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Circadian Disruption and Psychiatric Disorders: the Importance of Entrainment

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Circadian Disruption and Psychiatric Disorders: the Importance of Entrainment This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Circadian Disruption and Psychiatric Disorders: The Importance of Entrainment AnnaWirz-Justice, PhD*,VivienBromundt, MSc, Christian Cajochen, PhD KEYWORDS Circadian rhythms Sleep regulation Actigraphy Major depression Dementia Psychiatric illness There is a need for more knowledge of sleep medi- investigations, because masking effects of cine to be integrated into psychiatric training and behavior and environment on the rhythms practice. Although many psychiatrists are aware measured often have not been controlled for. that most patients have some sort of a sleep Thus, this article will not address evidence for problem, these mainly are addressed separately circadian disruption as etiology. Do clock genes from the primary diagnosis, with appropriate play a role in bipolar disorder?4 What is the choice of sleep-promoting psychopharmacologic evidence for phase–delayed rhythms in winter agents or additional treatment with benzodiaze- depression?5,6 Do different dementias have pines or newer hypnotics. Consideration of circa- different rhythm abnormalities?7 Rather, circadian dian rhythms and their impact on sleep–wake disruption of rest–activity cycles will be consid- behavior in psychiatric disorders is still rare in ered as a clinical symptom, which leads to prag- psychiatric practice. matic use of circadian-based treatments to This is somewhat surprising, because observa- support re-entrainment. tions linking rhythmic behavior and psychopa- Hypotheses of biological clock disorder postu- thology have a long tradition in clinical late alterations in suprachiasmatic nuclei (SCN) psychiatric research, particularly in major depres- function that may result in a low amplitude or sion. These observations have been reviewed abnormal phase of the observed circadian rhythm. comprehensively,1–3 albeit with rather ambiguous Alterations in SCN function may be caused not conclusions. The precise nature of the links only by malfunction of the clock per se, but by remains elusive, and it may be too simplistic to means of changes in factors that set the clock. expect that the enormous variety of psychiatric Importantly, the SCN—and all the peripheral disorders have common dysfunctions related to clocks in the brain and the rest of the body— the biological clock. It is not only the problem of require zeitgebers (synchronizing agents) to clearly defining patient groups within and among ensure circadian entrainment (coupling of an diagnoses, but also, different treatments make it endogenous rhythm to an environmental oscillator difficult to define a specific circadian rhythm with the result that both oscillations have the same abnormality. It may be more the symptoms such frequency), internally among themselves and as anxiety and depressed mood rather than the externally with respect to the light-dark cycle. diagnosis that are related to sleep disorders. In With insufficient zeitgebers, even correctly func- addition, methodological issues cloud most tioning biological clocks can become Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Wilhelm Klein Strasse 27, CH-4025 Basel, Switzerland * Corresponding author. E-mail address: [email protected] (A. Wirz-Justice). Sleep Med Clin 4 (2009) 273–284 doi:10.1016/j.jsmc.2009.01.008 1556-407X/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved. sleep.theclinics.com Author's personal copy 274 Wirz-Justice et al desynchronized. This points to the important role relatively easy and noninvasive objective measure for the major zeitgeber light, and the usefulness of the circadian rest–activity cycle. of melatonin, which feeds back on the SCN. Non- photic zeitgebers such as physical exercise, sleep, ACTIGRAPHYAS A CLINICAL TOOL or food also contribute to entrainment of periph- eral clocks. Social zeitgebers (eg, personal rela- Actigraphs are small, lightweight, wrist-worn solid- tionships, jobs, social demands) act indirectly on state recorders that record movement-induced the SCN, because they determine the timing of accelerations (Fig. 1). The wrist-worn accelero- meals, sleep, physical activity, and out- and indoor meter generates activity counts, which are propor- light exposure. In addition, the zeitgebers must tional to the intensity, frequency, and duration of impact on correct functioning receptors to be motion (the higher the black bars, the more active). effective (eg, retinal photoreceptors for light The activity counts are summed over a given time perception). interval (eg, 2-minutes) and depicted either as A major tenet of chronobiology is that appro- single plots (24-hours) or double plots (48-hours priate entrainment or synchronization to the represent day 1 and day 2 next to one another); 24-hour day–night/light–dark cycle is important time of day (x axis) begins at midnight. The subse- for health. This may be particularly relevant to quent days (y axis) are plotted beneath each psychiatric illness.8 Circadian malentrainment another. does not necessarily cause the individual psycho- In general, two sets of parameters can be pathology, but may perpetuate or exacerbate the derived—one representing sleep measures such clinical symptoms. In general, entrainment is not as sleep fragmentation and movement time, which only a prerequisite for good nighttime sleep and correlate reasonably well with electroencephalo- daytime alertness, but also for adequate mood gram (EEG) data9—and one set defining circadian state, cognition, and neurobehavioral function. rhythm characteristics, such as interdaily stability The chronobiological strategy of attending to (IS), intradaily variability (IV), the timing of the entrainment of patients, independent of psychi- most active and most inactive episodes, and the atric diagnosis, is not entirely new, because it relative amplitude (RA).10 IS indicates the degree merely reformulates the classical clinical strategy of resemblance between activity patterns on of establishing stable daily structures to support different days, documenting the consistency the process of clinical improvement. The primary across days of the daily circadian signal and the postulate is that integrity of the circadian rest– strength of its coupling to stable zeitgebers. A activity cycle promotes healthy functioning in all higher value indicates a more stable rhythm. IV psychiatric disorders. indicates the degree of fragmentation of the Here the focus lies on the importance of well-en- rhythm (ie, the frequency of transitions between trained sleep–wake cycles for mental health, with periods of rest and periods of activity during examples from various diagnostic categories. The a given day). A lower value indicates a less frag- accent will be on actigraphy, as a well-established, mented rhythm. The sequence of the most active Fig.1. The circadian rest–activity cycle is documented using an actigraph worn on the wrist of the nondominant hand (inset, Cambridge Neurotechnology Limited, Cambridge, UK, with light meter). Social zeitgebers in a married couple showing weekday work times affecting the onset of daily activity in the employed partner (63-year-old man), left, and free choice of wake-up time in the at-home partner (65 year-old woman), right. (Data from A. Wirz-Justice, unpublished data, 2009.) Author's personal copy Circadian Disruption and Psychiatric Disorders 275 10 hours (day) indicates the mean hourly peak of differences found are related to the illness and the rhythm, and the sequence of the least active not the sociological circumstances. 5 hours (night) indicates the nadir of the rhythm.10 Thus, to avoid pitfalls with actigraphy, informa- These two values are used to calculate the third tion of the patient’s daily routine (diaries) should important characteristic, the RA. be gathered, a circadian marker measured, and if Many psychiatric illnesses are accompanied or feasible, to compare patient groups only when characterized by changes in the circadian sleep– they live under similar conditions of employment wake cycle. The advantage of actigraphy is to or ward schedules. reveal 24-hour patterns that cannot be obtained otherwise, and which provide objective data for the patient’s sleep disturbance. The technique is PHARMACOLOGIC TREATMENTS, DRUG ABUSE, noninvasive, reliable, and can be interpreted within AND CIRCADIAN REST^ACTIVITY CYCLES the paradigm of animal circadian rest–activity cycles, where a large literature can be invoked to There is mounting evidence that successful phar- interpret the entrainment patterns seen. Impor- macologic treatment in patients suffering psychi- tantly, actigraphy can be implemented in everyday atric disorders also improves circadian life, thus not altering behavior as a laboratory situ- entrainment, which is important for therapeutic ation might do so, and is accepted by most
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