Time and depression: when the internal clock does not work




Hans-Jürgen MÖLLER, MD, Prof
Florian H. SEEMÜLLER, MD
Michael RIEDEL, MD, Prof
Department of Psychiatry
Ludwig-Maximilians University
Munich, GERMANY

Time and depression:
when the internal clock
does not work

by G. Hajak and
M. Landgrebe,Germany

An operational definition of time may involve describing a certain number of repetitions of one or another standard cyclical events. Time is a dimension tightly associated with the biology of living species; evolution has resulted in humans—as other organisms—adapting to repetitive temporal information from the 24-hour cycle determined by sunrise and sunset. This circadian rhythm reflects an approximate 24-hour cycle in the biochemical, physiological, and behavioral processes of living entities, which crucially influences human well-being and health. Increasing evidence from clinical and neurobiological research suggests that disrupted temporal organization impairs behavior, cognition, mood, sleep, and social activity, and may be implicated in mental disorders. It has been proposed that altered timing of the biological system, ie, circadian malfunction, is a major core feature of mood disorders—in particular, depression. In depressed patients, circadian rhythms and homeostatic processes are disrupted, thereby affecting mood, sleep, activity, and a variety of biological functions such as hormone secretion and body temperature. Depression, therefore, appears to be a circadian rhythm disorder in which biological functions that follow rhythmic internally and externally generated time patterns are disturbed. This may be caused by individual genetic disposition, whereby an individual’s socially-determined circadian profile is vulnerable to life events, that together with altered environmental time cues (zeitgebers), can destabilize the circadian homeostasis of the body andmind. Entrainment of circadian rhythms via internal pathways affecting the body’s circadian clock, provision of regular external time cues, and normalization of homeostatic biological function promise acute and sustained symptom relief in depression and may prevent relapse over the long term.

Medicographia. 2010;32:146-151 (see French abstract on page 151)

Time and its relation to the circadian rhythm

Time constitutes a component of the measuring system used to sequence events and to compare the durations of events and the intervals between them. Operational definitions of units of time, in which one states that a certain specified number of repetitions of one or another standard cyclical event constitutes a defined time unit, have helped significantly in improving our understanding and shaping modern theories regarding human pathophysiology, including theories relating to psychiatric disorders. Periodic events and periodic motion have long served as standards for units of time, including the most prominent daily recurring event, the apparent motion of the sun across the sky.

Humankind has developed in an environment that is exposed to the rotation of the earth around its own axis, which results in daily rhythmic changes in light intensity. As a consequence, over the course of evolution, organisms have developed cellular clock mechanisms sensitive to light, and have adapted by organizing their activities into 24-hour cycles determined by sunrise and sunset. This circadian rhythm reflects a roughly 24-hour cycle in the biochemical, physiological, and behavioral processes of living entities, with the term circadian, coined by one of the founders of modern chronobiology, the scientist Franz Halberg, coming from the Latin circa, “around” and diem or dies, “day,” meaning literally “approximately 1 day.” These circadian cycles do not simply reflect an organism’s passive response to environmental changes, such as the light-dark cycle, but rather represent pre-adapted endogenous rhythms, which arise from a timekeeping system within the organism and persist in the absence of environmental stimuli.1

Biological clocks exhibiting circadian rhythms exist in virtually all tissues, with a series of clock genes generating the rhythm through protein feedback effects on their own synthesis.2 It has been widely demonstrated that these multiple endogenous clocks are distributed in every cell of the organism,3 which may result in each organ having its own timed circadian rhythm. They represent self-sustained oscillator circuits, mediating the periodic induction of specific target genes, which are minimal genetic timekeeping devices found in the central, but also peripheral, circadian clocks. These clocks have attracted significant attention because of their intriguing dynamics and their importance in controlling critical repair, metabolic, and signaling pathways.4 As a result, nearly all physiological and behavioral functions in humans follow distinct time patterns.

The most prominent circadian pattern in human behavior is the sleep-wake cycle, for which clock genes affect both circadian and homeostatic function.5,6 An endless list of human physiological and behavioral functions has been documented as being influenced by the confounding impact of circadian and homeostatic patterns. They range from mental and physical performance, to metabolism and energy homeostasis in the liver and intestine,7 to parameters of the cardiometabolic system.8 Even memory formation and consolidation represent processes that are notably shaped by endogenous circadian oscillators.9 Recent studies also suggest that circadian rhythms play a role in sports performance.10

Among the most well-known rhythmic biological functions are the secretion patterns of hormones such as cortisol and corticotrophin, prolactin, growth hormone, and melatonin, all of them being critically involved in the organization of human psychological function. Robust circadian rhythms are also found in core body temperature variation, urine output, and bronchial smooth muscle reactivity. These rhythms enable the organism to synchronize endogenous processes of the internal milieu and to anticipate the periodic fluctuations in its external environment, with the aim of optimally dealing with them.1

A hallmark publication in the early 2000s showed individual cellular clocks to be integrated into a stable and robust pacemaker with a periodicity of about 24 hours.11 This publication confirmed in mammals that circadian rhythms are synchronized by a central clock or pacemaker located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. This clock generates a genetically programmed endogenous rhythmicity, which is slightly longer than 24 hours and needs to be synchronized (entrained) to the 24-hour day by external timekeeping cues.12 These external cues have been named zeitgebers (coming from the German words, zeit, “time” and geber, meaning “giving”) and represent a variety of physical events (eg, change between daylight and darkness) and social events (eg, mealtimes, social contact, etc). Healthy human life is thereby assured by a circadian biological system in which time-related patterns, meaning the temporal cyclical organization of recurring events, are synchronized. This comprises a harmonized interaction between diverse clock functions in peripheral tissues, the orchestrating function of the master clock in the central nervous system, the appropriate influence of external time cues acting as rhythm-stabilizing zeitgebers, and homeostatic components positively masking the circadian functions. The latter, eg, the increasing sleep drive resulting from increasing duration of sleep deprivation, have to be taken into account when investigating the role of circadian malfunction.

Temporal alterations in biological functions that affect human behavior and health

While the importance of human circadian rhythms has been known about for centuries, it has been widely neglected in modern society’s way of life. In fact, people living in Western industrialized countries increasingly neglect their biological circadian disposition. Working around a 24-hour day, traveling across several time zones, internet-based intercontinental business, and access to 24-hour television are leading to an increasing number of people living their lives against their own biological clocks.13 The American National Sleep Foundation14 pointed out that between 1998 and 2005, the amount of Americans sleeping for less than 6 hours per night increased from 12% to 16%, while those sleeping for over 8 hours decreased from 35% to 26%. Obviously, we are marching toward a sleepless and chronopathological society.15

Increasing evidence suggests that disrupted temporal organization impairs behavior, cognition, affect, and emotion; furthermore, disruption of circadian clock genes impairs the sleep-wake cycle and social rhythms. Altogether, these alterations of physiological circadian function may be implicated in particular in mental disorders. This is supported by stud- ies demonstrating interactions between circadian oscillators via molecular clocks, and the neural circuits subserving higher brain functions and behaviors crucially linked to mental health. In particular, disturbances in sleep and arousal, cognition, and mood show close relations to altered circadian rhythms.16 A variety of mental disorders have been related to disturbances in the temporal organization of biological functions, such as shift-work disorder, seasonal affective disorder, bipolar disorder including mania, major depression, nocturnal eating syndrome, schizophrenia, dementia, and others.7

_ Depression
There are an increasing number of journal publications1,16,18-20 and books21 summarizing our present knowledge on the circadian basis of affective disorders. Among the evidence to come from neurobiological research supporting a dysregulation of the clock-related circadian system in depression, is the flattening and phase shift of the circadian profiles of core body temperature and of corticoid, prolactin, growth hormone, and melatonin secretion seen in depression. For more than two decades, evidence has been continuously increasing to suggest that a blunted amplitude of the circadian profile is the main chronobiological abnormality in depression.22 Elevated core body temperature with a diminished amplitude is the most consistently observed circadian abnormality in depression, and generally normalizes with clinical improvement.23,24 Although not confirmed by all studies, a phase advance in the overall 24-hour pattern of body temperature has also been reported in many patients. As body temperature may be the most robust parameter indicating the output of the circadian pacemaker, changes to normal body temperature variation mirror a functional disturbance located at the central nervous level of circadian organization.

Plenty of evidence has been gathered to indicate a dysregulation of the hypothalamic pituitary adrenal axis in depression25-28 and an overall increase in cortisol secretion, with the largest effect at the nadir of the circadian rhythm, and an earlier onset of the first cortisol secretory episode, consistent with a phase advance of the cortisol circadian rhythm.29 Studies have also reported reduced melatonin secretion and a trend toward a phase advance of the melatonin circadian rhythm in patients suffering from major depression.30,31 Melatonin is secreted by the pineal gland, with major input from the SCN, thereby indicating a function of the central pacemaker in its secretion.

A most prominent finding in depression is alteration of the sleep-wake cycle, including sleep architecture abnormalities such as frequent awakenings, loss of slow-wave–rich deep sleep, and a shift of the position during the night of rapid eye movement sleep. These disturbances of the sleep-wake cycle are the most obvious circadian rhythm alteration in humans, resulting in the prominence of sleep disturbance as a feature of depression.32-34 Finally, results from animal models of depression have supported the presence of circadian malfunction through the identification of polymorphisms in circadian genes such as CLOCK, BMAL1, TIM, PER, NPAS2, and others associated with mood disorders.20,35,36 While research linking clock genes and mood disorders is still in its early stages, it suggests a likely involvement of these genes in the susceptibility to mood disorders.1

Figure 1
Figure 1. The circadian model of depression.

A zeitgeber is an exogenous (external) cue that synchronizes an organism’s endogenous (internal) timekeeping system (clock) to the earth’s 24-hour light/dark
cycle. SCN, suprachiasmatic nucleus.

Scientific debate has addressed several theoretical ways1,16,17,37,38 in which disrupted circadian rhythms might lead to depression. On the one hand, alterations in biological clocks at the molecular level could lead to neurobiological dysfunction, which in turnmay lead to the depressive state. On the other hand, a primary circadian disturbance of the sleepwake cycle could lead to insomnia that might facilitate or exacerbate the depressed state. Moreover, unpredictable changes to an individual’s circadian profile induced by chronic stress, life events, or physical disease may alter the stability of the circadian system. Changes in external time cues acting as zeitgebers may in addition further destabilize the thereby altered circadian system. As a result, desynchronization of the rhythmic features of biological and psychological function may cause the mental disease.

From the present evidence, one can conclude that the widely accepted biopsychosocial model39 of the pathophysiology of mental illness may be extended to include the important component of circadian rhythm alterations. Depression, therefore, appears to be a circadian rhythm disorder in which biological functions following rhythmic internally and externally generated time patterns are disturbed. This may be due to individual genetic disposition and a socially-determined circadian profile that is particularly vulnerable to life events, which, together with changes in environmental time cues, destabilizes the circadian homeostasis of body and mind (Figure 1).

Clinical signs of circadian dysregulation in depression

The clinical finding that depression-related symptoms include sleep-wake disorder with nocturnal insomnia and daytime sleepiness, lack of activity, loss of appetite, and diurnal changes of mood has encouraged the idea that abnormalities in circadian rhythms may underlie the development of affective disorders. From the point of view of clinical psychiatrists, quite a number of depressive symptoms have a temporal pattern that parallels the circadian malfunction found in the biological parameters (Figure 2). Beside symptoms of a disturbed sleep-wake cycle, diurnal variation in depressive symptoms appears to be central to the core of depression. Yet, longitudinal investigation of individual temporal pattern, regularity, and relation to clinical state and clinical improvement has revealed little homogeneity. Morning lows, afternoon slump, evening worsening can all occur during a single depressive episode. Mood variability, or the propensity to produce mood swings, appears to be the characteristic that most predicts the capacity to respond to treatment.40

Figure 2
Figure 2. Clinical evidence for circadian rhythm disturbance in depression.

Circadian functions as targets in the treatment of mood disorders

The corresponding clinical and neurobiological findings in depression have stimulated the idea that the restoration of normal circadian rhythms could have antidepressant potential. It is well established that chronotherapeutics—behavioral and biological treatments based on the principle of circadian rhythm reorganization—contribute significantly to the treatment of affective disorders. These clinical interventions include sleep deprivation, shifting of sleep time (sleep phase advance), light and dark therapy, as well as circadian behavioral entrainment strategies (eg, social rhythm therapy). In contrast to pharmacological treatments, some chronobiological interventions such as sleep deprivation treatment dramatically reduce depressive symptoms within 24-48 hours in 40%-60% of depressed subjects.36 The aim of chronotherapeutic interventions, thought to act by shifting and resetting the circadian clock, is to normalize circadian disturbances in depression. A growing number of clinical studies support the usefulness of chronotherapeutic interventions, even as first-line treatment. Consensus has not yet been achieved in terms of defining the underlying chronobiological mechanisms of optimal methods of producing rapid and sustained antidepressant responses to circadian interventions.36 The therapeutic effects of such interventions are rapid and often transient, but they can be stabilized by combining them with other such interventions, or by combining them with common drug treatments41,42 (Table) or biophysical treatments like repetitive transcranial magnetic stimulation.43

Table
Table. Interventions with scientific evidence showing an effect on circadian function in depression.

Based on data from references 41 and 42.

At a behavioral level, in clinical practice, it is necessary to reset and to stabilize the circadian rhythm regulated by central and peripheral clocks, which have to be entrained through environmental and social cues. This demands appropriate entrainment to the light-dark and sleep-wake cycles, as well as the provision of a sufficient level of social zeitgebers, including regular interpersonal contact, timed activities, and regular meal times.

There is a growing body of evidence from recent research that even certain antidepressant drugs may have chronobiotic properties in the treatment of depression. This is the case in particular for drugs that may act at receptors located in the SCN, the human master clock.44 Lithium has been shown to change circadian periods and the phase position of circadian rhythms, and to enhance and prolong the therapeutic effect of sleep deprivation, ensuring the most likelihood of clinical benefit in patients with bipolar depression, who demonstrate altered circadian rhythms. Lithium also slows down the abnormally rapid circadian periodicities in patients with bipolar disorder, an effect that appears to be crucial to therapeutic success. There is converging evidence that the chronobiological effects of lithium on circadian cycles are essential for its therapeutic efficacy.45

In the treatment of depression, tricyclic antidepressants as well as selective serotonin reuptake inhibitors such as fluoxetine have demonstrated some chronobiological effects in changing the circadian amplitude of body temperature and melatonin secretion and producing a phase advance in circadian activity.46 Recently, the antidepressant agomelatine, an agonist atmelatonergic MT1 and MT2 receptors and an antagonist at 5-HT2C receptors, has been proven to have robust clinical efficacy and tolerability in major depressive disorder.47,48 This drug binds to MT1, MT2, and 5-HT2C receptors, and exhibits marked circadian properties.49,50 Behavioral studies in animal models of depression demonstrated that agomelatine is able to dose-dependently alter circadian rhythms and to resynchronize the sleep-wake cycle in models with disrupted circadian rhythms. In humans, it was shown to shift the circadian rhythm of melatonin secretion and the core body temperature in healthy individuals,51 and to restore the sleep architecture and sleep patterns of depressed patients.52,53

Conclusion

In summary, the organization of psychobiological time patterns has a serious influence on human functioning. Resynchronization, normalization, and stabilization of circadian rhythms represent promising new pathways in the search for effective nonpharmacological and pharmacological treatments of depression. Strong and adequate entrainment of biological rhythms appears to be the key to good behavioral, cognitive, and emotional wellbeing.54 Resetting the internal clock in depression by considering the individual disturbed time pattern in a patient appears to be a promising therapeutic approach that reaches even beyond the realm of psychiatry. _

References

1. Monteleone P, Maj M. The circadian basis of mood disorders: Recent developments and treatment implications. Eur Neuropsychopharmacology. 2008;18: 701-711.
2. Schulz P, Steimer T. Neurobiology of circadian systems. CNS Drugs. 2009;23 (suppl 2):3-13.
3. BuijsMR, Kalsbeek A. Hypothalamic integration of central and peripheral clocks. Nat Rev Neurosci. 2001;2:521-526.
4. Tigges M, Marquez-Lago TT, Stelling J, Fussenegger M. A tunable synthetic mammalian oscillator. Nature. 2009;457:309-312.
5. Franken P, Dijk DJ. Circadian clock genes and sleep homeostasis. Eur J Neurosci. 2009;29:1820-1829.
6. Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6:367-378.
7. Froy O. Metabolism and circadian rhythms—implications for obesity. Endocr Rev. 2009, October 23. Epub ahead of print.
8. Rüger M, Scheer FA. Effects of circadian disruption on the cardiometabolic system. Rev Endocr Metab Disord. 2009, September 26. Epub ahead of print.
9. Gerstner JR, Lyons LC, Wright KP Jr, et al. Cycling behavior and memory formation. J Neurosci. 2009;29:12824-12830.
10. Reilly T, Waterhouse J. Sports performance: is there evidence that the body clock plays a role? Eur J Appl Physiol. 2009;106:321-332.
11. Yamaguchi S, Isejima H, Matsuo T, et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science. 2003;302:1408-1412.
12. Gorwood P. Depression and circadian rhythm disturbances. Medicographia. 2007;29:22-27.
13. Basner M, Fomberstein KM, Razavi FM, et al. America, time use survey: sleep time and its relationship to waking activities. Sleep. 2007;30:1085-1095.
14. National Sleep Foundation USA. http://www.sleepfoundation.org. Accessed October 22, 2009.
15. Hajak G. Clocks drive human behavior: disturbance of clock function may cause depression. Editorial. Reference in Psychiatry. In press.
16. Benca R, Duncan MJ, Frank E, McClung C, Nelson RJ, Vicentic A. Biological rhythms, higher brain function, and behavior: gaps, opportunities, and challenges. Brain Res Rev. 2009, September 18. Epub ahead of print.
17. Lamont EW, Legault-Coutu D, Cermakian N, Boivin DB. The role of circadian clock genes in mental disorders. Dialogues Clin Neurosci. 2007;9:333-342.
18. Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry. 2008;165:820-829.
19. McClung CA. Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther. 2007;114:222-232.
20. Germain A, Kupfer DJ. Circadian rhythm disturbances in depression. Hum Psychopharmacol. 2008;23:571-585.
21. Mendlewicz J. Circadian Rhythms and Depression. Current Understanding and New Therapeutic Perspectives. Paris, France: Wolters Kluwer Health; 2008.
22. Souêtre E, Salvati E, Belugou JL, et al. Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Res. 1989;28:263-278.
23. Souêtre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G. Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry. 1988;145:1133-1137.
24. Parry BL, Mendelson WB, Duncan WC, Sack DA, Wehr TA. Longitudinal sleep EEG, temperature, and activity measurements across the menstrual cycle in patients with premenstrual depression and in age-matched controls. Psychiatry Res. 1989;30:285-303.
25. Antonijevic I. HPA axis and sleep: identifying subtypes of major depression. Stress. 2008;11:15-27.
26. Tichomirowa MA, Keck ME, Schneider HJ, et al. Endocrine disturbances in depression. J Endocrinol Invest. 2005;28:89-99.
27. McKay MS, Zakzanis KK. The impact of treatment on HPA axis activity in unipolar major depression. J Psychiatr Res. 2009, September 9. Epub ahead of print.
28. Lopez-Duran NL, Kovacs M, George CJ. Hypothalamic-pituitary-adrenal axis dysregulation in depressed children and adolescents: a meta-analysis. Psychoneuroendocrinology. 2009;34:1272-1283.
29. Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 1996;81:2468- 2473.
30. Srinivasan V, Smits M, Spence W, et al. Melatonin in mood disorders. World J Biol Psychiatry. 2006;7:138-151.
31. Carvalho LA, Gorenstein C, Moreno RA, Markus RP. Melatonin levels in drugfree patients with major depression from the southern hemisphere. Psychoneuroendocrinology. 2006;31:761-768.
32. Brunello N, Armitage R, Feinberg I, et al. Depression and sleep disorders: clinical relevance, economic burden and pharmacological treatment. Neuropsychobiology. 2000;42:107-119.
33. Riemann D. Insomnia and comorbid psychiatric disorders. Sleep Med. 2007; 8(suppl 4):S15-S20.
34. Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci. 2008;10:473-481.
35. Mendlewicz J. Disruption of the circadian timing systems: molecular mechanisms in mood disorders. CNS Drugs. 2009;23(suppl 2):15-26.
36. Bunney JN, Potkin SG. Circadian abnormalities, molecular clock genes and chronobiological treatments in depression. Br Med Bull. 2008;86:23-32.
37. Srinivasan V, Pandi-Perumal SR, Trakht I, et al. Pathophysiology of depression: role of sleep and the melatonergic system. Psychiatry Res. 2009;165:201-214.
38. Chellappa SL, Schröder C, Cajochen C. Chronobiology, excessive daytime sleepiness and depression: is there a link? Sleep Med. 2009;10:505-514.
39. Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196:129-136.
40. Wirz-Justice A. Diurnal variation of depressive symptoms. Dialogues Clin Neurosci. 2008;10:337-343.
41. Benedetti F, Barbini B, Colombo C, Smeraldi E. Chronotherapeutics in a psychiatric ward. Sleep Med Rev. 2007;11:509-522.
42. Hajak G, Popp R. Circadian rhythm resynchronisation in treatment of depression. In:Mendlewicz J, ed. Circadian Rhythms and Depression. Current Understanding and New Therapeutic Perspectives. Paris, France: Wolters Kluwer Health; 2008:77-95.
43. Eichhammer P, Kharraz A, Wiegand R, et al. Sleep deprivation in depression: stabilizing antidepressant effects by repetitive transcranial magnetic stimulation. Life Sci. 2002;70:1-9.
44. Hajak G. Agomelatine and sleep-wake-rhythm in depression. Psychopharmakotherapie. 2009;(suppl 19):15-20.
45. Yin L, Wang J, Klein PS, Lazar MA. Nuclear receptor Rev-erb alpha is a critical lithium-sensitive component of the circadian clock. Science. 2006;311:1002- 1005.
46. Tan ZL, Bao AM, Zhao GQ, Liu YJ, Zhou JN. Effect of fluoxetine on circadian rhythm of melatonin in patients with major depressive disorder. Neuro Endocrinol lett. 2007;28:28-32.
47. Kennedy SH. Agomelatine: an antidepressant with a novel mechanism of action. Future Neurol. 2007;2:145-151.
48. San L, Arranz B. Agomelatine: a novel mechanism of antidepressant action involving the melatonergic and the serotonergic system. Eur Psychiatry. 2008; 23:396-402.
49. Delagrange P, Boutin JA. Therapeutic potential of melatonin ligands. Chronobiol Int. 2006;23:413-418.
50. Racagni G, Riva MA, Popoli M. The interaction between the internal clock and antidepressant efficacy. Int Clin Psychopharmacol. 2007;22(suppl 2):S9-S14.
51. Kräuchi K. The thermophysiological cascade leading to sleep initiation in relation to phase of entrainment. Sleep Med Rev. 2007;11:439-451.
52. Quera Salva MA, Vanier B, Laredo J, et al. Major depressive disorder, sleep EEG and agomelatine: an open-label study. Int J Neuropsychopharmacol. 2007;10: 691-696.
53. Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry. 2007;68:1723- 1732.
54. Wirz-Justice A. Chronobiology and psychiatry. Sleep Med Rev. 2007;11:423-427.