Depression: A Disorder of Timekeeping?

DEPRESSION: A DISORDER OF TIMEKEEPING? EVE VAN CAUTER* and FRED W. TUREKt A Clock in Each Body All but the simplest of living organisms exhibit regular changes from day to night [1, 2]. Indeed, almost every biochemical, physiological, or behavioral process in plants and animals varies on a diurnal basis. Humans are no exception to this basic rule oflife [3]. An immense variety of daily rhythms have been observed in man. Diurnal changes occur in a wide range of blood constituents such as hormones, white blood cells, amino acids; in innumerable physiological variables such as body temperature , pulse rate, blood pressure, urinary volume; and in behavioral parameters such as mood and performance. What is truly remarkable about these daily rhythms is that they are not simply a response to the 24-hour changes in the physical environment imposed by celestial mechanics but instead arise from an internal timekeeping system. The endogenous nature of the "clock" underlying diurnal rhythms in humans was demonstrated in the early 1960s in experiments isolating subjects from all time cues in the environment. These heroic investigations were conducted in natural caves by the French speleologist Michel Siffre and in artificial underground isolation units in Bavaria by Jürgen Aschoff. It was found that, in the absence of any man-made (e.g., wristwatch ) or natural (e.g., light-dark cycle) temporal cues, diurnal rhythms persist throughout the duration of observation, even when the latter spans several months [1—3]. During temporal isolation, endogenous rhythms are said to be "free-running." Importantly, the period of these free-running rhythms is not exactly 24 hours, a further indication that they are not generated by some subtle variation of the environment that the experimental setting failed to eliminate. The term "circadian," from *Institute of Interdisciplinary Research, Free University of Brussels, Belgium, and Department of Medicine, University of Chicago. Address: Institute of Interdisciplinary Research , Campus Erasme, bat. C, 808 route de Lennik, B 1070 Brussels, Belgium. fDepartment of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60201.© 1986 by The University of Chicago. AU rights reserved. 003 1-5982/86/2904-0503$0 1 .00 5 10 I Eve Van Cauter and Fred W. Turek ¦ A Disorder of Timekeeping? the Latin "circa," that is, about, and "diem," that is, day, was coined to designate these endogenous periodicities. The free-running period is an individual characteristic: one person will free run with a period of 25 hours and another with a period of 23.5 hours. In man, free-running periods are generally longer than 24 hours. When normal temporal variations are present in the environment, the endogenous rhythms are entrained or synchronized to a period of exactly 24 hours. Among environmental factors which can entrain human rhythms are the lightdark cycle and the schedule of social activities. The driving force behind the evolution ofcircadian rhythmicity seems deceptively obvious: because of the rotation ofthe earth on its axis, there are enormous fluctuations in the physical environment associated with the alternance of day and night. Natural selection has insured that organisms respond appropriately to these changes so that internal events are adequately timed with respect to these external cycles. However, an equally important reason to establish internal rhythmicity in living organisms may be the need for "internal synchronization," that is, the temporal coordination of internal physiological and biochemical events. Temporal organization in living systems is probably as important as spatial organization. Any function which, like circadian rhythmicity, is ubiquitous in organisms as diverse as mosquito and man and also influences hundreds of physiological events must be important and, in fact, essential, to the normal health and well-being of the organism. Pathological phenomena must be associated with any major disruption of this function. However, to date, not a single human disease can be definitely characterized as a "disorder of circadian timekeeping." There are, of course, hints that the normal functioning of our circadian clock is important for the maintenance of health. Common sense suggests that a healthy, happy, and active individual, such as the one depicted in figure 1, has a circadian clock synchronized to the environmental time. In contrast, when the body clock is out of phase with the external world, such...