed and go into another room when unable to fall asleep or return to sleep within 15 to 20 min. When out of bed, engage in relaxing and pleasant activities in a dimly lit room. Return to bed only when sleepy again. If still unable to sleep, repeat the same instructions Maintain a regular arising time in the morning regardless of how much or how little sleep you got during the prior nights. Expose yourself to outdoor light for 30 min within 15 min of arising Avoid daytime napping unless there are safety issues. If so, take a short early afternoon nap (less than 1 h) Table II. Multicomponent therapy instructions.
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Circadian rhythm disorders Delayed and advanced sleep phase disorders Disorders of circadian sleep-wake rhythms can present with complaints of chronic insomnia as well as excessive daytime somnolence.4,7,49-54 Delayed sleep phase syndrome sufferers report inability to fall asleep until the early morning hours and difficulty arising until late morning or early afternoon; sleep is normal after onset. PSG shows delayed sleep latency if the sufferer sleeps at the desired bedtime rather than the usual bedtime. In contrast, advanced sleep phase syndrome sufferers complain of severe inability to delay their bedtime (usually between 6 PM to 9 PM) and subsequent awakening earlier than desired (often between 1 AM to 3 AM).4,7,49,54 PSG performed at the persons desired bedtime reveals shortened sleep latency and early morning awakening. Patients with delayed and advanced sleep phase insomnia can be treated with proper timing of bright light and behavioral changes.4,7,49 The goal of light therapy is to entrain the endogenous sleep-wake rhythm to coincide with the patients social and occupational schedule. Melatonin administration can be utilized to entrain freerunning circadian rhythms and may be helpful in blind subjects.51 For delayed sleep phase syndrome patients, Dahl utilizes chronotherapy with cognitive behavioral therapy to advance the sleep phase, employing successive 3-h delays in bedtime for 6 days.47 To minimize school or work disruption, he prefers to start on a Thursday (Table III). To phase delay the circadian clock for advanced sleep phase syndrome patients, combine bright light exposure (10 000 lux for 30-45 min) between 7 and 9 PM together with a 15-min delay in bedtime every few days.7 Once the desired schedule is achieved for either phase delay or phase advance, it is crucial to lock in the wake-up time to
maintain a stable sleep-wake rhythm. The benefit of light therapy is dependent upon the magnitude of light intensity and exposure time. Either natural outdoors light or a light box (10 000 lux) or light visor (3000-5000 lux) can be utilized, with minimum exposure of at least 30 min. Shift work sleep disorder Shift work sleep disorder sufferers complain of difficulty initiating or maintaining sleep or poor quality sleep or excessive sleepiness that is temporally related to a work period that occurs during the habitual sleep phase.4,7,55 These patients are chronically fatigued and have an increased incidence of accidents at work. Shift workers have a higher incidence of chronic depression, emotional problems, family life dysfunction, excessive drug and alcohol use, ulcers, and myocardial infarction compared to the general population. Disturbances in circadian rhythms with internal desynchrony secondary to work shift time changes or sleep loss are postulated to cause this disorder. PSG shows increased sleep latency, numerous arousals during sleep, and early awakening, as well as sleep efficiency below 85%.4,7 A twofold approach to shift work problems involves treatment directed individually toward the patient, in addition to attempts to encourage the workplace (through occupational medicine and workers compensation programs) to adapt to the workers needs and reduce the overall incidence of shift workrelated sleep disorders.55-60 Treatment recommendations include the following: maintain a regular sleep and meal schedule; take naps to limit sleep loss; and practice good sleep hygiene. If sleep is necessary during daylight hours, optimize sleep by darkening the room and screening for noise and interruptions. Light environment is importantexposure to bright light during the first portion of the shift and protection from bright light after work (sun-
Patient takes responsibility for the success of the treatment and reorganizes habits and associations to improve sleep hygiene. Cognitive behavioral therapy focuses on positive thoughts at bedtime For adolescents, behavioral contract with parents/guardian specifies rewards and consequences One-week induction phase. Stay up the whole night on Wednesday. Bedtime schedules are as follows: Thursday 6 AM to 3 AM, Friday 9 AM to 5 AM, Saturday 12 noon to 8 AM, Sunday 3 AM to 12 midnight, Monday 6 AM to 2 AM, Tuesday and thereafter 9 AM to 6 AM. Stay in bed between 8.5 and 9 h Maintenance phase. Adhere to the schedule rigidly for at least 1 month. After this, allow minor changes during the weekend (wake-up time is still within 2 h of school or work time). Only permit one late night on the weekend, but impose strict wakeup within 2 h of school or work time. No napping is allowed Table III. Chronotherapy instructions to advance sleep phase.47
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glasses) and before sleep may be beneficial. Shorthalflife hypnotics can be used by those who only occasionally work shifts to help initiate sleep; chronic hypnotic use by long-term shift workers is not encouraged.7,55 Disorders of excessive somnolence Sleep apnea, hypopnea, and upper airway resistance syndrome Apnea is defined as cessation in airflow for longer than 10 s. Hypopnea refers to an abnormal respiratory event lasting longer than 10 s associated with at least a 30% reduction in thoracoabdominal movement or airflow compared to baseline, associated with 4% oxygen desaturation.61 Figure 1 demonstrates hypopneas seen during PSG monitoring of a patient with sleep apnea. Apneas and hypopneas are combined to form the AHI (ratio of total apneas and hypopneas to the total sleep time in hours), also known as respiratory disturbance index (RDI). An AHI>5 in an adult is abnormal. Apneas and hypopneas can result from upper airway obstruction (obstructive), loss of ventilatory effort (central), or a mixture of both (mixed). OSAS is characterized by repetitive episodes of upper airway obstruction that occur during sleep, usually associated with oxygen desaturation.4 The clinical features of OSAS are listed in Table IV. Some patients have increased upper airway resistance without observed apneas or hypopneas and exhibit increased respiratory effort with Pes (esophageal pressure) crescendos and Pes reversals. Guilleminault et al described the upper airway resistance syndrome (UARS) in patients who had Pes-documented increased respiratory effort associated with increased arousals and daytime sleepiness.62-64 Sleep-disordered breathing (OSAS and UARS) in children peaks between ages 2 to 5 with a second peak in
C3-A2 O1-A2 EMG ROC-A1 LOC-A2 URAT EKG MIC

+100
SpO2
+80 +60
Cannula Airflow
Chest Abd PES

-20 -25 -30 -35
Figure 1. Hypopnea in a patient with obstructive sleep apnea syndrome. Note the low amplitude signals seen in the nasal cannula and airflow channels with increasing effort demonstrated on the chest and abdominal (Abd) channels. The Pes (esophageal pressure [PES]) channel shows crescendo increases in esophageal pressure with reversal.
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middle to late adolescence. Continuous snoring, failure to thrive, mouth breathing, enlarged tonsils and adenoids, and predominance of hypopneas rather than apneas are common features in childhood OSAS.62,65-68 Children with sleep-disordered breathing have a threefold increase in behavioral and neurocognitive abnormalities. It has been estimated that 5% to 39% of attention-deficit/hyperactivity disorder (ADHD) could be attributed to sleep-disordered breathing.65-69 In OSAS, the PSG demonstrates more than five obstructive apneas per hour of sleep and one or more of the following: frequent arousals associated with the apneas; bradytachycardia; and arterial oxygen desaturation in association with the apneas. Sleep architecture in OSAS and UARS patients is abnormal with fragmented sleep (mainly during nonrapid eye movement [NREM] stages I and II) and frequent arousals and awakenings. The amount of SWS (NREM stages III and IV) and REM sleep is decreased.4,7 MSLT performed the day after the PSG may or may not demonstrate sleepiness (ie, mean sleep latency <10 min). Treatment for OSAS consists of nonsurgical as well as surgical treatments. Nonsurgical treatment encompasses general/behavioral measures, such as weight loss, body position during sleep (avoid supine position), and mechanical measures, which include continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP) and oral appliances. A consensus statement by Loube and colleagues recommended CPAP treatment for all OSAS patients with RDI30 regardless of symptoms and for patients with RDI=5 or 30 events per hour if accompanied by symptoms of excessive daytime somnolence, impaired cogniCardinal symptoms - Excessive sleepiness or insomnia - Frequent episodes of obstructed breathing during sleep - Loud snoring - Morning headaches - Dryness of the mouth or sore throat on awakening
tion, mood disorders, insomnia, or documented cardiovascular diseases (ischemic heart disease, hypertension), or stroke.70 Improvement or elimination of apneas improves sleep architecture and reduces daytime sleepiness.71,72 Beneficial effects of CPAP or surgery reported in patients with frequent sleep apneas (>20) and patients with sleep-disordered breathing (RDI<20) without subjective pathological sleepiness include improvement in well-being, mood, functional status, breathing, oxygen saturation, and cardiac rhythm.71-76 CPAP has also been successfully utilized to treat OSAS in infants and children younger than 2 years of age.77,78 However, compliance with CPAP is problematic, with published rates ranging from 65% to 95% when assessed subjectively.79-87 Strollo and colleagues have recommended management strategies for common side effects of nasal CPAP.80 Autotitrating continuous positive airway pressure (APAP) can be used to treat many patients with OSAS or to identify an effective optimal fixed level of CPAP for treatment, but is not recommended for patients with congestive heart failure, chronic obstructive pulmonary disease, daytime hypoxemia and respiratory failure from any cause, or prominent nocturnal desaturation other than from OSAS.88,89 Indications for BIPAP include intolerance of CPAP, development of central apneas resulting in sleep fragmentation, mask leaks at a high CPAP pressure, and persistent alveolar hypoventilation.80 Patients with OSAS on CPAP or BIPAP should be reevaluated at regular intervals to assess compliance, address problems, and reinforce the importance of continued treatment. Surgery is indicated for OSAS patients who have an underlying specific surgically correctable abnormality that is causing sleep apnea and may be indicated in
Physical examination findings - Increased body mass index (BMI) - Nasal obstruction - High-arched hard palate - Low hanging soft palate - Large or long uvula - Crowded and small oropharynx with or without enlarged tonsils and adenoids - Malocclusion of the jaw with overjet - Micrognathia, retrognathia, mandibular hypoplasia - Macroglossia, scalloping of the tongue - Neck circumference >44 cm in men - Brachycephalic head shape
Other symptoms - Nonrestorative sleep - Gasping or choking at night - Gastroesophageal reflux - Sexual dysfunction with decreased libido and impotence - Cognitive deficits with memory and intellectual impairment - Decreased vigilance - Mood changes with either depression or anxiety
Table IV. Clinical features of obstructive sleep apnea syndrome.
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patients who are not candidates for or have failed other noninvasive treatments, desire surgery, and are medically stable.90 Identification of the site(s) of obstruction is necessary in choosing the appropriate surgical intervention. Methods of localizing the site of obstruction include endoscopy, pressure catheters, fluoroscopy, computed tomography (CT) scan, or magnetic resonance imaging (MRI).91 Surgical procedures can be divided into phase I and phase II surgical procedures.92-96 Phase I involves palatal and lingual surgery: tonsillectomy, uvulopalatopharyngoplasty (UPPP), uvulopalatal flap (UPF), modified UPPP, palatal advancement, genioglossus advancement, hyoid suspension, laser midline glossectomy, lingualoplasty, and radiofrequency of the soft palate and tongue base. Phase II procedures either advance the jaws (maxillomandibular osteotomy) or widen the jaws using distraction procedures. Central sleep apnea is characterized by either shallow or absent breathing during sleep associated with one of the following features: gasping, grunting, choking movements, frequent body movement, and cyanosis. The PSG shows central apneic pauses >10 s (20 s in infancy) in duration, with one or more of the following: bradytachycardia; frequent arousals from sleep; or oxygen desaturation associated with apneas.4 MSLT may or may not demonstrate a mean sleep latency <10 min. Treatment of central sleep apnea involves treatment of comorbid medical conditions (congestive heart failure, nasal congestion, OSAS), consideration of supplemental oxygen (1-2 L/min via nasal cannula), or use of acetazolamide (125-250 mg, two to three times per day).7 Patients with central apneas before and after an arousal, without evidence of desaturation, may benefit from a trial of a hypnotic agent (zolpidem, 5-10 mg at night).7 RLS and PLMD RLS has a prevalence of 10% to 15% among patients between the ages of 27 to 41 years.97 It consists of unpleasant creeping or crawling sensations inside the calves and generalized aches and pains in the legs associated with a desire to move the extremities, motor restlessness, worsening of symptoms at rest with at least temporary relief by activity, nocturnal worsening of symptoms (circadian pattern), and difficulty initiating sleep in the absence of any medical, mental, or other sleep disorder that would account for the symptoms.97-99 RLS can be idiopathic or secondary to iron deficiency, peripheral neuropathies, or uremia. There are two recognized phenotypes in the idiopathic category: earlyonset RLS starts before age 45 and progresses slowly, demonstrating autosomal dominant inheritance, while late-onset RLS starts after age 45 and progresses rapidly, with limited familial aggregation.101 Increased cerebrospinal fluid (CSF) hypocretin-1 levels are present in early-onset RLS patients, whereas levels in late-onset RLS patients are normal. Allen et al postulate that increased hypocretin levels may modulate or promote insomnia and increase motor activity.101 RLS involves various areas in the nervous system from the spinal cord up to the basal ganglia.98,101,102 Using single photo emission computed tomography (SPECT) and positron emission tomography (PET), various researchers have demonstrated a decrease in dopamine D2 receptor binding in the striatum of RLS patients, suggesting that RLS is related to a deficiency of dopaminergic function.97,100,102-104 Iron deficiency accompanying RLS may be associated with hypofunction of the D2 receptor.97,100 More than 80% of RLS patients manifest periodic limb movements (PLMs) during sleep.100 PLMs consist of four or more repetitive episodes of muscle contraction (0.55 s in duration) separated by an interval (5 s but <90 s), which may be associated with an arousal. A PLM index (events/hour) >5 is abnormal. Tricyclic antidepressants, lithium, and selective serotonin reuptake inhibitors (SSRIs) can increase PLMs. Saletu and colleagues performed EEG mapping in RLS patients and demonstrated an increase in both absolute and absolute and relative 2 power, a decrease in absolute and relative 1 power, an acceleration of the dominant frequency and the centroid, and a slowing of the / centroid, as well as a nonsignificant attenuation in total power.105 These findings are characteristic of dissociated vigilance changes described in depression and correlated with higher depression and anxiety scores, lower quality of life, and deteriorated sleep quality despite normal Epworth Sleepiness scale scores. Treatment options for RLS include dopaminergic agents (pramipexole, ropinirole, pergolide, levodopa/carbidopa), opioids (oxycodone, propoxyphene), benzodiazepines (clonazepam), anticonvulsants (gabapentin, carbamazepine), and clonidine.97,102,106-117 Patients with low serum ferritin levels may benefit from iron therapy. Treatment with dopaminergic agents is complicated by rebound (worsening of symptoms at the end of the dosing period with late night or morning recurrence of
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symptoms and PLMs) and augmentation (worsening of symptoms seen with long-term use, particularly with higher doses, presenting with earlier time-of-day onset of symptoms and expansion of symptoms beyond the legs). With levodopa, rebound occurs in 20% of RLS patients, while augmentation affects 82% of patients; augmentation is increased in patients with more severe RLS and in those receiving higher doses.7,106,117 Dopamine agonists are useful in treating patients with RLS.108 Pergolide therapy reduced PLMs and increased total sleep time in 83% of RLS patients, but mild augmentation also occurred. Augmentation may be managed through a combination of behavioral strategies (walking and other physical activities) and medication-timing strategies.7,102 Narcolepsy Westphal described the first unequivocal case of narcolepsy in 1877, and Gelineau coined the term narcolepsy in 1880.The prevalence of narcolepsy in the United States is 1/2000.3,118 Narcolepsy is a neurological disorder that affects men and women equally, with usual age of onset between 15 and 30 years. It is characterized by the following tetrad of symptoms: excessive daytime somnolence (EDS), which can be a continuous feeling of sleepiness or sleep attacks, cataplexy, hypnagogic or hypnapompic hallucinations, and sleep paralysis.4,118-125 Guilleminault et al reported that EDS alone or in combination with sleep paralysis or hypnagogic hallucinations is the initial symptom in 90% of patients and that 5% to 8% of patients present with cataplexy.126,127 Only 10% of patients experience the full tetrad.119 After onset, EDS persists daily, although it can fluctuate during the day in a stereotyped individual pattern. Attention fluctuates modulated by situational circumstances. The attack usually starts with drowsiness associated with blurry or double vision and usually lasts for less than 20 min. Sleepiness is often relieved by a sleep attack, but the relief lasts for only several hours. Cataplexy involves sudden bilateral atonia of striated muscles with partial or complete weakness that is brought on by emotion or excitement. Laughter is the most typical trigger and, less frequently, anger or surprise. Other triggers include anticipation of something special or hilarious, attempts at bantering, feeling amused, or immobility in response to a call for immediate action. The patients state and circumstances also influence whether an attack occurs: sleep deprivation or strong
feeling of sleepiness can lower the attack threshold. The attacks start abruptly, but take several seconds to reach their maximum, with most attacks lasting less than a minute. During partial attacks, the knees may give way and there may be sagging of the jaw, inclination of the head, and weakness of the muscles responsible for speech so that the patient is either unable to speak or has slurred speech. Even with severe attacks, eye movements and respiration are spared. Neurological examination during the attack shows atonia, loss of tendon reflexes, and extensor plantar responses. Prolonged episodes may be associated with hallucinations and rarely, status cataplexicus. Video-polygraphic analysis of cataplectic attacks demonstrate three phases: (i) initial phase, consisting of arrest of eye movements and phasic, massive, inhibitory muscular events; (ii) falling phase, characterized by a rhythmic pattern of suppressions and enhancements of muscular activity leading to the fall; and (iii) atonic phase, associated with complete muscle atonia.128 Injury is uncommon because most people are able to find support or sit down at the onset of the attack. A consistent individual pattern is seen. Attacks vary in frequency from more than 10 per day to less than 1 per month. Hypnagogic hallucinations (at sleep onset) or hypnapompic hallucinations (on waking) represent vivid dreamlike experiences of visual imagery (constant or changing colored forms), auditory hallucinations, or tactile sensations. Smell and taste are rarely affected. Some patients describe out-of-body experiences at sleep onset.Attacks usually last less than 10 min, and the frequency varies from less than once a month to more than once a day. Sleep paralysis represents inability to move either at sleep onset or upon awakening; the episode can last up to 10 min. Patients can be frightened because they are unable to open their eyes or move their fingers and feel they have to struggle to move. Disturbed nocturnal sleep is the fifth component of the tetrad and is due to frequent awakenings. Although patients typically have short SOL, they may have trouble returning to sleep once awakened. Other reported symptoms include automatic behavior (episodes of amnesia associated with semipurposeful activity), subjective memory impairment that is not validated during standard memory testing, tiredness or fatigue, blurry or double vision, and sexual dysfunction (which may be related to drug therapy).124 The PSG demonstrates SOL less than 10 min and REM sleep latency less than 20 min.4 An MSLT demonstrates
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a mean sleep latency of less than 5 min with two or more sleep-onset REM (SOREM) episodes.4 Figure 2 depicts SOREM during an MSLT nap. HLA typing demonstrates an increased frequency of DQB1*0602 or DR2 in patients with narcolepsy, especially with cataplexy. Low CSF levels of hypocretin-1 are highly associated with narcolepsy with cataplexy (89.5%), particularly in patients with cataplexy who are HLA DQB1*0602positive (95.7%).129-132 Stimulant medications are the mainstay of treatment of EDS, with the objective of allowing the fullest possible return of normal function for patients at work, home, and school.118,122,123,125,133-135 The most common stimulants used, listed in incrementing order of relative efficacy are: pemoline, modafinil, dextroamphetamine, methamphetamine, and methylphenidate.133,135 The maximum recommended daily dosages of stimulants in adults are: dextroamphetamine sulfate, 100 mg; methamphetamine hydrochloride, 80 mg; and methylphenidate, 100 mg.133 Pemoline was utilized in the past, but is not currently recommended due to concerns about the risk of acute hepatic failure.7 Apart from modafinil, all stimulants are centrally acting sympathomimetic agents that enhance the release of monoamines in the synaptic cleft and block their reuptake.133,134 Modafinil is a novel stimulant with an
REM C3-A2
uncertain mechanism of action that may increase dopamine signaling.136 For newly diagnosed narcoleptics, modafinil may represent a reasonable initial choice because of its long duration of action, low frequency and severity of side effects, and low potential for dependence or tolerance. However, patients should be cautioned about drug interference with other medications, such as oral contraceptives. There are no well-controlled studies of pregnant women using stimulants. The benefits for the patient have to be weighed against the potential risks for the fetus. Mitler and colleagues recommend dosage reduction or discontinuation of stimulants during attempts at conception and during pregnancy.133 REM-suppressant drugs are utilized in the treatment of cataplexy, hypnagogic hallucinations, and sleep paralysis. Drugs that block norepinephrine reuptake, such as the tricyclic antidepressants, protriptyline, clomipramine, and imipramine, have been effective, but are frequently associated with tolerance and anticholinergic side effects. Tricyclics should not be discontinued abruptly because of the risk of severe aggravation of cataplexy, including status cataplecticus.136 SSRIs such as fluoxetine, paroxetine, and citalopram are also effective. Venlafaxine, a norepinephrine/serotonin reuptake inhibitor, is highly effective and well tolerated.
O2-A1
EMG-Chin
ROC-A1
LOC-A2
EKG
Figure 2. Sleep-onset rapid eye movement (REM) during an mean sleep latency test (MSLT) nap in a patient with narcolepsy. Electroencephalogram (EEG) leads (C3-A2 and O2-A1) demonstrate low voltage mixed frequency theta activity. EMG-Chin shows atonia with phasic events. Electrooculography (EOG) demonstrates REM.
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-Hydroxybutyrate (GHB), a short-acting putative neurotransmitter that acts as a hypnotic, reduces cataplexy, hypnagogic hallucinations, and subjective sleepiness. Three to nine grams of GHB is administered in bed with half of the dose at bedtime and the remainder 2.5 to 3 h later. Nausea, dizziness, and incontinence have been reported with high doses. Due to the risk of precipitating confusional arousals and even coma, doses >9 g should never be prescribed. Triazolam may be useful in treating insomnia in narcoleptics by increasing total sleep time and sleep efficiency without affecting alertness the following day.137 Nonpharmacological therapy includes regular sleep and wake times, short scheduled naps, prevention of sleep deprivation, avoidance of shift work, and working in a stimulating environment. Narcoleptic patients need to be cautioned about driving risks when undertreated. Idiopathic hypersomnia Idiopathic hypersomnia is a clinically heterogeneous disorder of chronic sleepiness without cataplexy that has a prevalence of 2 to 5/100 000.138,139 Symptoms present between ages 15 to 30 years and include variable daytime drowsiness (nonimperative versus irresistible), naps that range from short and refreshing to long and unrefreshing, prolonged nighttime sleep >12 h or restless sleep with frequent arousals, sleep drunkenness, and automatic behavior associated with blank stares and microsleep episodes.4,138,139 Three subgroups of patients are recognized. Subgroup 1 consists of patients with HLA Cw2 antigen and a positive family history of EDS associated with autonomic dysfunction (syncope, orthostatic hypotension, Raynaudtype phenomena). Subgroup 2 consists of individuals who had a viral illness (Guillain-Barre, mononucleosis, hepatitis, atypical viral pneumonia) followed by persistent EDS. Subgroup 3 includes patients with no family history or viral infection prior to onset of EDS. The PSG demonstrates a combination of normal or long nocturnal sleep, and the MSLT performed the day after the PSG shows short SOL without sleep-onset REM periods.139 Pharmacological treatment involves use of stimulants, starting with either modafinil or methylphenidate and switching to dexedrine spansules if initial treatment is ineffective. Nonpharmacological treatment includes one scheduled daily nap (noon or late afternoon) no longer than 45 min; avoidance of alcohol, sleep deprivation, heavy meals and
shift work; and observance of regular sleep (at least 8.5 h per night) and wake schedules. Parasomnias Parasomnias are characterized by undesirable physical phenomena or behaviors that occur predominantly during sleep. Skeletal muscle activity and autonomic nervous system changes are prominent. Parasomnias are composed of disorders of arousal, partial arousal, and sleepstage transition (Table I). Disorders of arousal are the most common form of parasomnia. They usually occur during SWS (NREM stages III and IV), and symptoms typically present in the first third of the night. Studies of twin cohorts and families with sleep terror and sleepwalking suggest that genetic factors may be involved, and there may be a family history of the same or other NREM arousal parasomnia.140-142 Factors that increase SWS, such as young age, natural deep sleeper, recovery from sleep deprivation, central nervous system (CNS) depressant medications (sedatives, hypnotics, alcohol), fever, and the hypersomniac period in Kleine-Levin syndrome, may aggravate the arousal disorder. Factors that lead to sleep fragmentation, including stress, environmental stimuli, endogenous stimuli, pain, pregnancy, stimulants, thyroxine taken in the evening, migraine headaches, or Tourettes syndrome, may trigger the parasomnia. Confusional arousals (nocturnal sleep drunkenness) This disorder is more common in children younger than 5 years of age, becomes less frequent during adolescence, and is rare in adulthood. The patient partially awakens from a deep sleep during the first third of the night, is confused and slow in mentation, disoriented to time and space, poorly/partially responsive to external stimuli, manifests automatic behavior (picking at bedclothes), and moans and mumbles incomprehensibly. Attacks last from 30 s to 10 min, and the patient is amnesic for the behavior and for any dream-like or thought-like mentation. PSG shows movement arousal in SWS followed by decreased amplitude of the EEG and the appearance during the period of mental confusion of either NREM stage I or a diffuse that is slower by 1 to 2 Hz compared to that of wakefulness. Confusional arousals in children do not necessarily warrant treatment. In adults who exhibit aggression towards others or self-injury, room
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safety precautions need to be implemented and conditions facilitating or triggering attacks need to be avoided. The attacks should be allowed to terminate spontaneously. Benzodiazepines or tricyclic medications may be useful as short-term therapy for a few days or weeks during periods when attacks are more common. Sleep terrors The peak prevalence of sleep terrors is between 5 and 7 years of age. By age 8, half of the children are attack-free, while 36% continue to have attacks until adolescence. Episodes of sleep terror occur during the first third of the night and also during daytime naps.The child sits up, emits a piercing scream, and appears frightened, with increased pulse and respiratory rates and profuse sweating. The episodes last from 30 s to 5 min, and the child is amnesic for the events during the episode. PSG shows explosive arousal with marked increases in muscle tone, heart rate, and respiratory rate, and a rapid decrease in skin resistance. Facilitating and precipitating factors need to be avoided.Treatment may include either a short-acting benzodiazepine, such as midazolam (10-20 mg), oxazepam (1020 mg), or clonazepam (0.5-2 mg). Patients unresponsive to benzodiazepines may benefit from tricyclic antidepressants such as clomipramine, desipramine, or imipramine (10-50 mg at hour of sleep). If total control of the episodes occurs and is sustained over several months, a slow and progressive withdrawal of medication may be performed. Sleepwalking (somnambulism) The patient ambulates during sleep, is difficult to arouse during an episode, and is usually amnesic following the episode. Guilleminault et al indicated that children over the age of 4 reported vague memories of having to act, run away, escape or defend themselves against monsters, animals, snakes, spiders, ants, intruders, or other threats, and that they felt completely isolated and fearful.143,144 Episodes usually occur in the first third of the night during SWS.4,143,144 This disorder has a peak age of onset at 5 years of age and peak prevalence at about 12 years. Most children outgrow the episodes by age 15. PSG recordings demonstrate 2 abnormalities during the first sleep cycle: frequent, brief, nonbehavioral EEG-defined arousals prior to the somnambulistic episode and abnormally low (0.75-2.0 Hz) EEG power on spectral analysis, correlating with high-voltage hypersynchronic waves lasting 10 to 15 s occurring just prior to the movement.140,142-145 This is followed by stage I NREM sleep, and there is no evidence of complete awakening. REM behavior sleep disorder In REM behavior sleep disorder (RBD), the patient complains of violent or injurious behavior during sleep with disruption of sleep continuity and excessive motor activity during dreaming, accompanied by loss of REM sleep EMG atonia.4,145-151 The frequency of nocturnal events varies from several times a night to once every 3 months. The most common behaviors consist of arm flailing and punching, kicking, and vocalizations; these behaviors occur in bed or result in falling out of bed. About 32% of patients report self-injury ranging from falling out of bed to striking or bumping into the furniture or walls. Olson reported one patient attempted to fire an unloaded gun, while another attempted to set fire to his bed.147 Sixty-four percent of spouses report being assaulted during sleep.147 Dream content in RBD has aggressive themes in about 89% of patients, with the most common one being defense of the sleeper against attack. Although RBD is usually idiopathic, it can occur secondarily on a transient or chronic basis.Acute RBD can result from drug withdrawal (meprobamate, pentazocine, nitrazepam, and butalbital)152 or intoxication (biperiden, tricyclic antidepressants, monoamine oxidase [MAO] inhibitors, or caffeine).149,153 Chronic RBD can be produced by drugs (tricyclic antidepressants, fluoxetine, venlafaxine, mirtazapine, selegeline, and anticholinergic medications), vascular problems (subarachnoid hemorrhage, vasculitis), tumors (pontine neoplasms, acoustic tumors), infectious/postinfectious diseases (Guillain-Barre), degenerative or demyelinating conditions (amyotrophic lateral sclerosis, fatal familial insomnia, dementia, Parkinsons disease, multiple sclerosis, olivopontocerebellar degeneration, Shy-Drager syndrome, multiple system atrophy), and developmental, congenital, or familial diseases (narcolepsy, Tourettes syndrome, Group A xeroderma pigmentosum, mitochondrial encephalomyopathy).147,149,153-155 Because of the overwhelming male preponderance (90%), questions of relationships between sexual hormones, aggression, and violence have been raised.148,149 Diffuse lesions of the hemispheres, bilateral thalamic abnormalities, or primary brain stem lesions may result in RBD.150 The PSG shows at least one of the following: excessive augmentation of chin-EMG tone or excessive chin/limb
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phasic EMG twitching associated with one or more of the following: excessive limb or body jerking, complex vigorous/violent behaviors, and absence of epileptic activity in association with the disorder. Shirakawa and colleagues performed MRI and SPECT imaging on 20 patients with RBD and reported decreased blood flow in the upper portions of the frontal lobe and pons.156 Albin and colleagues found decreased striatal dopaminergic innervation in RBD patients.157 Treatment of RBD has been effective in 90% of patients using clonazepam starting at 0.5 mg at bedtime and gradually incrementing the dose until control is effected. Other drugs, such as gabapentin, clonidine, carbamazepine, donezepil, levodopa, and melatonin have been anecdotally reported to be useful.149,158-162 Environmental safety measures are very important. Potentially dangerous objects should be removed from
the bedroom, weapons (if any) should be stored and locked away safely outside the bedroom with the key entrusted to another person, the corners around the bed should be padded or cushioned, the mattress may be placed on the floor, and window protection should be considered.
Conclusions
Sleep disorders constitute a ubiquitous group of diseases that have important consequences for individual health as well as economic costs to society. The diagnosis of sleep disorders requires careful history taking, examination, and laboratory testing. Although general guidelines in management for the more common and important sleep disorders have been discussed, treatment needs to be tailored to the individual patient.
Diagnstico y tratamiento de los trastornos del sueo: una breve revisin para los clnicos
Los trastornos del sueo incluyen un amplio espectro de enfermedades con consecuencias significativas para la salud individual y altos costos econmicos para la sociedad. Para facilitar el diagnstico y tratamiento de los trastornos del sueo esta revisin se estructur utilizando la Clasificacin Internacional de Trastornos del Sueo. Se diferencia el insomnio primario y secundario, y se discuten los tratamientos farmacolgicos y no farmacolgicos. Se describen los trastornos comunes del ritmo circadiano en conjunto con intervenciones que incluyen la cronoterapia y la fototerapia. Tambin se revisa el diagnstico y tratamiento del sndrome de las piernas inquietas o trastorno del movimiento peridico de las piernas. Adems se centra la atencin en la apnea obstructiva del sueo y el sndrome de resistencia de la va area superior y su tratamiento. Se revisa la constelacin de sntomas y hallazgos de la narcolepsia, junto con las pruebas diagnsticas y la terapia. Se describen las parasomnias, incluyendo los terrores nocturnos, el sonambulismo y los trastornos de conducta asociados al sueo REM (movimiento rpido de ojos) junto con los resultados de las pruebas de laboratorio y el tratamiento.
Diagnostic et traitement des troubles du sommeil : brve revue pour les cliniciens
Les troubles du sommeil comprennent un large spectre de maladies avec des consquences significatives individuelles en termes de sant et un cot conomique lev pour la socit. Pour faciliter le diagnostic et le traitement des troubles du sommeil, cette revue fournit un cadre utilisant la classification internationale des troubles du sommeil. Les insomnies primaires et secondaires sont diffrencies et les traitements pharmacologiques et non pharmacologiques sont discuts. Les troubles courants du rythme circadien sont dcrits conjointement avec les interventions dont la chronothrapie et la luxthrapie. Le diagnostic et le traitement du syndrome des jambes sans repos/mouvements priodiques des membres sont abords. Les apnes obstructives du sommeil et le syndrome de rsistance des voies ariennes suprieures et leur traitement reoivent une attention particulire. La constellation de symptmes et les acquisitions sur la narcolepsie sont passes en revue ainsi que les preuves diagnostiques et le traitement. Les parasomnies dont les terreurs nocturnes, le somnambulisme et les perturbations des mouvements oculaires rapides (REM, rapid eye movement) sont dcrits conjointement avec les rsultats des tests de laboratoire et le traitement.
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107. Chesson A, Wise M, Davila D, et al. Practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999;22:961-968. 108. Comella C. Restless legs syndrome. Treatment with dopaminergic agents. Neurology. 2002;58:S87-S92. 109. Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep. 1993;16:327-332. 110. Kaplan PW, Allen RP, Buchholz DW, Walters, JK. A double-blind placebocontrolled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep. 1993;16:717-723. 111. Montagna P, Sassoli de Bianchi L, Zucconi M, et al. Clonazepam and vibration in restless legs syndrome. Acta Neurol Scand. 1984;69:428-430. 112. Boghen D, Lamothe L, Elie R, et al. The treatment of the restless legs syndrome with clonazepam: a prospective controlled study. Can J Neurol Sci. 1986;13:245-247. 113. Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J Kidney Dis. 2001;38:104-108. 114. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome with gabapentin. A double-blind, cross-over study. Neurology. 2002;59:1573-1579. 115. Telstaad W, Sorensen O, Larsen S, et al. Treatment of the restless legs syndrome with carbamazepine: a double-blind study. BMJ (Clin Res Ed). 1984;288:444-446. 116. Wagner ML, Walters AS, Coleman RG, Hening WA, Grasing K, Chokroverty S. Randomized, double-blind placebo-controlled study of clonidine in restless legs syndrome. Sleep. 1996;19:52-58. 117. Guilleminault C, Cetel M, Philip P. Dopaminergic treatment of restless legs and rebound phenomenon. Neurology. 1993;43:443-445. 118. Guilleminault C, Anagnos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders; 2000:676-686. 119. Overeem S, Mignot E, van Dijk JG, Lammers GJ. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol. 2001;18:78-105. 120. Stores G. Recognition and management of narcolepsy. Arch Dis Child. 1999; 81:519-524. 121. Gerhardstein R, Day R, Rosenthal L. Narcolepsy and other causes of excessive daytime sleepiness. Respir Care Clin N Am. 1999;5:427-446. 122. Guilleminault C, Pelayo R. Narcolepsy in children: a practical guide to its diagnosis, treatment, and follow-up. Paediatr Drugs. 2000;2:1-9. 123. Krahn LE, Black JL, Silber MH. Krahn, L. Narcolepsy: new understanding of irresistible sleep. Mayo Clinic Proc. 2001;76:185-194. 124. Aldrich M. Narcolepsy. N Engl J Med. 1990;323:389-394. 125. Black J. Narcolepsy: evaluation and management. CNS News Special Ed. 2001:25-29. 126. Guilleminault C, Wilson RA, Dement WC. A study on cataplexy. Arch Neurol. 1974;31:255-261. 127. Guilleminault C, Anders TF. The pathophysiology of sleep disorders in pediatrics. Part II. Sleep disorders in children. Adv Pediatr. 1976;22:151-174. 128. Rubboli G, d'Orsi G, Zaniboni A, et al. A video-polygraphic analysis of the cataplectic attack. Clin Neurophysiol. 2000;111(suppl 2):S120-S128. 129. Overeem S, Scammell T, Lammers G. Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy. Curr Opin Neurol. 2002;15:739-745. 130. Mignot E, Lammers GJ, Ripley B, et al. The role for cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59:1553-1562. 131. Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep. 2002;25:733-736. 132. Kanbayashi T, Inoue Y, Chiba S, et al. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res. 2002;11:91-93. 133. Mitler MM, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with stimulants: ASDA standards of practice. Sleep. 1994;17:352-371. 134. Parkes D. Introduction to the mechanism of action of different treatments of narcolepsy. Sleep. 1994;17(8 suppl):S93-S96. 135. Littner M, Johnson SF, McCall WV, et al. Standards of Practice Committee. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep. 2001;24:451-466. 136. Scamell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53:154-166. 137. Thorpy MJ, Snyder M, Aloe FS, Ledereich PS, Starz KE. Short-term triazolam use improves nocturnal sleep of narcoleptics. Sleep. 1992;15:212-216. 138. Bassetti C, Aldrich M. Idiopathic hypersomnia. A series of 42 patients. Brain. 1997;120:1423-1435. 139. Guilleminault C, Brooks S. Idiopathic hypersomnia: a neurological dilemma. Sleep Med Rev. 2001;5:347-349. 140. Broughton R. NREM arousal parasomnias. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders; 2000:687-692. 141. Kales A, Soldatos CR, Bixler EO, et al. Hereditary factors in sleepwalking and night terrors. Br J Psychiatry. 1980;137:111-118. 142. Abe K, Amatomi M, Oda N. Sleepwalking and recurrent sleep talking in children of childhood sleepwalkers. Am J Psychiatry. 1984;141:800-801. 143. Guilleminault C, Poyares D, Abat F, Palombini L. Sleep and wakefulness in somnambulism. A spectral analysis study. J Psychosom Res. 2001;51:411-416. 144. Guilleminault C, Palombini L, Pelayo R, Chervin R. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics. 2003;111:e17-e25. 145. Guilleminault C, Moscovich A, Leger D. Forensic sleep medicine and nocturnal wandering and violence. Sleep. 1995;15:173-184. 146. Broughton RJ, Shimuzu T. Sleep-related violence: a medical and forensic challenge. Sleep. 1995;18:727-730. 147. Olson E, Boeve B, Silbert M. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain. 2000;123:331-339. 148. Mahowald M, Schenk C. Medical-legal aspects of sleep medicine. Neurol Clin. 1999;17:215-234. 149. Mahowald M, Schenk C. REM sleep parasomnias. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders; 2000:724-741. 150. Ferini-Strambi L, Zucconi M. REM sleep behavior disorder. Clin Neurophysiol. 2000;111(suppl 2):S136-S140. 151. Schenck C, Bundlie S, Ettinger M, Mahowald M. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep. 1986;9:293308. 152. Silber M. REM sleep behavior disorder associated with barbiturate withdrawal. APSS Abstract. Sleep Res. 1996;25:371. 153. Husain A, Miller P, Carwile S. REM sleep behavior disorder: potential relationship to post-traumatic stress disorder. J Clin Neurophysiol. 2001;18:148-157. 154. Onofrj M, Luciano AL, Thomas A, et al. Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism. Neurology. 2003;60:113-115. 155. Schutte S, Doghramji K. REM behavior disorder seen with venlafaxine (Effexor). APSS Abstract. Sleep Res. 1996;25:364. 156. Shirakawa S, Takeuchi N, Uchimura N, et al. Study of image findings in rapid eye movement sleep behavioural disorder. Psychiatry Clin Neurosci. 2002;56:291-292. 157. Albin RL, Koeppe RA, Chervin RD, et al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology. 2000;55:1410-1412. 158. Ringman JM, Simmons JH. Treatment of REM sleep behavior disorder with donezepil: a report of three cases. Neurology. 2000;55:870-871. 159. Bamford C. Carbamazepine in REM sleep behavior disorder. Sleep. 1993;16:33. 160. Mike ME, Kranz AJ. MAOI suppression of RBD refractory to clonazepam and other agents. Sleep Res. 1996;25:63. 161. Takeuchi N, Uchimura N, Hashizume Y, et al. Melatonin therapy for REM sleep behavior disorder. Psychiatry Clin Neurosci. 2001;55:267-279. 162. Kunz D, Bes F. Melatonin as a therapy in REM sleep behavior patients: an open-labeled pilot study on the possible influence of melatonin on REM sleep regulation. Mov Disord. 1999;14:507-511.
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Treatment of seasonal affective disorders
Nicole Praschak-Rieder, MD; Matthus Willeit, MD
Seasonal affective disorder (SAD) is a subform of major depressive disorder, recurrent, or bipolar disorder with a regular onset of depressive episodes at a certain time of year, usually the winter. The treatment of SAD is similar to that of other forms of affective disorder, except that bright light therapy is recommended as the first-line option. Light therapy conventionally involves exposure to visible light of at least 2500 lux intensity at eye level. The effects of light therapy are thought to be mediated exclusively by the eyes, not the skin, although this assumption has not yet been verified. Morning light therapy has proven to be superior to treatment regimens in the evening. Response rates to light therapy are about 80% in selected patient populations, with atypical depressive symptoms being the best predictor of a favorable treatment outcome. Data from randomized, controlled trials suggest that antidepressants are effective in the treatment of SAD. Three double-blind, placebo-controlled trials have been conducted showing promising results for the selective serotonin reuptake inhibitors (SSRIs) sertraline and fluoxetine, as well as for moclobemide, a reversible inhibitor of monoamine oxidase A.
easonal affective disorder (SAD), as originally described in 1984,1 is a condition characterized by the annual recurrence of depressive episodes in fall and winter followed by remission of depressive symptoms in spring and summer.1 Patients with SAD have to meet diagnostic criteria for major depression, recurrent, or bipolar disorder. In the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), SAD is listed as a specifier of either bipolar or recurrent major depressive disorder, with a seasonal pattern of major depressive episodes.2 Subsyndromal SAD is a disorder with similar but milder symptoms that do not grossly disrupt patients social and occupational functioning.3 The four central features characterizing SAD are listed in Table I. Patients with SAD have the usual symptoms of depression, including low mood, lack of drive, decreased concentration, and reduced interest. Typically, many SAD patients also tend to have a specific symptom cluster consisting of the so-called reverse vegetative or atypical depressive symptoms. These symptoms include increased sleep (70%-90% of SAD patients), increased appetite (70%-80%), carbohydrate craving (80%-90%), and weight gain (70%-80%).4
Pathophysiology
The etiology of SAD remains unclear. It is thought that the decreasing daylight period as winter approaches triggers depressive episodes in individuals vulnerable to SAD. However, although bright light exposure is used in the treatment of SAD, no causal relation can be drawn between the occurrence of SAD and the shortage of light in fall and winter. Patients with SAD may be sensitive to factors that are common to various forms of recurrent
Address for correspondence: Nicole Praschak-Rieder, MD, Centre for Addiction and Mental Health, PET Centre, 250 College Street, Toronto, Ontario, Canada M5T 1R8 (e-mail: nicole@camhpet.on.ca) www.dialogues-cns.org
Keywords: seasonal affective disorder; depression; light therapy; pharmacotherapy; treatment guidelines Author affiliations: Centre for Addiction and Mental Health, PET Centre, Toronto, ON, Canada Copyright 2003 LLS SAS. All rights reserved
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affective disorder, and SAD can be seen as a disorder driven by endogenous annual rhythms and characterized by an imbalance of indoleamines, serotonin, and melatonin, as well as catecholamines, over the year. known that improvement may sometimes be seen as late as 2 to 4 weeks after beginning BLT.18 The obvious obstacles in the search for plausible placebos and blinded designs for studying the efficacy of BLT have led to concerns about the adequacy of control conditions. Early studies mostly used dim-light of an intensity of 300 lux or less, delivered through a light source otherwise identical to that used in the active condition (mostly light of 2500 lux intensity). As it was still possible to distinguish between the bright and dim-light conditions, these studies have been questioned as to whether they measured real biological effects and whether they could reliably separate a true antidepressant effect from placebo effects. However, fantasy and creativity of researchers in the field has led to further studies, which now unequivocally prove that light is an active biological agent with antidepressant effects in SAD. Some of these studies used (deactivated) negative ion generators as placebo condition.18-20 Like a light box, the negative ion generator is a device, has a plausible mechanism of antidepressant action, and requires the subject to sit beside it. Light had the better antidepressant effect and produced significantly more remissions, although expectations were equal for both conditions. Interestingly enough, high doses of negative ions do seem to have an antidepressant effect as well.20
Light therapy is an effective first-line treatment for seasonal affective disorder A fluorescent light box with light intensities greater than 2500 lux is the preferred device for light therapy An optimal starting dose for light therapy is 10 000 lux for 30 min/day Light boxes emitting 2500 lux are effective with a treatment duration of 2 h/day Morning light is more effective than evening light. Patients should be encouraged to undergo light therapy as early as possible (eg, before/during breakfast). However, evening light may be effective for some patients Many patients will respond as early as after 1 week. However, in some cases a response may occur after only 2 to 4 weeks If there is no sufficient response after two treatment weeks, the dose should be doubled to 30 min in the morning plus 30 min in the evening If this regimen does not lead to sufficient improvement, consider adding a pharmacological treatment (best evidence available for serotonin reuptake inhibitors) Table II. Guidelines for bright light therapy (BLT).
Light therapy
Bright light therapy (BLT) has become a first-line clinical standard for treatment of SAD (Table II).The use of BLT as a therapy for SAD evolves directly out of neuroscience. In the early 1980s, knowledge that light could shift circadian and seasonal rhythms in animals, together with the heuristic idea of extending daylight during the winter months, led to the first clinical study on BLT in SAD.1 Since then, numerous studies have not only proven its efficacy, but also greatly refined our knowledge on treatment strategies, thereby allowing for astonishingly high response rates of 80% in selected patient populations.5 BLT is safe, effective, and it has few and benign side effects. It is generally well accepted by the patients,6 and indications other than SAD, eg, disturbances of circadian rhythm due to jet lag or shift work,7,8 circadian-phaserelated disturbances in dementia,9,10 sleep disorders,11,12 and nonseasonal affective disorders,13-15 are expanding research fields. Efficacy The first controlled clinical trial already showed the beneficial effects of light against symptoms of SAD. Since then, more than 60 controlled studies and two metaanalyses16,17 have shown the efficacy of this treatment. Using stringent criteria, the meta-analysis of Terman et al16 found remission rates of up to 67% of patients with milder depression and up to 40% of more severely depressed patients. These benefits were seen as early as 1 week after beginning treatment. However, it is now
1
Recurrent major depressive episodes that start around the same time each year (eg, fall and winter) and end around the same time each year (eg, spring and summer) Full remission of symptoms during the unaffected period of the year (eg, summer) Over the lifetime course of the illness, there are relatively more seasonal depressive episodes than nonseasonal episodes Seasonal depressive episodes occur in at least 2 consecutive years Table I. Features of seasonal affective disorder (SAD).
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Treatment of seasonal affective disorders - Praschak-Rieder and Willeit
Another challenge for efficacy studies on light therapy is the light-noise inevitably encountered in a normal living environment. Depending on weather conditions, outdoor light intensities can easily surmount the intensities delivered by a light box, even in the winter. This has been compared to a study trying to prove the superiority of an antidepressant drug over placebo, with antidepressants occasionally delivered through the drinking water to all study subjects.21 Nevertheless, today there is sound evidence showing that antidepressant effects of light in SAD are real biological treatment effects.16,20,22 Dose Earlier studies have mostly used light intensities of 2500 lux. This is much more than the typical indoor illumination, ranging from 100 lux in average rooms to about 500 lux in brightly illuminated ones. Outdoor light intensities greatly vary with weather conditions ranging from about 2000 lux on a rainy winter day to 10 000 lux or more (usually 50 000 to 300 000 lux) in direct sunshine. Today, light treatment with intensity of 10 000 lux has become clinical standard. One great advantage of higher intensity light is that it allows for shorter exposure times. Current clinical guidelines recommend beginning treatment with 10 000 lux for 30 min in the morning.23 Nevertheless, intensities of 2500 lux have shown to have antidepressant effects when applied for 2 h daily. Timing A further finding that emerged from BLT studies is the superiority of morning light over light administered in the evening.16,20,22 By further refining timing of light administration in relationship to the position of the circadian phase, Terman and coworkers achieved remission rates up to 80% in selected patient populations.5 They were able to show that response to BLT critically depends on time of delivery relative to the position of the circadian phase as determined by the onset of melatonin secretion in the evening (dim-light melatonin onset). The study suggests that the ideal therapy time is around 8.5 h after melatonin onset. Although the superiority of morning light in the majority of patients with SAD had been demonstrated before,16,20,22 Terman and colleagues showed that, for clinical purposes, circadian phase position can simply and reliably be determined by administration of a modified version Horne-st-
berg morningness-eveningness scale.24 The authors also provide an online-questionnaire25 together with recommendations for individually optimized light therapy timing as based on morningness-eveningness or individual circadian phase position. In summary, now there is sufficient evidence that light administered in the early morning is superior to evening light. Dawn stimulation Many patients with SAD experience markedly increased duration of sleep during the winter months.1,4,26 Usually, most of these patients have to force themselves out of bed during the weekdays despite feeling excessively drowsy. Dawn stimulation is a form of light therapy involving gradually increasing bedside light in the morning before awakening.27 Dawn stimulation has shown to improve symptoms of SAD compared with placebo light signals.28,29 In addition, dawn stimulation appears to be effective in ameliorating the difficulty awakening and morning drowsiness in SAD.30 In a comparison study, dawn stimulation using 100 to 300 lux for 60 to 90 min every morning improved symptoms of SAD similarly to light therapy using 1500 to 2500 lux for 2 h every morning.31 Adverse effects The adverse effects of light therapy include headache, eyestrain, nausea, and agitation.32,33 Usually, adverse effects are mild and subside spontaneously or with dose reduction. Bright light in the evening may be associated with sleep disturbances, and, occasionally, hypomania may arise during BLT.33 However, subjective benefits of light consistently outweigh its adverse effects.32,33 Altogether, it remains questionable whether the frequency of these symptoms under BLT significantly exceeds the frequency of side effects seen under placebo conditions. Risks There are no absolute contraindications for light therapy.23 Animal studies suggest increased risk for retinal damage with lithium, -blockers, tricyclic antidepressants, and tryptophan. However, no such interactions have been reported in humans, and there is no evidence that light therapy is associated with ocular or retinal damage in humans. Patients with severe ophthalmological conditions or patients taking photosensitizing medication should have
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an ophthalmological examination before starting light therapy. However, it is important that the UV spectrum is filtered out of the therapeutic light source. Although suicidality is commonly regarded as being rather infrequent in SAD, our own group has reported severe suicidal ideation and suicide attempts in three patients after the initiation of light therapy.34 All three patients had suicidal thoughts before light therapy was started.As always when dealing with depressed patients, patients with SAD should be carefully assessed for suicidality before light therapy, and therapy outcome should frequently and regularly be evaluated by health care professionals. Treatment predictors Atypical depressive symptoms, specifically hyperphagia, hypersomnia, and carbohydrate craving, seem to be associated with favorable response to BLT.35,36 Younger age also seems to predict a good response,37 while comorbid personality disorders seem to compromise the response to BLT.38,39 Mechanism of action Theories on the mechanism of action of BLT are closely connected to what is known about the pathogenesis of SAD.40 Two mainmutually not exclusivetheories have been raised by researchers in the field: one concentrates on the evidence for reduced serotonin neurotransmission in SAD, the other theory relates light therapyinduced improvement to corrections of altered circadian rhythms during depression in SAD. Serotonin Several lines of evidence suggest an alteration in serotonin neurotransmission in SAD.40-42 A keystone of the serotonin hypothesis on the mechanism of action of light therapy is the finding that lowering brain serotonin by tryptophan depletion leads to a transient depressive relapse in patients with SAD who are in light therapyinduced remission.43 In line with this theory is the beneficial effect of selective serotonin reuptake inhibitors (SSRIs) in SAD. Although there is evidence for a seasonal variation in serotonin neurotransmission,44 and although there seems to be a close relationship between brain serotonin and atypical depressive symptoms,41 serotonergic alterations are not specific for the pathogenesis of SAD or the antidepressant action of light. They rather seem to constitute a pathway common to depressive syndromes and their treatment in general. Circadian phase shifts More specific for SAD are the theories concerning alterations in circadian and circannual rhythms. Neurons of the hypothalamic suprachiasmatic nucleus (SCN) act as the main zeitgeber in the mammalian organism. Having an intrinsic near to 24-h rhythm, they are also known as the internal clock. These neurons are reset by environmental light, and they are believed to be the main determinant for the position of the circadian phase. Several body functions, such as hormonal rhythms, including nocturnal melatonin secretion, sleep, or eating behavior, are subjected to a specific circadian rhythm. The best studied marker for the position of the circadian phase is the onset of melatonin secretion by the pineal gland.45 In humans, the beginning of melatonin secretion occurs in the evening, usually between 1 and 2 h before falling asleep. Light can shift the position of the circadian phase, and amount and direction of that shift greatly depend on the time of light exposure: light in the evening leads to a phase delay (eg, melatonin onset occurs later), morning light advances the circadian phase.20,22 Early theories on the pathogenesis of SAD held that a delay in the circadian phase was responsible for the appearance of SAD symptoms.46 Although the phasedelay hypothesis on the pathogenesis of SAD did not hold up, as there does not seem a consistent pattern of phase alterations in SAD, recent work has shown the circannual variation in circadian phase to be altered in patients with SAD when compared with healthy control subjects.47 Recent work by Terman and colleagues showed a correlation between light-induced changes in the phase angle (the relationship between the circadian phase as measured by melatonin onset and, eg, sleep onset) and antidepressant response to light in SAD.5 Practical issues Sufficient and clear instructions to patients are critical for a satisfactory treatment response. Patients should be informed that the beneficial effects of light are not enduring, ie, that a relapse is to be expected after a few days when treatment is discontinued.Although one study48 suggested a transcutaneous effect of light on melatonin secre-
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tion, these results have not been replicated.49,50 It is so far safe to state that the antidepressant effect of light is mediated by the eye.The patient therefore needs to make sure that light of sufficient intensity meets the eye. Light projection does not need to be foveal, ie, it is not necessary to look directly into the light source. The ideal is an angle of about 30 to 60 to let enough light meet the eye and allow for the patient to, for example, read or eat during light therapy. The intensity of light critically depends upon the distance from the light source. Light boxes should be powerful enough to deliver an intensity of about 10 000 lux at a distance of 60 to 90 cm. If the light box is less powerful, treatment time should be expanded (see above). Patients should be encouraged to seek exposure to environmental light on sunny days. Sunlight has much higher intensity than light delivered by a light therapy device (see above). Despite the fact that light therapy is now recommended as a treatment of choice for SAD, only in Switzerland has the economic argument that in the long run, light is cheaper than drugs, attained government endorsement and mandatory reimbursement by medical insurance.51 The fact that there is no reimbursement for light therapy has been widely criticized by patients with SAD, their relatives, and experts in the field of SAD.52 Case reports on SAD patients resistant to several antidepressants, but finally responsive to light therapy illustrate that, although depressive symptoms may often be only moderate, SAD can lead to severe impairment in occupational and social functioning and can precipitate catastrophic life events.52,53
like L-tryptophan and vitamin D have been investigated in small studies. The efficacy of these medications has not yet been proven in SAD. Open trials, controlled studies, and placebo-controlled studies in SAD are listed in Tables III to V.54-75 New pharmacological agents are of potential value in the treatment of SAD, for example, agomelatine (Valdoxan). This new dual melatonergic and specific serotonergic antidepressant has been shown to be efficient in the treatment of major depression76: it exhibits a specific core action on circadian rhythms, and therefore could be of particular value in the treatment of SAD. More specific studies are underway to more obtain information about its activity in SAD. Open studies A survey of open studies in SAD is given in Table III.54-61 There is some suggestion from pilot data with small sample sizes that serotonergic agents like fluoxetine, citalopram, and trazodone may be treatment options for SAD.54,57 Tranylcypromine, a nonselective monoamine oxidase inhibitor was effective in the treatment of 14 patients leading to an average 91% reduction in depressive symptoms within 4 weeks of initiation of treatment.55 A study in 20 patients indicates that St Johns wort (Hypericum perforatum) may be helpful in treating SAD. An add-on therapy with bright light in 10 of these patients treated with hypericum did not lead to a significantly better treatment outcome.59 Two studies in 6 patients each report beneficial effects of the benzodiazepine alprazolam.56,60 A 6week open trial investigating efficacy and tolerability of reboxetine, a selective noradrenaline reuptake inhibitor, led to rapid full remission of depressive symptoms in 11 out of 16 patients.61 A rapid relief of preexistent severe atypical symptoms was observed in 9 patients within the
Authors Number Medication of patients Jacobsen et al,54 1989 n=3 Fluoxetine, trazodone Dilsaver and Jaeckle,55 1990 n=14 Tranylcypromine Teicher and Glod,56 1990 n=6 Alprazolam Wirz-Justice et al,57 1992 n=1 Citalopram Lingjaerde et al,58 1993 n=5 Moclobemide Martinez et al,59 1994 n=20 Hypericum Yamadera et al,60 2001 n=6 Alprazolam n=16 Reboxetine Hilger et al,61 2001 Table III. Open studies of pharmacotherapy of seasonal affective disorder (SAD).54-61
Pharmacotherapy
Although light therapy is recommended as the first-line option for SAD, some patients do not experience sufficient relief of depressive symptoms with light. BLT can then be supplemented with antidepressant drugs. Other patients with SAD feel unable to integrate light therapy into their daily routine, or other logistical difficulties in administering light therapy are present. The evidence of SAD being associated with a dysfunction in brain serotonin systems has guided the search for promising pharmacological treatments of SAD. Data emerging from multicenter placebo-controlled trials has led to the recommendation of the SSRIs sertraline and fluoxetine as first-line treatments of SAD. Other antidepressant compounds, like monoamine oxidase inhibitors, dopaminergic and noradrenergic agents, melatonin, -blockers as melatonin antagonists, herbs, and nutritional supplements
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first week of treatment. This finding is of pathophysiological interest since, so far, atypical depressive symptoms like increased appetite, carbohydrate craving, and hypersomnia have been strongly associated with a dysfunction in brain serotonin systems. Controlled studies Placebo-controlled studies Controlled studies of pharmacotherapy in SAD are presented in Table IV.62-66 A study by Ruhrmann et al comparing the SSRI fluoxetine and light therapy in 40 patients with SAD found no significant difference in treatment outcome between the groups, but a faster onset of antidepressant action in the light therapy group.63 Because SAD is prevalent in winter when vitamin D stores are typically low, and because light therapy includes wavelengths that allow the skin to produce vitamin D, the potential role of vitamin D in SAD has been investigated in a small pilot study.65 Vitamin D was reported to lead to a greater improvement of depressive symptoms than light therapy. However, no difference in vitamin D levels has been observed between patients with SAD and healthy subjects,70,77 and the antidepressant effect of light therapy has been shown to be independent of changes in vitamin D levels.77 So far, any benefits of vitamin D on SAD remain unproven. In two small, preliminary trials, 4 to 6 g daily doses of the amino acid Ltryptophan, the precursor of serotonin, were as effective as light therapy.62,64 In a postal survey using an 11-item rating scale, 301 patients with SAD treated with hypericum at 300 mg three times daily for 8 weeks were asked to report changes in their symptoms.66 Of these patients,
Authors McGrath et al,62 1990 Ruhrmann et al,63 1998 Number of patients n=13 n=40
133 used additional light therapy. Significant overall improvement was reported in both treatment groups. Improvement in sleep was greater in the hypericum and light therapy group. However, double-blind research is needed to confirm the usefulness of hypericum (St Johns wort) for treating SAD.
Table V58,67-75 presents placebo-controlled studies of pharmacotherapy in SAD. The best evidence for efficacy of antidepressants in SAD comes from studies of SSRIs. Multicenter, double-blind, randomized studies of fluoxetine and sertraline confirm that these medications are effective in the treatment of SAD. In the fluoxetine study (68 patients), significant improvement in mood was present in both fluoxetine and placebo-treated patients at termination of the study. However, there was significant superiority of fluoxetine over placebo in the clinical response rates (59% versus 34%, respectively).71 In the sertraline study (187 patients), a significant superiority to placebo in both clinical response rates (62% versus 46%, respectively) and depression scores was found. Although they have been widely cited, the data from the sertraline study have only been published as an abstract so far.78 A double-blind study by Lingjaerde et al58 investigating the efficacy of moclobemide, a reversible inhibitor of monoamine oxidase A, versus placebo over 14 weeks found no significant difference in depression scores between groups at study termination. However, within the first week of treatment, patients in the moclobemide group, but not in the placebo group, had a significant reduction in atypical depression symptoms. Testing the
Outcome No significant difference No significant difference, but faster onset of antidepressant action in LT group No significant difference Vitamin D superior to LT Significant improvement in both groups, improvement in sleep greater in hypericum and LT group
Medication and study design L-Tryptophan and LT versus L-tryptophan alone Fluoxetine versus LT
Ghadirian et al,64 1998 Gloth et al,65 1999 Wheatley,66 1999
n=13 n=15 n=168
L-Tryptophan versus LT, crossover study Vitamin D versus LT Hypericum and LT versus hypericum alone
Table IV. Controlled studies of pharmacotherapy of seasonal affective disorder (SAD).62-66 LT, light therapy.
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hypothesis that a dopaminergic deficiency plays a role in the pathophysiology of SAD, Oren et al conducted a small study investigating the efficacy of levodopa plus carbidopa as a treatment for SAD.68 No differences to placebo were found in the rates of response. The melatonin hypothesis of SAD was tested in two studies using the -blockers atenolol67 and propanolol69 to suppress melatonin secretion. No difference in antidepressant efficacy was found between atenolol and placebo. Propanolol was superior to placebo in preventing a depressive relapse in patients with SAD who had previously responded to an open treatment with propanolol. Supplementation with melatonin has shown to be ineffective in patients with SAD when taken at night or in the morning.79 Melatonin has also been reported to even reverse the benefits of light therapy.80 However, a small pilot study with low doses of melatonin in the afternoon showed a significant decrease in depression ratings compared to placebo.72 The authors argue that a replication of this finding in an adequate sample with documentation of expected phase shifts would substantially support the phase shift hypothesis of SAD. A recent 1-year pilot study73 aimed at investigating possible advantages of combining light therapy with the SSRI citalopram. No significant group difference
Authors Number of patients Rosenthal et al,67 1988 n=19 Lingjaerde et al,58 1993 n=34
was found during the initial 10-day light therapy period. However, during the follow-up period depression ratings were significantly lower in the citalopram group compared with the placebo group. The authors conclude that light therapy with continued SSRI treatment may be a useful strategy to achieve beneficial long-term effects in patients with SAD. A study by Lingjaerde et al74 testing the hypothesis that Ginkgo biloba extract may prevent the symptoms of winter depression in patients with SAD yielded negative results. In a recent study metergoline, a nonspecific serotonin antagonist, did not demonstrate a sustained significant effect on mood compared with placebo.75
General management issues

Since there is little evidence comparing light therapy with antidepressant medication, the choice between these alternatives relies on individual assessment of risks and benefits.23 Generally, light therapy is very well accepted by patients.Availability and costs of a light therapy device are sometimes limiting factors, as is the time patients need to commit for daily light therapy. However, BLT should be considered first-line treatment for moderately depressed
Outcome No significant difference No significant difference, but significant reduction of atypical symptoms in moclobemide group No significant difference Significantly higher relapse rates in placebo group No significant difference No significant difference, higher response rate in fluoxetine group Melatonin superior to placebo No significant difference between citalopram and placebo during LT; after LT citalopram superior to placebo No significant difference; gingko significant more effective in preventing new depressive episodes No significant difference
Medication and study design Atenolol versus placebo Moclobemide versus placebo
Oren et al,68 1994 Schlager,69 1994 Oren et al,70 1994 Lam et al,71 1995 Lewy et al,72 1998 Thorell et al,73 1999
n=25 n=23 n=27 n=78 n=10 n=8
Levodopa + carbidopa versus placebo Propanolol versus placebo Vitamin B12 (cyanocobalamine) versus placebo Fluoxetine versus placebo Melatonin versus placebo LT and citalopram versus LT and placebo Ginkgo biloba versus placebo
Lingjaerde et al,74 1999
n=27
Turner et al,75 2002
n=16
Metergoline versus placebo
Table V. Placebo-controlled studies of pharmacotherapy of seasonal affective disorder (SAD).58,67-75 LT, light therapy.
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patients and patients with prominent atypical depressive symptoms. Generally, light therapy alone or in combination with antidepressants should be given for the duration of the dark time of year, ie, until April or May in the northern hemisphere.A trial of light therapy should last at least 2 to 4 weeks. A trial of antidepressants should last 4 to 6 weeks. Light therapy and medication trials should be applied sequentially, as combining them from the beginning on will lead to a loss of information about which treatment is beneficial, or which treatment is causing side effects. A combination of both treatments should be considered if there is insufficient response to either pharmacological or light treatment. If a depressive episode is resistant to the combination of BLT and an antidepressant, options are lengthening light treatment time, raising the dose of the antidepressant, or switching to a drug of a different class. Although there are no specific data available for SAD, treatment should follow algorithms for treatment-resistant depression if a sufficient response still cannot be achieved. Pharmacological augmentation strategies, electroconvulsive therapy, or sleep deprivation procedures81 should then be considered.
Tratamiento de los trastornos afectivos estacionales

El trastorno afectivo estacional (TAE) es un subtipo del trastorno depresivo mayor recurrente o del trastorno bipolar, con una aparicin regular de episodios depresivos en cierta poca del ao, especialmente en invierno. El tratamiento del TAE es similar al de otros tipos de trastorno afectivo, excepto que la terapia con luz brillante se recomienda como opcin de primera lnea. Convencionalmente la terapia lumnica se refiere a la exposicin a luz visible de al menos 2500 lux de intensidad a nivel del ojo. Se piensa que los efectos de la fototerapia son mediados exclusivamente por los ojos, no por la piel, aunque esta hiptesis no ha sido aun verificada. La terapia lumnica matinal ha probado ser superior a las aplicaciones vespertinas. Los porcentajes de respuesta a la fototerapia son cercanos al 80% en poblaciones seleccionadas de pacientes y los sntomas depresivos atpicos son el mejor predictor de una evolucin favorable al tratamiento. Datos de ensayos controlados, randomizados sugieren que los antidepresivos son efectivos en el tratamiento del TAE. Se han realizado tres estudios doble ciego, controlados con placebo que han mostrado resultados promisorios para los inhibidores selectivos de la recaptacin de serotonina (ISRS) sertralina y fluoxetina, y tambin para moclobemida, un inhibidor reversible de la monoamino-oxidasa A.
Traitement du trouble affectif saisonnier

Le trouble affectif saisonnier (TAS) reprsente un sous-groupe des troubles dpressif majeur rcurrent ou bipolaire et se caractrise par linstallation rgulire dpisodes dpressifs certaines priodes de lanne, gnralement en hiver. Le traitement du TAS est semblable celui des autres formes de troubles affectifs, si ce nest que la photothrapie lumire vive est recommande en premire intention. La photothrapie conventionnelle implique lexposition une lumire du spectre visible dune intensit suprieure 2 500 lux au niveau de lil. Les effets de la photothrapie sont considrs comme mdis exclusivement par les yeux et non la peau, bien que cette hypothse nait pas encore t vrifie. La photothrapie matinale sest avre suprieure au schma thrapeutique vespral. Les taux de rponse la photothrapie sont denviron 80 % dans des populations slectionnes de patients, les symptmes dpressifs atypiques tant le meilleur facteur prdictif dvolution thrapeutique favorable. Des donnes issues dtudes randomises, contrles, suggrent que les antidpresseurs sont efficaces dans le traitement du TAS. Trois tudes en double aveugle, contre placebo, ont t ralises, montrant des rsultats prometteurs pour les inhibiteurs slectifs de la recapture de la srotonine (ISRS), la sertraline et la fluoxtine, ainsi que pour un inhibiteur de la monoamine oxydase slectif A (IMAO slectif A), le moclobmide.
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REFERENCES
1. Rosenthal NE, Sack DA, Gillin JC, et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry. 1984;41:72-80. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 3. Kasper S, Wehr TA, Bartko JJ, Gaist PA, Rosenthal NE. Epidemiological findings of seasonal changes in mood and behavior. A telephone survey of Montgomery County, Maryland. Arch Gen Psychiatry. 1989;46:823-833. 4. Winkler D, Willeit M, Praschak-Rieder N, et al. Changes of clinical pattern in seasonal affective disorder (SAD) over time in a German-speaking sample. Eur Arch Psychiatry Clin Neurosci. 2002;252:54-62. 5. Terman JS, Terman M, Lo ES, Cooper TB. Circadian time of morning light administration and therapeutic response in winter depression. Arch Gen Psychiatry. 2001;58:69-75. 6. Michalak EE, Hayes S, Wilkinson C, Hood K, Dowrick C. Treatment compliance in light therapy. Do patients do as they say they do? J Affect Disord. 2002;68:341-342. 7. Horowitz TS, Tanigawa T. Circadian-based new technologies for night workers. Ind Health. 2002;40:223-236. 8. Burgess HJ, Sharkey KM, Eastman CI. Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Sleep Med Rev. 2002;6:407-420. 9. Graf A, Wallner C, Schubert V, et al. The effects of light therapy on minimental state examination scores in demented patients. Biol Psychiatry. 2001;50:725-727. 10. Ancoli-Israel S, Martin JL, Kripke DF, Marler M, Klauber MR. Effect of light treatment on sleep and circadian rhythms in demented nursing home patients. J Am Geriatr Soc. 2002;50:282-299. 11. Terman M, Lewy AJ, Dijk DJ, Boulos Z, Eastman CI, Campbell SS. Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances. J Biol Rhythms. 1995;10:135-147. 12. Montgomery P, Dennis J. Bright light therapy for sleep problems in adults aged 60+. Cochrane Database Syst Rev. 2002:CD003403. 13. Loving RT, Kripke DF, Shuchter SR. Bright light augments antidepressant effects of medication and wake therapy. Depress Anxiety. 2002;16:1-3. 14. Oren DA, Wisner KL, Spinelli M, et al. An open trial of morning light therapy for treatment of antepartum depression. Am J Psychiatry. 2002;159:666-669. 15. Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita M, Smeraldi E. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psychiatry. 2003;64:648-653. 16. Terman M, Terman JS, Quitkin FM, McGrath PJ, Stewart JW, Rafferty B. Light therapy for seasonal affective disorder. A review of efficacy. Neuropsychopharmacology. 1989;2:1-22. 17. Thompson C, Rodin I, Birtwhistle J. Light therapy for seasonal and nonseasonal affective disorder: a Cochrane meta-analysis. Soc Light Treatment Biol Rhythms Abstr. 1999:11. Abstract. 18. Eastman CI, Young MA, Fogg LF, Liu L, Meaden PM. Bright light treatment of winter depression: a placebo-controlled trial. Arch Gen Psychiatry. 1998;55:883-889. 19. Eastman CI, Lahmeyer HW, Watell LG, Good GD, Young MA. A placebocontrolled trial of light treatment for winter depression. J Affect Disord. 1992;26:211-221. 20. Terman M, Terman JS, Ross DC. A controlled trial of timed bright light and negative air ionization for treatment of winter depression. Arch Gen Psychiatry. 1998;55:875-882. 21. Avery DH. A turning point for seasonal affective disorder and light therapy research? Arch Gen Psychiatry. 1998;55:863-864. 22. Lewy AJ, Bauer VK, Cutler NL, et al. Morning vs evening light treatment of patients with winter depression. Arch Gen Psychiatry. 1998;55:890-896. 23. Lam RW, Levitt AJ. Canadian Consensus Guidelines for the Treatment of SAD. A Summary of the Report of the Canadian Consensus Group on SAD. Vancouver, Canada: Clinical & Academic Publishing; 1999. 24. Horne JA, stberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol. 1976;4:97-110.
25. The Automated Morningness-Eveningness Questionnaire. Available at: http://www.cet.org. Norwood, NJ: Center for Environmental Therapeutics. Accessed 22 September 2003. 26. Thalen BE, Kjellman BF, Morkrid L, Wetterberg L. Seasonal and nonseasonal depression. A comparison of clinical characteristics in Swedish patients. Eur Arch Psychiatry Clin Neurosci. 1995;245:101-108. 27. Terman M, Schlager D, Fairhurst S, Perlman B. Dawn and dusk simulation as a therapeutic intervention. Biol Psychiatry. 1989;25:966-970. 28. Avery DH, Bolte MA, Dager SR, et al. Dawn simulation treatment of winter depression: a controlled study. Am J Psychiatry. 1993;150:113-117. 29. Avery DH, Bolte MA, Wolfson JK, Kazaras AL. Dawn simulation compared with a dim red signal in the treatment of winter depression. Biol Psychiatry. 1994;36:180-188. 30. Avery DH, Kouri ME, Monaghan K, Bolte MA, Hellekson C, Eder D. Is dawn simulation effective in ameliorating the difficulty awakening in seasonal affective disorder associated with hypersomnia? J Affect Disord. 2002;69:231-236. 31. Lingjaerde O, Foreland AR, Dankertsen J. Dawn simulation vs lightbox treatment in winter depression: a comparative study. Acta Psychiatr Scand. 1998;98:73-80. 32. Terman M, Terman JS. Bright light therapy: side effects and benefits across the symptom spectrum. J Clin Psychiatry. 1999;60:799-808. Quiz 809. 33. Labbate LA, Lafer B, Thibault A, Sachs GS. Side effects induced by bright light treatment for seasonal affective disorder. J Clin Psychiatry. 1994;55:189191. 34. Praschak-Rieder N, Neumeister A, Hesselmann B, Willeit M, Barnas C, Kasper S. Suicidal tendencies as a complication of light therapy for seasonal affective disorder: a report of three cases. J Clin Psychiatry. 1997;58:389-392. 35. Oren DA, Jacobsen FM, Wehr TA, Cameron CL, Rosenthal NE. Predictors of response to phototherapy in seasonal affective disorder. Compr Psychiatry. 1992;33:111-114. 36. Terman M, Amira L, Terman JS, Ross DC. Predictors of response and nonresponse to light treatment for winter depression. Am J Psychiatry . 1996;153:1423-1429. 37. Lam RW. Morning light therapy for winter depression: predictors of response. Acta Psychiatr Scand. 1994;89:97-101. 38. Reichborn-Kjennerud T, Lingjaerde O. Response to light therapy in seasonal affective disorder: personality disorders and temperament as predictors of outcome. J Affect Disord. 1996;41:101-110. 39. Levitt AJ, Joffe RT, Brecher D, MacDonald C. Anxiety disorders and anxiety symptoms in a clinic sample of seasonal and non-seasonal depressives. J Affect Disord. 1993;28:51-56. 40. Lam RW, Levitan RD. Pathophysiology of seasonal affective disorder: a review. J Psychiatry Neurosci. 2000;25:469-480. 41. Neumeister A, Konstantinidis A, Praschak-Rieder N, et al. Monoaminergic function in the pathogenesis of seasonal affective disorder. Int J Neuropsychopharmacol. 2001;4:409-420. 42. Willeit M, Praschak-Rieder N, Neumeister A, et al. [123I]-Beta-CIT SPECT imaging shows reduced brain serotonin transporter availability in drugfree depressed patients with seasonal affective disorder. Biol Psychiatry. 2000;47:482-489. 43. Neumeister A, Praschak-Rieder N, Besselmann B, Rao ML, Gluck J, Kasper S. Effects of tryptophan depletion on drug-free patients with seasonal affective disorder during a stable response to bright light therapy. Arch Gen Psychiatry. 1997;54:133-138. 44. Neumeister A, Pirker W, Willeit M, et al. Seasonal variation of availability of serotonin transporter binding sites in healthy female subjects as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry. 2000;47:158160. 45. Lewy AJ, Cutler NL, Sack RL. The endogenous melatonin profile as a marker for circadian phase position. J Biol Rhythms. 1999;14:227-236. 46. Lewy AJ, Sack RL, Miller LS, Hoban TM. Antidepressant and circadian phase-shifting effects of light. Science. 1987;235:352-354. 47. Wehr TA, Duncan WC, Jr, Sher L, et al. A circadian signal of change of season in patients with seasonal affective disorder. Arch Gen Psychiatry. 2001;58:1108-1114.
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48. Campbell SS, Murphy PJ. Extraocular circadian phototransduction in humans. Science. 1998;279:396-399. 49. Lockley SW, Skene DJ, Thapan K, et al. Extraocular light exposure does not suppress plasma melatonin in humans. J Clin Endocrinol Metab. 1998;83:3369-3372. 50. Eastman CI, Martin SK, Hebert M. Failure of extraocular light to facilitate circadian rhythm reentrainment in humans. Chronobiol Int. 2000;17:807-826. 51. Wirz-Justice A. Beginning to see the light. Arch Gen Psychiatry. 1998;55:861-862. 52. Kanofsky JD, Aspengren KL, Watts GR. Medicaid reimbursement for light therapy. Am J Psychiatry. 2003;160:796-797. 53. Ibatoullina E, Praschak-Rieder N, Kasper S. Severe atypical symptoms without depression in SAD: effects of bright light therapy. J Clin Psychiatry. 1997;58:495. 54. Jacobsen FM, Murphy DL, Rosenthal NE. The role of serotonin in seasonal affective disorder and the antidepressant response to phototherapy. In: Rosenthal NE, Blehar MC, eds. Seasonal Affective Disorder and Phototherapy. New York, NY: Guilford; 1989:333-341. 55. Dilsaver SC, Jaeckle RS. Winter depression responds to an open trial of tranylcypromine. J Clin Psychiatry. 1990;51:326-329. 56. Teicher MH, Glod CA. Seasonal affective disorder: rapid resolution by low-dose alprazolam. Psychopharmacol Bull. 1990;26:197-202. 57. Wirz-Justice A, van der Velde P, Bucher A, Nil R. Comparison of light treatment with citalopram in winter depression: a longitudinal single case study. Int Clin Psychopharmacol. 1992;7:109-116. 58. Lingjaerde O, Reichborn-Kjennerud T, Haggag A, Gartner I, Narud K, Berg EM. Treatment of winter depression in Norway. II. A comparison of the selective monoamine oxidase A inhibitor moclobemide and placebo. Acta Psychiatr Scand. 1993;88:372-380. 59. Martinez B, Kasper S, Ruhrmann S, Moller HJ. Hypericum in the treatment of seasonal affective disorders. J Geriatr Psychiatry Neurol. 1994;7(suppl 1):S29-S33. 60. Yamadera H, Okawa M, Takahashi K. Open study of effects of alprazolam on seasonal affective disorder. Psychiatry Clin Neurosci. 2001;55:27-30. 61. Hilger E, Willeit M, Praschak-Rieder N, Stastny J, Neumeister A, Kasper S. Reboxetine in seasonal affective disorder: an open trial. Eur Neuropsychopharmacol. 2001;11:1-5. 62. McGrath RE, Buckwald B, Resnick EV. The effect of L-tryptophan on seasonal affective disorder. J Clin Psychiatry. 1990;51:162-163. 63. Ruhrmann S, Kasper S, Hawellek B, et al. Effects of fluoxetine versus bright light in the treatment of seasonal affective disorder. Psychol Med. 1998;28:923-933. 64. Ghadirian AM, Murphy BE, Gendron MJ. Efficacy of light versus tryptophan therapy in seasonal affective disorder. J Affect Disord. 1998;50:23-27. 65. Gloth FM, 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging. 1999;3:5-7. 66. Wheatley D. Hypericum in seasonal affective disorder (SAD). Curr Med Res Opin. 1999;15:33-37. 67. Rosenthal NE, Jacobsen FM, Sack DA, et al. Atenolol in seasonal affective disorder: a test of the melatonin hypothesis. Am J Psychiatry. 1988;145:52-56. 68. Oren DA, Moul DE, Schwartz PJ, Wehr TA, Rosenthal NE. A controlled trial of levodopa plus carbidopa in the treatment of winter seasonal affective disorder: a test of the dopamine hypothesis. J Clin Psychopharmacol. 1994;14:196-200. 69. Schlager DS. Early-morning administration of short-acting -blockers for treatment of winter depression. Am J Psychiatry. 1994;151:1383-1385. 70. Oren DA, Schulkin J, Rosenthal NE. 1,25-(OH)2-Vitamin D3 levels in seasonal affective disorder: effects of light. Psychopharmacology (Berl). 1994;116:515-516. 71. Lam RW, Gorman CP, Michalon M, et al. Multicenter, placebo-controlled study of fluoxetine in seasonal affective disorder. Am J Psychiatry. 1995;152:1765-1770. 72. Lewy AJ, Bauer VK, Cutler NL, Sack RL. Melatonin treatment of winter depression: a pilot study. Psychiatry Res. 1998;77:57-61. 73. Thorell LH, Kjellman B, Arned M, Lindwall-Sundel K, Walinder J, Wetterberg L. Light treatment of seasonal affective disorder in combination with citalopram or placebo with 1-year follow-up. Int Clin Psychopharmacol. 1999;14(suppl 2):S7-S11. 74. Lingjaerde O, Foreland AR, Magnusson A. Can winter depression be prevented by Ginkgo biloba extract? A placebo-controlled trial. Acta Psychiatr Scand. 1999;100:62-66. 75. Turner EH, Schwartz PJ, Lowe CH, et al. Double-blind, placebo-controlled study of single-dose metergoline in depressed patients with seasonal affective disorder. J Clin Psychopharmacol. 2002;22:216-220. 76. Lo H, Hale A, Dhaenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2c antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol. 2002;17:239-247. 76. Partonen T, Vakkuri O, Lamberg-Allardt C, Lonnqvist J. Effects of bright light on sleepiness, melatonin, and 25-hydroxyvitamin D(3) in winter seasonal affective disorder. Biol Psychiatry. 1996;39:865-872. 77. Moscovitch A, Blashko C, Wiseman R. A double-blind, placebo-controlled study of sertraline in patients with seasonal affective disorder. New Research Abstracts, 151st Meeting of the American Psychiatric Association. Toronto, Canada.1995. Abstract. 78. Wirz-Justice A, Graw P, Krauchi K, et al. Morning or night-time melatonin is ineffective in seasonal affective disorder. J Psychiatr Res. 1990;24:129-137. 79. Rosenthal NE, Sack DA, Jacobsen FM, et al. Melatonin in seasonal affective disorder and phototherapy. J Neural Transm Suppl. 1986;21:257-267. 80. Graw P, Haug HJ, Leonhardt G, Wirz-Justice A. Sleep deprivation response in seasonal affective disorder during a 40-h constant routine. J Affect Disord. 1998;48:69-74.
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Clinical applications of melatonin in circadian disorders
Alfred J. Lewy, MD, PhD
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 some cases, it may be necessary to measure internal circadian phase, using the time when endogenous melatonin levels rise.
Keywords: melatonin; circadian phase; seasonal affective disorder; circadian sleep disorder; the blind; jet lag; shift work Author affiliations: Sleep and Mood Disorders Laboratory, Oregon Health Science University, Portland, Ore, USA Address for correspondence: Sleep and Mood Disorders Laboratory, Oregon Health Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA (e-mail: lewy@ohsu.edu) Copyright 2003 LLS SAS. All rights reserved
elatonin appears to be useful in two ways to the field of human chronobiology. One role is as a marker for biological rhythms.The other role is as a circadian phaseshifting agent. Both roles appear to be important. In virtually all organisms, melatonin is produced mainly during nighttime darkness.1,2 In most vertebrates, circulating melatonin levels are derived exclusively from the pineal gland.3,4 In most mammals, the changing duration of melatonin production throughout the year is the cue for seasonal rhythms.5 In some mammals, such as humans, a feedback loop exists between melatonin and the endogenous circadian pacemaker.6-13 An approximately 24-h (hence, circadian) rhythm in melatonin is generated by 12 h of (usually daytime) inhibition of an otherwise constantly on signal from the paraventricular nucleus of the hypothalamus.14 This inhibition comes from the endogenous circadian pacemaker, located in the suprachiasmatic nucleus (SCN).15-17 The pineal gland is then stimulated to produce melatonin for about 12 h via a neural pathway that traverses through the intermedullary column and thoracic sympathetic outflow (Figure 1).18 Preganglionic neurons synapse in the superior cervical ganglion with postganglionic neurons that enter the cranium and innervate pinealocytes.19 The latter release the sympathetic neurotransmitter, norepinephrine, which stimulates 1-adrenergic receptors and results in the synthesis and secretion of melatonin, which is then released into blood and cerebrospinal fluid (CSF).20 Receptors for melatonin have been identified in a number of sites, including the SCN.21,22 The approximately 24-h rhythm generated by the SCN becomes precisely 24 h via photic input from ganglion cells in the retina.23,24 At least one novel photoreceptor has been identified that mediates circadian entrainment.25 The pathway from the retina to the hypothalamus, the retinohypothalamic tract, is different from that which mediates vision.26
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ASPS BFR CSD CT DLMO DSPS MO PRC PSH SAD SCN ZT advanced sleep phase syndrome blind free-runner circadian sleep disorder circadian time dim light melatonin onset delayed sleep phase syndrome melatonin onset phase response curve phase shift hypothesis seasonal affective disorder suprachiasmatic nucleus zeitgeber time about 14 h after waketime in entrained, sighted people, and the DLMO2 occurs about 1 h earlier.13,44,45 The light zeitgeber (German for time-giver, or time cue) first occurs each day at waketime.46 In the circadian literature, this is called zeitgeber time 0 (ZT 0). (Sometimes the term circadian time [CT] is used under certain circumstances; although they are technically different, ZT and CT will be used interchangeably in this monograph, in order to minimize confusion on the part of readers who are not experts in chronobiology.) As mentioned above, the average CT or ZT of the plasma DLMO10 is 14 h in entrained, sighted people. The DLMO ZT also describes the relationship between the circadian rhythms that are tightly coupled to the SCN (such as melatonin) and those that are more loosely coupled (such as the
The light/dark cycle synchronizes the SCN, and therefore its many driven circadian rhythms, to the 24-h day.27,28 Unique to melatonin, light acutely suppresses its production.29 Thus, if the SCN has not turned off melatonin production in the morning, exposure to light will. Also, light exposure at the end of the day will suppress the evening rise in melatonin production.30 These effects of light shape the melatonin profile. As mentioned above, annual rhythms common to many mammals receive their seasonal time cue from the changing duration of melatonin production, thought to define the biological night. Whether or not humans have important seasonal rhythms is a matter of some controversy.31,32 If humans have important seasonal rhythms, it is thought that the duration of melatonin production would regulate them. Not controversial is the fact that, similar to other animals, humans have circadian rhythms that are primarily regulated by the light/dark cycle.30,33-38
Neuroanatomy of the circadian system
Pineal gland
Retinohypothalamic tract
The endogenous melatonin profile as a marker for circadian phase position

In humans, the melatonin profile is the most reliable marker for circadian phase (Figure 2).39-41 The time that melatonin levels rise appears to be a useful phase maker. The melatonin onset (MO) is a clearly demarcated event. It can be operationally defined in a number of ways, some of which use a threshold (2 pg/mL, 10 pg/mL, etc), which appears as a subscript in the acronym.42 In order to minimize the acute suppressant effect of light, plasma samples are collected under dim light (optimally, less than 30 lux). Therefore, in sighted people this marker is called the dim light melatonin onset (DLMO).43 The plasma DLMO10 occurs on average
Suprachiasmatic nuclei Paraventricular nucleus Superior cervical ganglion
Thoracic intermediolateral nuclei
Figure 1. Schematic diagram depicting neuroanatomic regulation of mammalian melatonin production.

Reproduced from reference 18: Vessely LH, Lewy AJ. Melatonin as a hormone and as a marker for circadian phase position in humans. In: Pfaff D, Arnold A, Etgen A, Fahrbach S, Rubin R, eds. Hormones, Brain and Behavior, Vol 5. San Diego, Calif: Elsevier Science; 2002:121-141. Copyright 2002, Elsevier Science.
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sleep/wake cycle, for example, waketime). Therefore, any mismatch in circadian rhythms will be reflected in a ZT that differs from the 14-h standard.
The light PRC

Lights phase-shifting effects on circadian rhythms can be explained by a phase response curve (PRC). Its essential features are that light exposure in the morning causes a phase advance (shift to an earlier time) and that light exposure in the evening causes a phase delay (shift to a later time).33,36,47 In addition, maximal phase shifts occur in the middle of the night, and minimal phase shifts occur during the middle of the day.48-51 PRCs are usually plotted according to CT. The break points that separate advance and delay responses for the light PRC are 12 h apart: they occur at CT 6 and CT 18. Converting to clock time for an individual who habitually awakens at 7.00 AM, these are 1.00 PM and 1.00 AM, respectively. With regard to the light PRC, there are several investigators who think that these break points occur a few hours later.52 The jury is out on this question.
50 Plasma melatonin levels (pg/mL) 40 30 20 10 Endogenous melatonin profile PRC
As mentioned above, light is the most potent circadian zeitgeber in virtually all organisms. However, this was not fully appreciated in humans until it was shown that humans require brighter light for this effect than other animals, which was dramatically demonstrated with respect to acute suppression of melatonin production.53 The phase-shifting and suppressant effects of light are thought to be closely associated. Since sunlight (10 000100 000 lux) is usually brighter than indoor light, humans might be responding to the natural light/dark cycle, relatively unaffected by ordinary-intensity indoor light (200500 lux). A second implication is that bright artificial light could be substituted for sunlight, in order to experimentally (and perhaps therapeutically) manipulate biological rhythms in humans.
Winter depression (SAD)

One of the first therapeutic uses of bright light was to treat winter depression, or seasonal affective disorder (SAD).54,55 Bright light has also been used to treat nonseasonal depression,56 which is reviewed elsewhere (see
The greatest phase advances occur when exogenous melatonin is given here.
2 pg/mL MO (CT 13)
The endogenous melatonin profile and the melatonin PRC shift later after each day in a BFR, relative to clock time and sleep.
CT 18
CT 6
The end of the delay zone of the melatonin PRC is 7 h before the 2 pg/mL MO.
CT 18
The end of the advance zone of the melatonin PRC is 5 h after the 2 pg/mL MO.
Relationship between the sleep/wake cycle and the endogenous melatonin profile/melatonin PRC, when the latter has drifted into the normal entrainment phase.
The 2 pg/mL occurs 3 h before sleep during normal entrainment.
Sleep
Figure 2. Relationship between the endogenous melatonin profile, the melatonin phase response curve (PRC), and the sleep/wake cycle. MO, melatonin onset; BFR, blind free-runner; CT, circadian time.
Adapted from reference 41: Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires MLN, Sack RL. Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin. Brain Res. 2001;918:96-100. Copyright 2001, Elsevier Science BV.
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Parrys and Wirz-Justices contributions to this volume57,58), as well as many of the hypotheses for SAD (see Parrys, Wirz-Justices and Praschak-Rieders contributions to this volume57-59) and so these will not be covered here. This monograph will concentrate on diagnosing circadian phase disorders using the endogenous melatonin profile and on the basic principles for treating them. The leading hypothesis for SAD is the phase shift hypothesis (PSH).33 According to the PSH, the typical SAD patient becomes depressed in the winter, at least in part because of a phase delay of circadian rhythms (marked by the DLMO) with respect to sleep,33,60,61 having a mismatch in circadian rhythms (similar to jet lag), which persists for several months. Therefore, bright light exposure should be most antidepressant when it is scheduled in the morning, when it would be expected to cause a corrective phase advance. Bright light exposure in the morning should certainly be more antidepressant than evening bright light, which would be expected to cause a phase delay. The first major test of the PSH was a crossover study of eight patients and seven control subjects.36 There was a small, but statistically significant, delay of the DLMO in patients compared to controls at prebaseline and at the end of the initial week of baseline conditions (sleep permitted only between 10.00 PM and 6.00 AM). Two hours of morning bright light (2500 lux) caused advances in the DLMO; evening bright light caused delays. The combination of morning plus evening light (which was the last treatment week) moved the DLMO towards its baseline time. Morning light produced a significant antidepressant effect compared with baseline and with evening light. The combination was again intermediate between that of morning light alone and evening light alone. This study was by and large replicated a few years later.62,63 Since then, not much has changed in the recommended light treatment regimen, except that light intensity can be as great as 10 000 lux,64 and perhaps 1 h per day is sufficient, as long as it is scheduled immediately upon awakening. Once treatment is satisfactory, the duration of light exposure can almost always be reduced.65 Several other studies have supported these findings, but some have not66,67: these studies were usually paralleldesigned, so that patients themselves did not have the opportunity to compare light exposure at different times (which would have minimized the placebo component). In 1998, three independent research groups published large-N studies in which morning light was shown to be more antidepressant than evening light, thereby moving the field towards consensus about the superiority of morning light.45,68,69 However, superior efficacy of morning light does not necessarily prove the PSH, because it could be more antidepressant at this time for some reason other than causing a phase advance. However, it has been shown that the antidepressant response to morning light does, in some circumstances, correlate with the amount of phase advance in the DLMO. This was first reported with respect to treatment group means,61 followed by an analysis70 of individual DLMOs and depression scores collected independently.36,63 More recently, this latter finding was essentially replicated using another data set.71 Further support of the PSH along these lines will be discussed below. It should also be noted that a very small subgroup of SAD patients appear to be cueing to dusk and should be treated with evening bright light; clinically, these patients can be identified by a history of early morning awakening year round, going to bed much earlier in the winter.65 In any event, the earliest and most common use of the DLMO has been to assess the phase-shifting effects of light. Bright light has also been used to treat a number of other circadian phase disorders, such as advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), jet lag, and shift work maladaptation (see below).
The melatonin PRC

The phase-shifting effects of melatonin are also described by a PRC. The melatonin PRC is about 12 h out of phase with the light PRC.13,44 Both PRCs are phase-locked to each other, as well as to the melatonin profile (Figure 2). As mentioned above, waketime is usually designated ZT 0. Sleep time is therefore usually ZT 16. In the melatonin PRC studies of sighted people, the baseline plasma DLMO10 was designated CT 14. It is also designated CT 14 in free-running blind people. We call this phase marker the MO in blind people. Saliva can also be used (at this time of the night, salivary melatonin levels are about one-third those of plasma).72 Measuring the MO in blind people provides a reference point to determine the phase of the endogenous circadian pacemaker and the melatonin PRC. Unless stated otherwise, in the following the MO refers to the plasma 10 pg/mL threshold or its salivary equivalent (3 pg/mL). The melatonin PRC was first described using four daily doses of 0.5 mg mela-
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tonin in sighted people. It has been by and large replicated by two other research groups.73,74 In sighted people who habitually awaken at 7.00 AM, the break points that divide the two intervals of the melatonin PRC occur at 1.00 PM (CT 6) and 1.00 AM (CT 18), just as with the light PRC. The phase-advance zone is between 1.00 AM and 1.00 PM; the phase-delay zone is between 1.00 AM and 1.00 PM. Once again, the phaseadvance zone of the melatonin PRC extends from CT 6 to CT 18, and the phase-delay zone extends from CT 18 to CT 6. Therefore, once the time of the MO is known, the advance zone extends from 8 h before the MO until 4 h after the MO. The delay zone extends from 4 h after the MO until 8 h before the MO.
Treating SAD patients with melatonin: the importance of creating overlap

Creating overlap may be an important principle in optimizing melatonins phase-shifting effects. This was demonstrated in a pilot study treating SAD patients with melatonin.75 In order to avoid the soporific side effect of sleepiness that occurs in some people, the dose of melatonin is kept to a minimum, so as to reduce the initial spike in melatonin levels following an oral, immediaterelease formulation. However, according to the melatonin PRC, the earlier melatonin is given in the afternoon (at least for the second half of the advance zone), the greater the magnitude of the phase-advance shift. If a low dose is given too early, however, there will be a melatonin-free interval between the end of the exogenous pulse and the beginning of the endogenous melatonin profile that occurs about 14 h after waketime in entrained, sighted people. Therefore, a second (or even a third or possibly fourth) small dose of melatonin is given to create overlap between elevated melatonin levels arising from exogenous and endogenous sources, so that the SCN is exposed to one continuous melatonin signal. Recently, a more definitive test of the PSH for SAD was completed, using three to four small doses of melatonin (0.075-0.1 mg) given every 2 h in the morning or in the afternoon/evening. One hundred patients were studied over four winters. One-third of them did not receive melatonin in any capsule, although all subjects took the same number of capsules per day. Subjects were held to consistent bedtimes and waketimes of their choosing. The results supported the PSH. In the most phase-delayed group of patients (those with a DLMO ZT >14.6), there
was a significant correlation between the amount of phase delay at baseline and the severity of depression ratings. After 3 weeks of treatment, this correlation remained significant, but only if depression severity was analyzed with regard to the absolute difference from the hypothesized normal ZT of 14. Change scores analyzed in this way were also statistically significant: as DLMO ZT normalized, depression ratings improved.This may be one of the first examples of a physiological marker that correlates with psychopathology at baseline and posttreatment. These data are consistent with the clinical observation that too much of a phase advance can result in a return of symptoms. In any event, morning light appears to be more antidepressant than evening light in typical SAD patients, because, at least in part, it is correcting a phase delay that occurs in SAD patients when they become depressed in the winter. Using SAD as a model chronobiological psychiatric (affective) disorder, it would now seem timely to investigate other disorders, in order to assess the contribution of a mismatch between circadian rhythms to the pathology.
Treating free-running totally blind people with melatonin: the importance of avoiding spillover
About 15% of blind people completely lack light perception. Most, if not all of them, have abnormal circadian rhythms, and many of them free-run, whereby their MOs drift a little later each day. When they are out of phase, they find it difficult to sleep at night and are tired during the daya burden described by some as second only to lack of vision. A daily drift in sleep times is not usually observed. However, assessment of physiological rhythms clearly indicates this daily drift in the phase of the endogenous circadian pacemaker. Any of several circadian rhythms can be measured, including cortisol and temperature.76-79 However, these are masked by changes in activity.80 Melatonin production is masked only by light,53 which is not an issue in blind people. A number of studies now document circadian abnormalities in the totally blind population.81-83 The MO has proved to be a useful phase marker in blind people, whether it is extracted from 1-h samples over 24 h or from sampling every 30 to 60 min within a narrower window when it is expected to occur. However, as will be explained below, assessing MOs is not absolutely necessary in diagnosing and treating most cases.
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0 24.92 h
60 150 24.87 h 24.34 h 24.89 h 270
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c
390 24.36 h
450 1060 24.95 h
1120
24.58 h 24.85 h
d e
1180 23.98 h 0 24
1240 48 72 96 120
Time (h)
Figure 3. A totally blind subject with free-running circadian rhythms during four trials of oral melatonin administration. Each data point represents an assessment of circadian phase as determined by successive measurements of the time that endogenous plasma melatonin concentrations rose above the 10 pg/mL threshold. Vertical lines represent the timing and duration of exogenous melatonin administration. The slopes of the fitted regression lines indicate circadian period (shown in hours beside the regression lines) during a given treatment. The calculated circadian periods represent mean determinations between days of assessment; fluctuation of circadian period probably occurs as the melatonin dose stimulates different parts of the shifting phase response curve (PRC). a. Baseline free-running circadian rhythm of 24.92 h. b. Administration of 10 mg melatonin for 17 days beginning at CT 20.5 led to a shortened period of 24.34 h without entrainment. c. Administration of 9 to 10 mg of melatonin over 83 days again failed to entrain this subject but shortened circadian period to 24.36 h. d. Administration of 20 mg initially at CT 14.6 shortened the subjects circadian period to 24.58 h after 60 days. e. Administration of 0.5 mg, initially at CT 20.6, caused entrainment (circadian period of 23.98 h) after 47 days.
Reproduced from reference 92: Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int. 2002;19:649-658. Copyright 2002, Marcel Dekker.
Following the discovery that light can suppress melatonin production in humans,53 the obvious next step was to assess the melatonin profiles of blind people. One-day assessments indicated that melatonin levels were continuously elevated for about 12 h out of every 24 h, similar to sighted people.84 However, it was not always confined to night. Two bilaterally enucleated people were studied longitudinally85: one of them appeared to be stably entrained, but 180 out of phase (that is, melatonin levels peaked in the middle of the day, week after week); the other was freerunning with an intrinsic circadian period (tau, or ) of 24.7 h (that is, the endogenous melatonin profile shifted later at a rate of about 0.7 h per day or about 5 h per week). Several studies have since confirmed that the circadian rhythms of blind people are of three types: normally entrained, abnormally entrained, and free-running.85 When out of phase, these individuals have difficulty sleeping at night and take more naps during the day.The melatonin rhythm reflects the phase of all other endogenous circadian rhythms, including those of cortisol, temperature, and sleep propensity (see above). As mentioned earlier, another use of melatonin is to give it exogenously in order to cause phase shifts.13 Inspired by animal studies,86 these effects were most conclusively demonstrated by entraining free-running blind people (blind free-runners [BFRs]) with a daily dose of melatonin.87 Although an early subject showed apparent entrainment to a dose of about 7 mg,88-90 entrainment of BFRs was conclusively demonstrated using a dose of 10 mg.87,91 Only one of seven BFRs failed to entrain to the 10-mg dose; this BFR had the longest tau (24.9 h). Although the melatonin PRC was experimentally determined in sighted people, it appears to apply to blind people as well. Currently, more is known about the phaseadvance zone of the melatonin PRC: for at least the second half of the advance zone, the earlier melatonin is given, the greater the magnitude of the phase-advance shift. When melatonin is given daily to a free-running blind person, the melatonin PRC will continue to drift later and later until exogenous melatonin is hitting the point on the melatonin PRC that will produce a phase advance equal to the daily drift (this is called the entrainment point on the melatonin PRC and will vary between individuals, depending in part on the intrinsic tau).Then, the endogenous pacemaker will lock on to the daily melatonin dose. For example, if a BFRs intrinsic circadian period, or tau, is 24.4 h, the melatonin dose will stop the pacemaker from drifting later when it is stimulating that part of the melatonin PRC when it pro-
Time (days)
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duces a phase advance of 0.4 h. Thus, entrainment occurs and the pacemaker now functionally has a tau of 24.0 h. The finding that low doses of melatonin may be more effective than high doses, leading to the idea of avoiding spillover, is illustrated in the treatment of the one BFR who failed to entrain to the 10-mg dose (recall that he had the longest tau, 24.9 h, in that study). Despite repeat treatment with 9 to 10 mg melatonin for 83 days and 20 mg melatonin for 60 days (Figure 3),92 he failed to entrain, although his tau did shorten to 24.36 and 24.58 h, respectively. He was finally entrained with 0.5 mg melatonin.92
21 000 17 000 13 000 9000 Plasma melatonin levels (pg/mL) 5000 1000 150
The melatonin PRC might explain why a lower dose of melatonin is more effective than higher doses (Figure 4).92 While administering melatonin earlier in the advance zone causes a greater phase advance and while higher melatonin levels probably cause more of a phase advance (perhaps by stimulating more of the phase-advance zone), it appears that if the dose is too high, it will stimulate more of the delay zone and therefore reduce the magnitude of the phase advance. In other words, a lower dose will have less spillover and might thus be more effective than a higher dose.
10 mg dose
0.5 mg dose 100 50 0 Endogenous melatonin profile Melatonin doses given at CT 15 Advance zone of PRC Delay zone of PRC CT 14 CT 18 CT 0
Delay zone CT 0 CT 6
Advance zone CT 6
The endogenous melatonin profile and the melatonin shift later after each day in a blind person with free-running rhythms, relative to clock time and sleep.
Wake 7 AM 11 PM 9 PM
Sleep 7 AM
Wake 11 PM
The melatonin onset (MO) occurs 2 h before sleep, when the MO has drifted into the normal phase.
Figure 4. Pharmacokinetic data from two different melatonin doses (0.5 and 10 mg) in relation to the endogenous melatonin profile and the melatonin phase response curve (PRC). The 0.5 mg dose and the endogenous melatonin profile are data from the subject in this study. The 10 mg data were from another subject and were not collected beyond 10 h; it is clear that they cause more stimulation of the delay zone of the melatonin PRC than the 0.5 mg dose. By convention, circadian time (CT) 14 is the endogenous melatonin onset (MO). In free-running subjects, the endogenous melatonin profile and the melatonin PRC (which are phase-locked) drift later each day with respect to the sleep/wake cycle. Normal phase is when the MO occurs 2 h before sleep onset (14 h after waketime). Exogenous melatonin causes phase advances when it is given between CT 6 and CT 18 and causes phase delays when it is given between CT 18 and CT 6; however, the concentrations and duration of exogenous melatonin levels as they spill over onto the wrong zone of the melatonin PRC may also affect the phase-shifting effect of exogenous melatonin.
Reproduced from reference 92: Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int. 2002;19:649-658. Copyright 2002, Marcel Dekker.
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The efficacy of low doses means that melatonin can be administered well before sleep without causing daytime or evening sleepiness. This is important, because the treatment goal is not only entrainment, but also entrainment at the optimal phase. Indeed, in the original study of 10 mg,87 successfully entrained BFRs had MOs occurring after sleep onset, often much later (Figure 5).93 In other words, the MO occurred at the same time each night, but later than normal. As in animal studies, the greater the pretreatment free-running tau, the later entrainment occurs relative to the time of the entraining stimulus. In our entrained BFRs, their sleep disorders had improved with treatment, but our subjects still had trouble falling asleep and getting up in the morning. About 30% of people become sleepy on melatonin, and this side effect appears to be dose-related and is troublesome at doses greater than 1 mg, certainly at 10 mg. Now that 0.5 mg has been shown to be an effective dose with minimal soporific side effects, it can be administered earlier than bedtime (which is when the 10 mg was originally given, in order to make use of this side effect). Melatonin can be given earlier in the evening, so that the MO occurs 2 h before desired sleep time, thus resulting in optimal sleep quality. When shifting the clock time of exogenous melatonin administration, the endogenous MO can be reset to any time. Shifting the clock time of administration earlier should be done gradually, so as not to cross over the break point on the melatonin PRC. The clock time of administration can also be shifted later, which can be done in 1 day without loss of entrainment. In either case, the pacemaker will shift with the time of the melatonin dose. In blind people who appear to be entrained (or at least have a tau virtually indistinguishable from 24.0 h) to a behaviorally related zeitgeber or to ambient light (perhaps in some blind people who are not bilaterally enucleated), MOs can be reset earlier or later with a daily dose of melatonin, so that the MO occurs 14 h after waketime. Several years ago, we also proposed that the abscissa and ordinate of Figure 5 could be reversed.94 Accordingly, the phase angle of entrainment could be used to predict tau. While the taus of BFRs are probably the most accurate estimate of the genetically programmed intrinsic tau (which might be of use in studying clock genes in humans9597 ), we also suggested that the DLMO ZT in sighted people might be a useful way to estimate at least the functional tau in people entrained to the light/dark cycle.
Melatonin treatment can be initiated at any time in BFRs

What would have happened if melatonin treatment were initiated in BFRs on the wrong zone of the melatonin PRC? In animal studies, it does not matter when the entraining stimulus is given: eventually, the pacemaker is stably entrained at a steady-state phase position, once the entraining stimulus comes into contact with the entrainment point of the PRC.98 However, in a study published a few years ago, the University of Surrey research group found that they were able to entrain only about half of their group of seven BRFs to a 5-mg dose of melatonin.99 They noted that entrainment was successful only when melatonin treatment was started on the advance zone of the PRC, but not when treatment was started on the delay zone, even if daily melatonin doses were continued through a complete circadian beat cycle, so that eventually melatonin stimulated all of the advance zone.They further noted that this finding contradicted those of animal studies, in which starting a zeitgeber on the delay zone did not affect its capability to eventually cause entrainment (it just took longer before the entrainment point was reached as the pacemaker, and the PRC, drifted into phase). If the Surrey group is correct, this would mean that all BFRs
9 8
Entrainment fails above this line
Phase angle of entrainment (h)
7 6 5 4 3 2 1 0 -1 -2 24.0 24.2 24.4 24.6 24.8 25.0
10 mg melatonin r2=0.5767 P<0.05
Tau (h)
Figure 5. Pretreatment tau predicts phase angle of entrainment (PAE). PAE is the interval (in hours) between the time of the bedtime 10 mg melatonin dose and the entrained melatonin onset (MO) of the endogenous melatonin profile. This figure is an updated version of what has been previously reported, and the tau of one person has been changed to 24.58 h from 24.63 h, correcting an error in the previous report. The horizontal dotted line indicates that entrainment will fail if the phase angle of entrainment is more than 8 h.
Reproduced from reference 93: Lewy AJ, Hasler BP, Emens JS, Sack RL. Pretreatment circadian period in free-running blind people may predict the phase angle of entrainment to melatonin. Neurosci Lett. 2001;313:158-160. Copyright 2001, Elsevier Science.
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should have frequent MO assessments to determine on what day melatonin treatment should be initiated. Fortunately, this does not appear to be true. We found in seven out of seven BFRs that when low-dose melatonin is initiated on the delay zone, entrainment eventually occurs when melatonin is given at the entrainment point in the advance zone.100 The following case (Figure 6) using 0.05 mg is an example; in the other cases, a dose of 0.5 mg was used. Recently, the Surrey group found that some BFRs entrained when 0.5 mg was initiated on the delay zone; however, they continue to recommend initiating melatonin treatment on the advance zone.
people, one does not need to start melatonin treatment on the advance zone, although it may take longer to reach the entrainment point when treatment begins on the delay zone. The clinical implications of this finding are very important: clinically, most blind people can be treated without having to measure their endogenous circadian phase. Work is on-going to entrain BFRs to doses of melatonin even lower than 0.05 mg. These doses produce peak melatonin levels that are less than what is maximally produced endogenously. Melatonin can also reset the phase of abnormally entrained blind people, even under circumstances when they may be entraining to a poorly perceived ambient light/dark cycle.101
Very low doses of melatonin are effective in entraining BFRs

In this case (Figure 6), a very low dose (0.05 mg) of melatonin was initiated in a BFR with a tau of 24.35 h on the delay zone (CT 4.95). Initially, a clear increase in tau occurred, consistent with a greater daily phase delay. Within a few days, melatonin was stimulating the advance zone and once the entrainment point was reached, the pacemaker locked on. As mentioned above, low doses of melatonin can usually entrain BFRs, no matter when treatment is initiated. Therefore, at least for most blind
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Guidelines for treating CSDs in blind people

The above database provides a preliminary set of treatment guidelines that should be effective in most blind people with circadian sleep disorders (CSDs). However, more studies need to be done, and there will clearly be some blind people who will have to be assessed using the MO for optimal treatment. Not every blind person has a CSD. Most, if not all, blind people completely lacking in light perception have CSDs, or at least merit treatment to prevent an eventual occurrence; however, the more light perception, the more likely stable entrainment at a normal phase will be the case. In any event, the first step is to take a sleep history to determine whether the patient has DSPS or ASPS, or sometimes has both that regularly recur, which would suggest free-running circadian rhythms. If possible, keeping a sleep diarynoting daily sleep times, naps, nighttime sleep quality, and daytime alertnessis advised; depressive symptoms may also occur when there is a mismatch between circadian rhythms and the sleep/wake cycle. Melatonin treatment should then be started. A dose of 0.5 mg at about 8.00 PM should result in entrainment of BFRs and to optimal phase resetting in most blind people. Stable steady-state entrainment at the normal phase will take shorter or longer, depending on the tau and on what day treatment was initiated. Although repeated assessments of MOs can determine these parameters with precision, they should not be necessary in most people: eventually this treatment should be successful. If 3 months have passed without marked improvement, referral to sleep a disorder center or some other facility in which MOs can be assessed is advised.
0.05 mg
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0.025 mg
Time (h)
Figure 6. Blue circles represent an assessment of circadian phase as determined by the time that endogenous salivary melatonin concentrations continuously rose above the 0.7 pg/mL threshold. Vertical lines represent the timing and duration (days) of exogenous melatonin administration of 0.05 mg (black line) and 0.025 mg (gray line). All times are presented in Pacific Standard Time (some times have been converted from Daylight Saving Time).
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In a few individuals, the 0.5 mg dose may cause some acute sleepiness. If unpleasant, the dose can be gradually tapered every 2 weeks in increments of 0.1 mg to as low as 0.1 mg, and then in increments of 0.025 mg to 0.05 mg, if desired. However, for individuals who have longer taus, the dose should not be reduced below 0.3 mg. Individuals who report bouts of symptoms as often as every 4 to 6 weeks are likely to have longer taus (>24.6 h). After finding a suitable maintenance dose, the clock time of administration can then be adjusted if the patient still complains of symptoms of ASPS or DSPS. When shifting the administration time earlier, advancing it no more than 30 min every 2 weeks should be sufficiently conservative, so that the entrainment point will not be crossed. Delaying a person with symptoms of ASPS need not be done incrementally. However, in either case shifting the clock time should be stopped when sleep symptoms abate. These patients should probably remain on melatonin treatment for the rest of their lives. Some minor shifts in clock time of administration may be required. If not taken daily, escape from steady-state entrainment at the normal phase will likely occur. However, after the pacemaker drifts through a complete cycle, the melatonin dose should again capture the pacemaker at the optimal phase. Although long-term studies of melatonin need to be done, it is likely that doses of 0.5 mg or less (which result in levels within the same order of magnitude as those produced by the pineal) should be safe.To date, no serious, irreversible side effects have been unequivocally linked to melatonin even at doses greater than 0.5 mg. Nevertheless, we recommend that continuous melatonin treatment be monitored by a physician or other responsible caregiver, who is familiar with the most recent scientific and medical literature. melatonin PRCs.44 To provide a corrective phase advance, bright light should be scheduled immediately upon awakening in the morning and melatonin should be taken in the afternoon/evening. To provide a corrective phase delay, bright light should be scheduled in the evening and melatonin should be taken in the morning. Delayed sleep phase syndrome Melatonin and light are both effective in treating DSPS.102,103 The first published report of treating DSPS with light was in 1983.33 This topic is reviewed elsewhere.104 Most people with DSPS are younger and prefer to sleep late in the morning, having difficulty falling asleep until as late as 4.00 AM. These individuals can be treated by scheduling their waketimes to occur gradually earlier (perhaps 15 min every other day) until the desired waketime is reached. Going outdoors immediately upon awakening for about 30 min will help advance the circadian rhythm of sleep propensity, as will taking 0.5 mg of melatonin about 8 h after waketime. One or both of these treatments may be necessary to hold the sleep/wake cycle to the desired time. If outdoor sunlight is not available or inconvenient, a portable fixture may be used for 30 to 60 min; the fixture should be at a distance from the eyes so that the intensity is about 10 000 lux. Research on the most potent wavelengths for phase shifting and melatonin suppression may eventually result in some modification of light sources. In the US, melatonin is widely available. If the dose of 0.5 mg happens to cause sleepiness in an individual who is unusually sensitive to this side effect, it should be decreased and a repeat dose should be given a few hours later. For individuals who become sleepy on (usually higher doses of) melatonin, 1 to 3 mg at bedtime may be usefully taken to induce sleep. Advanced sleep phase syndrome
Other circadian phase disorders

Research in SAD patients and blind people has helped us understand how to treat circadian phase disorders and syndromes in the general sighted population. These disorders include ASPS and DSPS, jet lag, and shift work maladaptation. All of these disorders and syndromes are to a greater or lesser extent related to the circadian timing system and can be phase typed, according to whether they are phase delayed or phase advanced (Table I). Treatment of these disorders is based on the light and ASPS generally occurs in older individuals, who tire early in the evening and wake up as early as 4.00 AM. The first reference to treating ASPS with light was published in 1985.105 This subject is reviewed elsewhere.104 Treatment recommendations include 1 to 2 h of 10 000 lux exposure in the evening, ending at least 1 h before desired bedtime. Melatonin (0.5 mg) should be taken at each awakening and upon final arising in the morning.Whenever melatonin is taken during waketime, people should not drive if they feel sleepy and lowering the dose should be considered.
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Jet lag Although sleep deprivation resulting from flying at night contributes to the malaise following air travel, there is little doubt that jet lag is caused by a mismatch between circadian rhythms that are tightly coupled to the endogenous circadian pacemaker and destination sleep/wake time. A good rule of thumb is that it takes 1 day to recover from every time zone crossed, with the caveat that jet lag is usually worse when traveling east than when traveling west. There have been numerous studies of light and melatonin in the amelioration of jet lag. These have been recently reviewed.106,107 The first study to test the effect of light on jet lag was published in 1984.108 The first study to test the effect of melatonin on jet lag was published in 1986.109 On the whole, both have been shown to be somewhat efficacious. However, optimal testing of melatonin in the treatment of jet lag has not yet occurred. For example, no peerreviewed report has included taking 0.5 mg melatonin in the afternoon before traveling east or in the morning before traveling west, which is what we recommend should be done for up to 2 days before travel, as well as on the day of travel.Taking melatonin at destination is more complicated.After traveling across more than five time zones, melatonin can be taken at bedtime. However, as the endogenous circadian pacemaker adjusts to local time, bedtime may not be the best timeand may even be the wrong timeto take melatonin (see below). Bright light exposure is not convenient to schedule before travel. At destination, obtaining sunlight exposure at the correct time can greatly facilitate circadian realignment. Even more important, particularly after crossing more than five time zones, is avoiding sunlight exposure at the wrong time, which will shift circadian rhythms in the direction opposite to that traveled. When flying from Los Angeles to Madrid, for example, it would take several more days to delay the body clock 15 h than to advance it 9 h. (However, extreme night owls might prefer to delay their clocks no matter which direction of travel.) Precise recommendations for obtaining and avoiding
Phase-advanced type Advanced sleep phase syndrome (ASPS) East-to-west jet lag Night work maladaptation (work days)
sunlight at destination depend on what are thought to be the light PRCs break points. The following recommendations are based on a light PRC with the break points at CT 6 and CT 18, using the beginning of the light pulse as its phase reference. Using the middle of a relatively long bout of bright light exposure as the phase reference, which is done in most human (but not animal) studies, would put these break points a few hours later; however, this requires people to schedule long periods of (preferably bright) light exposure. Furthermore, a recent study indicates that the beginning of the light pulse is its most powerful part, at least with respect to causing phase advances. After traveling across five or fewer time zones, start sunlight exposure as early as possible in the morning after going east or as late as possible in the afternoon after going west. After traveling across six or more time zones, obtain sunlight exposure in the middle of the day and avoid it in the morning after going east or at the end of the day after going west. On subsequent days, these times can be shifted, as if one had traveled through fewer time zones (see below). Using both light and melatonin at the optimal times, it is reasonable to assume a rate of phase shifting of 3 h per day. For example, after traveling nine time zones to the east, a person who habitually arises at 7.00 AM should avoid sunlight exposure before 10.00 AM and obtain at least 30 min of it shortly after this time. The next day sunlight exposure should occur shortly after 7.00 AM. Melatonin should be taken at 2.00 PM before travel and at 11.00 PM upon reaching the destination. It should then be taken 3 h earlier each day until it is again taken at 2.00 PM for a couple of days. After traveling nine time zones to the west, take melatonin at 10.00 PM the first night, but on subsequent nights it should be taken only if awake after 1.00 AM and then again upon final awakening in the morning. After traveling six or more time zones to the west, bright light should be avoided at the end of the day and sunlight should be obtained in the middle of the day. After 1 or 2 days, bright light should be obtained at the end of the
Phase-delayed type Delayed sleep phase syndrome (DSPS) West-to-east jet lag Night work maladaptation (weekends) Typical seasonal affective disorder (SAD)
Table I. Phase typing for circadian rhythm disorders.
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day. Melatonin can be taken at bedtime the first night at destination, but should not be taken before 1.00 AM on subsequent days, except under special circumstances. Optimal scheduling of light and melatonin depends on the habitual waketime of an individual, the direction of travel, the number of time zones crossed, and the presumed rate of phase shifting. A complete table of instructions would be helpful and will hopefully be available soon. We recommend taking the lowest dose of melatonin currently available or using a pill cutter. In a few people, even the 0.5 mg dose may cause sleepiness immediately after taking it during the day. Lowering the dose further will reduce the soporific side effect, but then a second dose should be taken a few hours later, particularly when a phase advance is desired, in order to create overlap between the exogenous melatonin pulse and the endogenous melatonin profile, as described above. Shift work maladaptation Although it is quite clear that very few shift workers adapt their circadian rhythms to conform to their work schedules, there is no consensus as to how best to help them. This topic has been reviewed elsewhere. The first use of light to treat shift workers was published in 1987.110 The first use of melatonin to treat shift workers was published in the early 1990s.111,112 When trying to sleep at odd hours, shift workers have a type of jet lag. Night workers have the same problems as someone who has traveled through 12 time zones, in fact, worse, since air travelers usually adjust at a rate of at least 1 h per day, as mentioned above. Night workers rarely adjust their circadian rhythms, probably because of the morning sunlight exposure that occurs on the way home from work. Evening workers have it somewhat easier. Chronobiologists uniformly recommend staying on the same schedule every day, week after week. Neither light nor melatonin would then be necessary. However, workers (certainly those who do so at night) are uniformly against sleeping during the day on their weekends. Because their circadian rhythms do not usually adapt to their work schedules, shift workers feel good only on their days off. After working each night, they force themselves to sleep during the day when their body clocks would have them stay up, and of course their work suffers as they soldier through the wee hours of the night when their body clock would have them sleep. A number of medical complaints often accompany shift work, and the older one gets, the harder it is to adapt. Experts do not agree on how to help shift workers. As mentioned above, part of the problem lies in the fact that some workers would rather feel better on their days off than on their workdays, while managers understandably want workers to be most rested and alert during their hours of employment. Even if this issue is resolved, the next conundrum is that one cannot shift more than 3 to 4 h per day. Compromise schedules that rely on the use of appropriately timed bright light and/or melatonin administration have been proposed that stabilize circadian phase midway between work and off-work schedules. For example, Eastman and associates have proposed such a compromise schedule.113 We are in the process of developing our own version of a compromise schedule, but its implementation may depend on the development of delayed-release melatonin formulations that are not yet available.
Supported by grants from the Public Health Service (R01 MH56874 to Drs Lewy and Sack; R01 MH55703, R01 AG21826 and R01 HD42125 to Dr Lewy; and MO1 RR00334 to the General Clinical Research Center of OHSU) and the National Alliance for Research on Schizophrenia and Depression (2000 NARSAD Distinguished Investigator Award to Dr Lewy). We are indebted to the nursing staff of the General Clinical Research Center, to Dr Robert Sack, Dr Jonathan Emens, Dr Paul Giger, Dr Kyle Johnson, Rick Boney, Nancy Stahl, Neil Cutler, Bryan Lefler, Krista Yuhas, and Angie Koenig for their valuable assistance, and to Keith Parrott, PharmD, for the formulation of the melatonin capsules.
REFERENCES
1. Lerner AB, Case JD, Takahashi Y, Lee TH, Mori N. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc. 1958;80:2587. 2. Arendt J. Melatonin and the Mammalian Pineal Gland. London, UK: Chapman & Hall; 1995. 3. Lewy AJ, Tetsuo M, Markey SP, Goodwin FK, Kopin IJ. Pinealectomy abolishes plasma melatonin in the rat. J Clin Endocr Metab. 1980;50:204-205.
4. Neuwelt EA, Lewy AJ. Disappearance of plasma melatonin after removal of a neoplastic pineal gland. N Engl J Med. 1983;308:1132-1135. 5. Goldman BD, Darrow JM. The pineal gland and mammalian photoperiodism. Neuroendocrinology. 1983;37:386-396. 6. Underwood H. Circadian rhythms in lizards: phase response curve for melatonin. J Pineal Res. 1986;3:187-196. 7. Armstrong SM, Thomas EMV, Chesworth MJ. Melatonin-induced phaseshifts of rat circadian rhythms. In: Reiter RJ, Pang SF, eds. Advances in Pineal Research. London, UK: John Libbey; 1989:265-290.
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8. Lewy AJ, Sack RL, Latham JM. Exogenous melatonin administration shifts circadian rhythms according to a phase response curve. Presented at The Vth Colloquium of the European Pineal Study Group. Guildford, UK; 1990. Abstract 021. 9. Lewy AJ, Sack RL, Latham JM. Circadian phase shifting of blind and sighted people with exogenous melatonin administration: evidence for a phase response curve. Soc Light Treatment Biol Rhythms Abst. 1990;2:22. 10. Lewy AJ, Sack RL, Latham J. A phase response curve for melatonin administration in humans. Sleep Res. 1991;20:461. 11. Lewy AJ, Sack RL, Latham JM. Melatonin and the acute suppressant effect of light may help regulate circadian rhythms in humans. In: Arendt J, Pevt P, eds. Advances in Pineal Research. London, UK: John Libbey; 1991:285-293. 12. Lewy AJ. The pineal gland. In: Wyngaarden JB, Smith LH, Bennett JC, eds. Cecil Textbook of Medicine. Philadephia, Pa: WB Saunders; 1991:1246-1248. 13. Lewy AJ, Ahmed S, Jackson JML, Sack RL. Melatonin shifts circadian rhythms according to a phase-response curve. Chronobiol Int. 1992;9:380-392. 14. Pickard GE, Turek FW. The hypothalamic paraventricular nucleus mediates the photoperiodic control of reproduction but not the effects of light on the circadian rhythm of activity. Neurosci Lett. 1983;43:67-72. 15. Hendrickson AE, Waggoner N, Cowan WM. An autoradiographic and electron microscopic study of retino-hypothalamic connections. Z Zellforsch. 1972;135:1-26. 16. Stephan FK, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A. 1972;69:1583-1586. 17. Moore RY, Eichler VB. Loss of circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res. 1972;42:201-206. 18. Vessely LH, Lewy AJ. Melatonin as a hormone and as a marker for circadian phase position in humans. In: Pfaff D, Arnold A, Etgen A, Fahrbach S, Rubin R, eds. Hormones, Brain and Behavior, Vol 5. San Diego, Calif: Elsevier Science; 2002:121-141. 19. Arins-Kappers J. The development, topographical relations and innervation of the epiphysis cerebri in the albino rat. Z Zellforsch Mikrosk Anat. 1960;52:163-215. 20. Axelrod J, Zatz M. The -adrenergic receptor and the regulation of circadian rhythms in the pineal gland. In: Litwack G, ed. Biochemical Actions of Hormones. New York, NY: Academic Press; 1977:249-268. 21. Reppert SM, Weaver DR, Rivkees SA, Stopa EG. Putative melatonin receptors are located in a human biological clock. Science. 1988;242:78-81. 22. Dubocovich ML, Benloucif S, Masana MI. Melatonin receptors in the mammalian suprachiasmatic nucleus. Behav Brain Res. 1996;73:141-147.
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Experiencia clnica con melatonina en los trastornos circadianos

Los sndromes y trastornos cronobiolgicos incluyen el trastorno afectivo estacional (TAE), la ceguera total, los sndromes de avance y retraso de fases del sueo, el jet lag y la mala adaptacin a los turnos laborales. Estos trastornos se tratan ajustando las fases circadianas, mediante la utilizacin de un tiempo apropiado de exposicin a la luz brillante y la administracin de melatonina (en dosis de 0,5 mg o menos). En algunos casos puede ser necesario medir las fases circadianas internas utilizando el perodo en que se elevan los niveles de melatonina endgena.
Applications cliniques de la mlatonine dans les troubles circadians

Les syndromes et troubles chronobiologiques regroupent le trouble affectif saisonnier (TAS), les desordres entrans par la ccit totale, les syndromes type retard ou avance de phase, les symptmes lis aux changements de fuseaux horaires (jet lag), et les perturbations dues au travail post. Ces troubles sont traits en rajustant le rythme circadien, grce lutilisation judicieuse et minute de lexposition la lumire brillante et ladministration de mlatonine (0,5 mg ou moins). Parfois, il semble ncessaire de mesurer le rythme circadien interne, au moment de llvation des concentrations de mlatonine endogne.
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Pierre Schulz __________________________________________________ 205
In this issue
Manfred Ackenheil ____________________________________________ 313
State of the art

The psychobiology of resilience and vulnerability to anxiety disorders: implications for prevention and treatment Dennis S. Charney ____________________________________________ 207
State of the art

Chronobiology and mood disorders Anna Wirz-Justice ____________________________________________ 315 Concepts in human biological rhythms Alain Reinberg, Israel Ashkenazi ____________________________ 327
Basic research
Evolutionary aspects of anxiety disorders John S. Price __________________________________________________ 223
Basic research
Melatonin and animal models Paul Pvet______________________________________________________ 343
Medication dependence and anxiety Lisa L. Von Moltke, David J. Greenblatt ____________________ 237
Light treatment of mood disorders Barbara L. Parry, Eva L. Maurer ____________________________ 353
Poster
fMRI in anxiety Thrse Schunck, Gilles Erb, Christian Gilles, Yann Hode, Izzie J. Namer, Hermann Fuder, Rmy Luthringer __________ 246
Poster
Sleep deprivation and antidepressant treatment Ulrich Voderholzer ____________________________________________ 366
Clinical research
Sleep and anxiety disorders Luc Staner______________________________________________________ 249 Obsessive-compulsive spectrum disorders Andrea Allen, Audrey King, Eric Hollander ________________ 259 Psychological and social aspects of resilience: a synthesis of risks and resources Saul Levine ____________________________________________________ 273
Clinical research
Diagnosis and treatment of sleep disorders: a brief review for clinicians Vivien C. Abad, Christian Guilleminault______________________ 371 Treatment of seasonal affective disorders Nicole Praschak-Rieder, Matthus Willeit ____________________ 389 Clinical applications of melatonin in circadian disorders Alfred J. Lewy__________________________________________________ 399
Free paper
Combination pharmacotherapy in Alzheimers disease Jacobo Mintzer, Dena Armstrong, Warachal E. Faison ______ 281
If you wish to receive future issues of Dialogues in Clinical Neuroscience, please contact mail.dialneuro@fr.netgrs.com This publication is supported by an educational grant from Servier www.servier.com www.dialogue-cns.org
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Chronobiology and Mood Disorders

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Chronobiology and Mood Disorders

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ISSN 1294-8322

State of the art

ISSUE COORDINATED BY: Manfred ACKENHEIL

Alain Reinberg, MD, PhD

Vivien C. Abad, MD, MBA

Author affiliations: Unit de Chronobiologie, Fondation Adolphe de Rothschild, Paris, France

Paul Pvet, PhD

Alfred J. Lewy, MD, PhD

Author affiliations: Department of Psychiatry, University of California, San Diego, USA

State of the art

State of the art

The neurobiology of circadian rhythms