ISSN 1294-8322

DialoguesinChronobiology and Mood Disorders

2003

Vo l u m e 5 . N o . 4

e

clinical neuroscience

DialoguesEditor-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

D

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 1294-8322Design: Christophe Caretti / Layout: Graphie 66 Imprim en France par SIP 1, rue Saint Simon - 95310 Saint-Ouen-lAumne

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ContentsPage

309 313 315 327 343 353 366 371 389 399

EditorialJean-Paul Macher, Marc-Antoine Crocq

In this issueManfred Ackenheil

State of the artChronobiology and mood disorders Anna Wirz-Justice Concepts in human biological rhythms Alain Reinberg, Israel Ashkenazi

Basic researchMelatonin and animal models Paul Pvet

Pharmacological aspectsLight treatment of mood disorders Barbara L. Parry, Eva L. Maurer

PosterSleep deprivation and antidepressant treatment Ulrich Voderholzer

Clinical researchDiagnosis 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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ContributorsAnna 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 artChronobiology and mood disordersAnna 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.

I

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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State of the artSelected abbreviations and acronymsHPA 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 observationsPeriodicity 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 rhythmsCircadian rhythms are generated by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the ante-

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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 artto 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 SThe 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, andFigure 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 processBuild-up of S S decline

S

Circadian processPhase

Phase relationship between C and sleep

Amplitude Zeitgebers

C

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 arteven 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 forSleep 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 rhythmsThe 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,60Zeitgebers 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 therapiesSleep 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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State of the artthe 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.

ConclusionWe 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 REFERENCES1. 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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State of the artCronobiologa y trastornos afectivosLas 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 lhumeurLes 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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State of the artConcepts in human biological rhythmsAlain 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. 2003, LLS SAS Dialogues Clin Neurosci. 2003;5:327-342.

T

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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State of the artSelected abbreviations and acronymsA 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