Circadian rhythm disturbances in depression: implications for treatment and quality of remission



by P. M o n t e l e o n e a n d M . M a j , I t a l y

Palmiero MONTELEONE, MD
Mario MAJ, MD, PhD
Department of Psychiatry
University of Naples SUN
Naples, ITALY

Mood disorders, especially unipolar depression and seasonal affective disorder, have been linked to endogenous circadian rhythm abnormalities. Evidence is emerging that disruption of the normal circadian rhythmicity occurs at least in a subgroup of depressed patients, although whether there is a causal link between endogenous circadian rhythm disruption and depression has not been firmly demonstrated. Nonetheless, improvements in some forms of depression in response to strategies that manipulate circadian rhythms support the idea that circadian abnormalities observed in depressed patients may constitute a core component of the pathophysiology of depression and are worthy of therapeutic consideration. Chronotherapeutic interventions, which include both nonpharmacological strategies, such as sleep deprivation, light therapy, and interpersonal and social rhythm therapy, and pharmacological treatments based on the use of drugs specifically endowed with chronobiotic properties, such as agomelatine, have been shown to have antidepressant effects. Therefore, normalization of circadian rhythms seems to represent a possible new direction for the development of either pharmacological or nonpharmacological innovative therapeutic strategies, which could have an important future role as alternatives or adjuvants to currently available antidepressant treatments, in order to achieve a better quality of remission and a persistent amelioration of patients’ social functioning and quality of life.
Medicographia. 2009;31:132-139. (see French abstract on page 139)

Keywords: circadian rhythm; depression; remission; chronotherapy; antidepressant

Over the course of evolution, organisms have developed cellular clock mechanisms sensitive to light, and have adapted by organizing their activities in 24-hour cycles determined by sunrise and sunset. These 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 that persist in the absence of any environmental stimuli. The endogenous timekeeping system or biological clock allows the organism to anticipate and prepare for the changes in the environment that are associated with day and night in order to function optimally. In humans and other mammals, circadian rhythms are generated by an internal clock or pacemaker, which is located in the suprachiasmatic nucleus (SCN) of the hypothalamus.1 Individual neurons from the SCN, when dissociated and held in vitro, retain a robust circadian rhythm in electrical firing, and this can continuously be recorded for several weeks, showing a slight deviation from 24 hours (usually longer).2 Thus, the intrinsic rhythmicity of the endogenous clock requires daily synchronization to the 24-hour day by regularly occurring environmental signals or “zeitgebers.” Light, the major zeitgeber for the SCN, reaches the SCN neurons directly via the retinohypothalamic tract, a non– image-forming pathway, and indirectly via the intergeniculate leaflet of the lateral geniculate complex. The activity of SCN neurons is also modulated by serotonin (5-HT) released by nervous fibers ascending from the raphe nuclei3 and by melatonin secreted in the pineal gland.4

The major output of the SCN is to the paraventricular nucleus (PVN) of the hypothalamus, and via a multisynaptic pathway, to the pineal gland, where melatonin is synthesized according to the length of the photoperiod. In this way, melatonin is secreted at night and suppressed by light during the day. Melatonin is a biochemical transducer of photoperiodic information to all cells in the body (including SCN neurons), signaling the seasonal variations of the day/night cycle length.5 The PVN is also the site of autonomic neurons, which communicate the time-of-day signal to different body organs, and corticotrophin-releasing factor–secreting neurons, which are part of the hypothalamopituitary- adrenal (HPA) axis, endowed with a diurnal rhythmicity. Therefore, the SCN time signal is translated into hormonal and autonomic signals for peripheral organs mainly within the PVN.
Beside light there are also other nonphotic zeitgebers (among them exercise, food availability, temperature, jobs, and social demands) and these also act directly or indirectly on the SCN to synchronize its rhythmic activity. Furthermore, it is now widely demonstrated that multiple endogenous clocks are distributed in every organ and perhaps in every cell of the organism, and each of them has its own zeitgebers.6
Nearly all physiological and behavioral functions in humans are rhythmic, and examples to be mentioned here are the secretion patterns of hormones (prolactin, corticotrophin, cortisol, growth hormone, melatonin), the sleep-wake cycle, core body temperature, thyroid function, 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.

Circadian rhythm disturbances
and depression

Given that most human functions demonstrate circadian rhythmicity, it is intuitive that alterations in the endogenous machinery regulating biorhythms may lead to both physical and mental disorders.7-9 In particular, disruptions of endogenous biological rhythms have been strongly associated with mood disorders, especially unipolar depression, for which alterations of circadian rhythms were first described more than 20 years ago.10 There are several lines of evidence supporting the occurrence of a dysregulation of the endogenous clock system in subgroups of affective patients (Table I).11-53

Diurnal mood variation
First of all, on the one hand, some affective disorder patients suffer from regular cycles of recurrence of mood episodes, and on the other hand, approximately 20% of depressive patients show marked diurnal mood swings. In a recent post-hoc analysis of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, it was reported that 21.6% of the depressed patients enrolled in the study experienced diurnal mood variation, and that compared with patients without diurnal mood variation, they exhibited more severe depression and were more likely to meet the criteria for the melancholic subtype of depression.11 Of note, a pattern of worse mood in the morning is incorporated into the formal formal DSM-IV (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) criteria for the melancholic subtype of major depression, although in the post-hoc STAR*D study analysis, diurnal mood variation was more meaningfully related to symptoms of melancholia if the definition was expanded to include also afternoon and evening worsening of mood.11 Also, patients with other forms of depression actually appear to report a pattern of diurnal mood variation.54 In a recent investigation using a two-factor model of mood categorized according to positive affect and negative affect, diurnal variations in these two mood dimensions were compared between a group of patients with major depression and a group of healthy controls.55 Results indicated that depressed patients showed lower overall levels of positive affect, which increased over the course of the day as in healthy controls but with a backward-shifted acrophase, and higher overall negative affect levels, with maximum values occurring in the late morning and then decreasing over the rest of the day. Furthermore, Germain et al12 provided preliminary evidence that diurnal mood variations in major depressive disorder patients were paralleled by diurnal variations in regional brain glucose metabolism.

Table I
Table I. Evidence in support of a dysregulation of the endogenous clock system in some patients with mood disorders.

Core body temperature
For core body temperature, a robust circadian rhythm has been well established, with the highest values occurring in the evening and the nadir occurring during the last third of the night. An elevated nocturnal body temperature is the most consistently observed circadian abnormality in depression,13,56 and this aberration generally normalizes with clinical improvement.57 Although not confirmed by all studies, a phase-advance in the overall 24-hour pattern of body temperature has been also reported in many depressed patients.13-16 Moreover, in subjects experiencing a depressive episode, nighttime changes in body temperature have been found to be inversely correlated with nighttime changes in plasma levels of thyroid stimulating hormone (TSH).13 The mean plasma concentration of TSH during sleep, its nocturnal peak concentration, and the amplitude of its circadian rhythm have been reported to be lower in depressed subjects compared with both normal controls and remitted patients.17 Finally, the time of the nocturnal TSH peak has been found to be advanced during a depressive episode.17

Cortisol secretion
In healthy subjects, maximal secretion of cortisol occurs in the morning; thereafter, there is a progressive decline over the day until the nadir is reached in the evening, immediately after falling asleep. Dysregulation of the HPA axis is extremely frequent in depressed patients. A meta-analysis on cortisol in depression revealed 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 in depression.18

Melatonin secretion and the sleep-wake cycle
Several studies have also reported on alterations in the melatonin secretory pattern in depression: the most consistent finding has been a lower blood concentration of melatonin and a phase advance, or a trend toward a phase advance, of the melatonin circadian rhythm in individuals suffering from major depression19,20; this was, however, not confirmed in all studies.58 Moreover, a modified sensitivity of demonstrated in bipolar patients and their offspring.21,22
The sleep-wake cycle is the most obvious circadian rhythm in humans, and sleep disturbances represent a prominent feature of depression. Epidemiological studies estimate that 50% to 90% of patients with diagnosed depression complain about impairment of their sleep quality.23,24 Typically, the complaints of depressed patients are about the difficulty in falling asleep, frequent nocturnal awakening, and early morning awakening. Insomnia is thereby not only experienced subjectively, but also reflected objectively in altered sleep architecture, as first demonstrated by Kupfer and colleagues in the early 1970s.25 These abnormalities consist of impaired sleep continuity and duration, a reduction of slow-wave sleep (SWS), a shortening latency of the initial rapid eye movement (REM) phase, an increase in the proportion of REM sleep in the early part of the night, a prolongation of the first REM period, an increased amount of total REM sleep, and an increased number of eye movements during REM periods (REM density).26 Longitudinal electroencephalogram studies in depressed patients have described a tendency for REM sleep abnormalities to resolve with improvement of the depression,59,60 and even total normalization has been reported after successful treatment.61 However, other studies have reported the persistence of REM sleep and SWS abnormalities during remission, even after nonpharmacological treatments.62-64 Persistent and/or residual sleep disturbance has thereby been associated with an increased risk of relapse,65 and the persistence of reduced SWS has similarly been associated with more rapid and more frequent recurrence of depression.66

Motor activity
Motor activity shows a typical circadian rhythm in humans, and most although not all investigations have documented a phase advance (early daily peak) of the circadian motor activity rhythm in bipolar disorder patients in both the depressive and the manic phases as well as during euthymia.27-29

Seasonal affective disorder
Seasonal changes in mood, appetite, sleep, and daily living function occur physiologically in many individuals. If these variations are of sufficient severity to meet the criteria for a major depressive episode, occur regularly during fall/winter, and are generally followed by a remission during the subsequent spring and summer period, they may be regarded as an episode of seasonal affective disorder (SAD). SAD is a disorder with a circannual period, and patients with SAD present with apparent chronobiological abnormalities; hence, it is currently assumed that SAD is a disorder of seasonal biological rhythms.67 Abnormalities of circadian rhythms in SAD patients include sleep disturbances, quantitative changes and phase delays in cortisol and melatonin secretion patterns, and increases in the minima of the nocturnal body temperature as well as a phase delay of its 24-hour rhythm.68-70

Disrupted circadian rhythms and the pathogenesis of major depression

The fact that a wide variety of endogenous rhythms are disrupted in individuals with depression has led to speculation that such disturbances are not unique to specific rhythms, but are associated, instead, with a disruption in the activity of the circadian master pacemaker in the SCN. Therefore, it is plausible that alterations of the molecular components of the endogenous clock system play a role in the disturbed circadian rhythms of mood disorder patients. The cellular machinery behind the circadian timing within the SCN neurons has been largely identified, and it is believed to be under genetic control. Genes encoding essential elements of the clock include, in mammals, period (per1, per2, per3), neuronal PAS domain protein-2 (NPAS2), circadian locomotor output cycles kaput (CLOCK), cryptochrome (Cry1, Cry2), and brain and muscle ARNT-like-1 (bmal1) genes. The proteins encoded by these genes are part of a circadian autoregulatory loop incorporating activators and suppressors of genes, whose activity thereby oscillates with a circadian period, thus generating the endogenous rhythmicity of SCN neurons.71
Both animal and human studies have provided preliminary evidence of a role for circadian genes in mood disorders. Mice carrying a mutation in the CLOCK gene display a behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, reduced depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation.72 Interestingly, many of those mania-like behaviors are reverted by chronic lithium administration and are rescued by expressing a functional CLOCK protein specifically in the ventral tegmental area of CLOCK mutant mice.72
Studies in humans have begun to identify polymorphisms in certain circadian genes that are associated with mood disorders and, in particular, bipolar disorder. The T3111C single nucleotide polymorphism (SNP) of the CLOCK gene has been investigated in both major depression and bipolar disorder. Whereas no differences were found in allelic frequencies between individuals with a history of major depression and healthy controls,30 the CC genotype has been associated with a greater severity of insomnia during antidepressant treatment, a higher recurrence rate of bipolar episodes, and a reduced need for sleep in bipolar patients.31-33 In a family-based sample of bipolar patients, an analysis of 46 SNPs in 8 clock genes revealed a significant although modest association of BMAL1 and TIM genes with the mood disorder.34 An independent study using haplotype analysis confirmed the association of bipolar disorder with the BMAL1 gene and detected a new association with the PER3 gene.35 Finally, bipolar patients with the TT genotype of the T50C SNP of the glycogen synthase kinase-3β gene, which encodes an enzymatic protein regulating central clock mechanisms, were found to be of an earlier age at the onset of bipolar disorder and to experience less improvement from lithium therapy than patients with the TC or CC genotypes.36,37 Recent studies suggest that SNPs of PER2, NPAS2, and BMAL1 genes are associated with an increased risk for SAD; furthermore, certain allelic combinations of SNPs of these three genes have an additive effect, increasing the risk of developing SAD by 4.43 over other genotypes, and 10.67 over the most protective genotype.38
Based on the above findings, it could be suggested that primary or secondary alterations of the biological clock at the molecular level could lead to disruptions in endogenous circadian rhythms, which in turn may generate the depressed state. Alternatively, it has been proposed that instead of or in addition to molecular abnormalities of the endogenous pacemaker, disturbances in environmental zeitgebers may cause depressive symptoms in biologically predisposed individuals.73 This social zeitgeber theory specifically postulates that depressive episodes arise as a consequence of life events causing a disturbance of social zeitgebers (ie, social factors such as the timing of meals, work schedules, social demands, personal relationships), which, in turn, derail an individual’s social rhythms. These disruptions can place substantial stress on the body’s capacity to maintain stable biological rhythms, particularly sleep-wake, energy, alertness, and appetite rhythms. Whereas in most individuals such rhythms will restabilize shortly after the destabilizing events, in predisposed subjects, they may precipitate a major depressive episode.
Finally, as suggested by Turek,74 the expression of most rhythms at the behavioral, physiological, and biochemical level is regulated by the integration of inputs from the circadian clock and the sleepwake state of the organism. Thus, the circadian and sleep control centers have evolved together to ensure a timely coordination between the internal and external environment in order to optimize the survival of the species. Therefore, it could be that a primary circadian disturbance of the sleep-wake cycle leads to insomnia that may desynchronize many endogenous rhythms, which then, in turn, may lead to a depressed state. In support of this latter view, evidence has been provided that insomnia is a risk factor for the development of depression,75-77 as well as for relapse and recurrence.78-80 Most of the circadian abnormalities observed in the depressed state normalize with recovery, therefore it cannot be excluded that they arise as consequence of depression and do not represent the primary determinants of the affective disorder. However, even if so, the presence of disrupted endogenous rhythms might potentially contribute to the maintenance of depressive symptoms and might affect the course and/or the prognosis of the affective episode. Therefore, circadian abnormalities of depressed patients are worthy of clinical and therapeutic consideration.

Disrupted circadian rhythms and the treatment of depression

The ideal antidepressant treatment should combine high short-term efficacy for the acute phase of treatment with long-term efficacy and tolerability for the maintenance phase. This would result in a high quality of remission, in which patients are asymptomatic with no or only minimal residual symptoms, and experience a full restoration of day-today functioning and quality of life. Currently used antidepressant drugs, which act more or less specifically on brain monoamines, are frequently associated with significant limitations such as low remission rates, high risk of relapse, slow onset of response, discontinuation symptoms, and side effects— especially sleep disturbances. Since a disruption of the normal circadian rhythmicity occurs at least in a subgroup of depressed patients and is believed to play a role in the pathophysiology of depression, it is theoretically likely that interventions able to induce phase shift within the circadian system, so that normal rhythmic patterns are restored, may result in a high quality of remission. Therefore, chronotherapeutic interventions have been developed, and these include both nonpharmacological strategies, such as sleep deprivation, light therapy, and interpersonal and social rhythm therapy (IPSRT), and pharmacological treatments based on the use of drugs specifically endowed with chronobiotic properties.

◆ Sleep deprivation
One night of total sleep deprivation induces rapid and effective, although short-lasting, antidepressant effects.39 Variants of total sleep deprivation, such as selective REM sleep deprivation and partial sleep deprivation, especially in the second half of the night, are also effective, although total sleep deprivation seems to be superior.39 However, the therapeutic effect of sleep deprivation does not last longer than one or maximally a few days, and this intervention seems to work in less than 50% of patients.39

◆ Light therapy
Light therapy is the treatment of choice for SAD, where its astonishing success has led to the conclusion that it has to be considered the most successful clinical application of the circadian rhythm concept in psychiatry. It moves from the hypothesis that reduced ambient light during fall/winter leads to SAD symptoms in predisposed individuals40; thus lengthening the photoperiod by exposing patients to bright light early in the morning before dawn or in the evening has been proven to exert antidepressant effects.41 It has subsequently been proposed that most patients with SAD become depressed in fall/winter at least in part because the later dawn in winter causes a delay in the patients’ endogenous circadian rhythms with respect to clock time and the sleep-wake cycle.42 Therefore, providing a corrective phase advance should be useful in realigning endogenous rhythms with the sleepwake cycle. In SAD patients, exposure to bright light in the morning, which causes a phase advance of endogenous circadian rhythms, has been shown to produce higher antidepressant effects than exposure in the evening, which causes a phase-delay of endogenous rhythms.40 However, some SAD patients are actually phase-advanced, and this may explain why in some studies, bright light scheduled in the evening has been proven to have an antidepressant effect that is equal to that of morning exposure.44 Guidelines for the treatment of SAD patients with bright light have recently been provided.45 Standard light treatment involves exposure to 1 to 2 hours of a 2500-10000 lux light box in the morning immediately upon awakening, and for those patients who do not respond to this schedule, a trial of evening bright light (7-9 PM) may be necessary.

◆ Interpersonal and social rhythm therapy
IPSRT was specifically designed to maintain regular daily rhythms, as well as identify and manage potential precipitants of rhythm disruptions, in accordance with the social zeitgeber theory that depressive episodes arise as a consequence of life events that disturb social zeitgebers.73 Therefore, restoring the depressed patient’s social zeitgebers, such as personal relationships, meals, exercise, and social demands, would result in normalization of biological rhythms and an improvement in mood. Two preliminary studies have shown that although increasing bipolar individuals’ social rhythm regularity did not improve their mood, participants treated with IPSRT experienced longer episode-free periods and were more likely to remain well in the 2-year preventive maintenance study phase.46,47

◆ Agomelatine
As for pharmacologic interventions, melatonin has been identified as having chronobiotic properties in both rodents and humans81,82; therefore, it is supposed that the pineal hormone has an antidepressant effect. However, the few studies in which melatonin has been administered to depressed patients have found an improvement in sleep, but no effect on depressive symptoms83,84 and no enhancing effect on existing antidepressant therapies in patients with treatment-resistant depression.85 By contrast, agomelatine, a compound with agonistic properties at melatonergic MT1 and MT2 receptors and antagonistic properties at 5-HT2C receptors,86 which are highly expressed in the SCN,87 has shown antidepressant properties in both preclinical and clinical studies.88-91 It must be pointed out that the antidepressant effect of agomelatine is not solely mediated via its melatonergic action at the MT1 and MT2 receptors, but rather also depends on the compound’s 5-HT2C antagonistic property.92 This may explain the above reported lack of antidepressant action of exogenous melatonin, which acts only on MT1 and MT2 receptors. It seems that, differently from currently available antidepressant drugs, agomelatine possesses specific chronobiotic properties, since it was able to regulate the sleep-wake cycle and restore abnormal circadian rhythms in animal models of disrupted circadian rhythms.48-50 In patients suffering from major depression, a recent polysomnographic study indicated that agomelatine increased the duration of SWS and normalized its distribution throughout the night.51 In a headto- head comparison study between venlafaxine and agomelatine in major depressive disorder patients, an earlier and better improvement of subjective measures of getting to sleep, quality of sleep, and ease of awakening have been reported with agomelatine.52 Moreover, agomelatine has been shown to be significantly superior to placebo in rates of clinical response and remission in a study in which the remission criteria (Hamilton Rating Scale for Depression score _6) were more stringent than usual53; the comparator in this study, paroxetine, had lower response and remission rates.53 Finally, in all the above clinical trials, agomelatine exhibited a favorable sexual side-effect profile and was in general well tolerated. All these data are indicative of agomelatine’s potential to renormalize circadian rhythms, including sleep-wake cycle alterations, without sedative effects and no sexual impairment, which could possibly lead to better adherence to antidepressant treatment, optimization of the achievement of full recovery with a high quality remission, and restoration of patients’ quality of life.

Conclusion

Although a number of effective antidepressant drugs have been introduced in recent years, there remain significant unmet needs in the treatment of depression. Only approximately 30% of depressed patients achieve remission, and even for remitted patients, residual symptoms or drug side effects (eg, sleep disturbances, sexual dysfunction, weight gain) can re- duce the quality of remission. Moreover, some antidepressant side effects can impair short-term and long-term patient adherence to treatment, thus favoring no response, relapse, and/or recurrence.
At present, it is clear at the descriptive level that some individuals with depression have circadian rhythm abnormalities; whether there is, however, a causal link between endogenous rhythm disruption and depression has not been firmly demonstrated, although evidence seems to be emerging that this is the case. Nonetheless, improvement in some forms of depression in response to strategies that manipulate circadian rhythms support the idea that circadian abnormalities observed in depressed patients may constitute a core component of the pathophysiology of depression. Therefore, normalization of circadian rhythms seems to represent a possible new direction for the development of either pharmacological or nonpharmacological innovative therapeutic strategies to treat depression. This new direction, in which circadian rhythms are directly targeted, could hold promise for the identification of chronotherapeutic strategies that, compared with currently-available antidepressant treatments, could have more solid efficacy and fewer side effects, achieving a better quality of remission and a persistent amelioration of patients’ social functioning with a more complete restoration of their quality of life. _

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TROUBLES DU RYTHME CIRCADIEN DANS LA DÉPRESSION :
CONSÉQUENCES POUR LE TRAITEMENT ET
LA QUALITÉ DE LA RÉMISSION

Les troubles de l’humeur, et en particulier les troubles dépressifs unipolaires et les troubles affectifs saisonniers, sont liés à des anomalies endogènes du rythme circadien. La perturbation de la rythmicité circadienne normale interviendrait au moins dans un certain sous-groupe de patients déprimés, le lien causal entre la perturbation du rythme circadien endogène et la dépression n’ayant néanmoins pas été formellement démontré. Cependant, l’amélioration de certaines formes de dépression en réponse à des stratégies agissant sur les rythmes circadiens permet de penser que les anomalies circadiennes observées chez les patients déprimés pourraient constituer une composante clé de la physiopathologie de la dépression méritant d’être prise en considération. Des actions chronothérapeutiques, comprenant à la fois des stratégies non pharmacologiques, telles que la privation de sommeil, la luminothérapie et la psychothérapie interpersonnelle et des rythmes sociaux (PTIRS), ainsi que des traitements pharmacologiques fondés sur l’utilisation de médicaments dotés de propriétés chronobiotiques, comme l’agomélatine, ont montré des effets antidépresseurs efficaces. Ainsi, la normalisation des rythmes circadiens représente une nouvelle direction possible pour le développement de stratégies thérapeutiques innovantes, pharmacologiques ou non, qui pourraient avoir un rôle futur important comme alternative ou adjuvant aux traitements antidépresseurs actuellement disponibles, afin d’obtenir une meilleure qualité de rémission et une amélioration durable de la qualité de vie et de fonctionnement social des patients.