CLINICAL Circadian rhythms Philip Boyce Erin Barriball and depression However, current treatments have been developed Background on the basis of a causal model for depression. Depression is a common disorder in primary care. Disruptions to the circadian rhythms Focused psychological treatments target those associated with depression have received little attention yet offer new and exciting depressions that arise from psychosocial approaches to treatment. difficulties. Examples include: Objective • cognitive behavioural therapy (CBT), which This article discusses circadian rhythms and the disruption to them associated with corrects maladaptive thinking patterns depression, and reviews nonpharmaceutical and pharmaceutical interventions to shift • behavioural treatments that aim to overcome circadian rhythms. ‘depressogenic’ behaviours such as avoiding Discussion pleasurable activities, and Features of depression suggestive of a disturbance to circadian rhythms include early • lifestyle modifications, particularly work-life morning waking, diurnal mood changes, changes in sleep architecture, changes in balance, diet and exercise and sleep-wake timing of the temperature nadir, and peak cortisol levels. Interpersonal social rhythm cycle management.5 therapy involves learning to manage interpersonal relationships more effectively Antidepressant medications target the and stabilisation of social cues, such as including sleep and wake times, meal times, neurotransmitter disturbances (serotonin or and timing of social contact. Bright light therapy is used to treat seasonal affective noradrenaline) considered to underlie biological disorders. Agomelatine is an antidepressant that works in a novel way by targeting depression. While the focus of biological melatonergic receptors. aspects of depression has centred on changes in Keywords: circadian rhythm, depression neurotransmitters, there has been relatively little attention paid to the changes in circadian rhythms associated with depression that offer new and rational treatment options for depression. Circadian rhythms Over the past 5–10 years, there has been The regular rhythm of night (dark) and day (light) growing community awareness about regulates our life, as it does for most living depression, with an increased emphasis organisms. Associated with this are regular on its treatment in primary care. Evidence changes in core body temperature, hormonal based pharmacological and psychological secretions, heart rate, renal output and gut treatments for depression have been motility. Our mental ability and energy levels outlined in clinical practice guidelines.1,2 are highest during daylight hours, when we These treatments are recommended on the engage in exercise and social interactions, with basis of severity rather than depression type. our metabolism and physiology adapted to this. While such an approach makes treatment During the night, when activity levels drop, core decisions relatively straightforward, it body temperature falls and reaches its nadir, does not take into account the different while cortisol levels rise before awakening. causal explanations for depression; There are cyclic changes in the level of sleep (as particularly whether the depression is shown by changes on an electroencephalogram predominantly biological, such as that seen [EEG]) with hormonal release, such as the in melancholia3,4 and bipolar depression, or release of growth hormone linked to specific the result of psychosocial factors. phases of the regular sleep cycle.6–8 When our Reprinted from AusTrAliAn FAmily PhysiCiAn Vol. 39, No. 5, May 2010 307 CLINICAL Circadian rhythms and depression sleep-wake cycle is out of phase with the day- in the day, while bright light applied in the with remission in spring and summer). some night cycle (eg. due to jetlag or shift work), we evening will have an opposite effect by delaying patients with bipolar disorder also experience can experience dysphoria, poor functioning and circadian rhythms.16–18 episodes of depression or (hypo)mania at the increased health risk.7,9 same time each year. These seasonal changes are Social zeitgebers considered to be the result of a failure to adapt Regulating circadian rhythms Regular patterns of social behaviour can also the shift in day length that accompanies seasonal These rhythmic changes in metabolism and affect circadian rhythms and aid in regulating change.20,21 This adaptive failure leads to psychological activity are under the control of them. These cues are known as ‘social zeitgebers’ circadian rhythms becoming uncoupled, resulting a circadian clock; this ensures that our body is and include time of going to bed and waking, in the onset of mood disorder. For patients with attuned to the level of mental and physical activity social interactions, and meal times. bipolar disorder, this has shown very clearly with associated with a particular time of day or night. disruptions to the sleep-wake cycle triggering off When free of external environmental clues, Disruption to circadian rhythms episodes of hypomania or mania.22 A phase delay the amplitude of our daily rhythm is longer than in depression in circadian rhythms are proposed as a mechanism the 24 hour day-night cycle (hence the name Disruptions to circadian rhythms have been found for seasonal affective disorder as demonstrated circa diem – about a day) as demonstrated in among patients with major depression.19 While by the temperature nadir and timing of melatonin experiments when individuals were placed these changes are thought to be a contributing secretion occurring later in the night.16 in temporal isolation10 or in conditions of factor to the depression (such as suggested permanent darkness such as subjects wintering by the dysphoria triggered by jetlag) it is also Manipulating circadian in the Antarctic.11 possible that they may arise as a consequence of rhythms The human circadian pacemaker or ‘clock‘ is the depression. The circadian rhythms disturbances of depression located in the suprachiasmatic nucleus of the can be corrected by novel nonpharmacological and Sleep anterior hypothalamus. This regulates the key pharmacological methods. circadian rhythmic changes such as cortisol, There are a number of features of depression Social zeitgebers thyroid hormone and core body temperature. suggestive of a disturbance to circadian rhythms; The mechanism for this is governed by a set of perhaps the most obvious are the changes in The timing of social zeitgebers, for example genes that operate through a series of feedback sleep, in particular waking early in the morning sleep or meal times, play a role in regulation and mechanisms with a regular cycle of about (but not which is usually linked to a diurnal mood change. disruption of circadian rhythms. Individuals who exactly) 24 hours.12–14 Sleep and polysomnographic studies demonstrate suffer from mood disorders show fewer routine The circadian pacemaker has to be other changes in circadian rhythms, particular activities than controls, and social rhythm resynchronised regularly to compensate to the sleep architecture that indicate a ‘phase regularity predicts time to prospective onset for the slightly longer than 24 hour cycle advance’ of such rhythms; specifically of the of a bipolar episode.23 In addition, it is thought of the ‘endogenous’ circadian rhythm. This temperature nadir and cortisol levels, which occur these individuals are more sensitive to circadian synchronisation to the external environment is earlier in the night.19 Sleep architecture also rhythm disruptions.24 mediated through the retinohypothalamic tract. reflects this with a shortened rapid eye movement The symptoms presented by patients with (rEm) latency and rEm sleep shifted to the first unipolar and bipolar depression tend to display Light zeitgebers third, rather than the latter third of the sleep circadian rhythmicity. For example, sleep, light acts a ‘zeitgeber’ or timekeeper, falling cycle. These observations, along with clinical hunger and concentration all have a propensity on the retina which then sends impulses to features, all support the notion of circadian to follow a 24 hour clock, and will be affected the suprachiasmatic nucleus; a process that is rhythm disturbance in depression.19 by disruption to biological rhythms. The mediated through the protein melanopsin (rather implementation of frequent and stable social Seasonal change than rods or cones).15 Bright light also has an rhythms has been shown to be an important effect by suppressing melatonin production. The most compelling evidence for a rhythm prophylactic treatment in affective disorders.24 For this to occur, a light intensity of at least disturbance hypothesis of depression is the link These activities, when performed regularly, have 1500 lux (brighter than standard artificial between mood disorders and seasonal change.20 the ability to entrain biological rhythms such as lighting) is required to switch off melatonin in addition to the 24 hour daily rhythm, there cortisol and body temperature.25 production. Suppressing melatonin can have are also regular rhythms over a year. These As a result, interpersonal social rhythm an effect in changing circadian rhythms: bright are known as circannual rhythms and reflect therapy (iPsrT) was created.24 interpersonal light administered in the early morning will the changing day length (photo period) during social rhythm therapy involves learning to manage suppress melatonin and therefore advance the year. Circannual rhythms