Background
Discussion
Basic science developments in relation to the circadian clock
Molecular regulators of the brain clock
Glycogen synthase kinase 3 beta (GSK-3β) as a therapeutic target
Circadian function and human health
Inputs to the brain clock
‘Morningness’ vs. ‘eveningness’
The outputs of the brain clock
Melatonin and communication via the pineal gland
Homeostatic sleep processes
The hypocretin/orexin systems
Clinical science developments in relation to the circadian clock
The epidemiology and sub-classification of major depression
Early-onset depressive disorders
Mood disorders and sleep-wake and circadian cycles
Mood syndromes | Sleep-wake and circadian features |
---|---|
Major depression | ● Subjective sleep-wake complaints (often preceding the onset or recurrence of depressive episodes) |
Disturbing dreams [133] | |
● Macro and microarchitecture of sleep | |
Abnormal sleep duration [136] | |
Prolonged sleep onset latency [136] | |
Reduced slow wave activity and number of slow waves [136] | |
● Biological rhythms | |
Abnormal sleep phase [71, 143 ] | |
Depressive symptoms associated with increased nocturnal blood pressure in males | |
Possible seasonal variations (not exclusive to seasonal affective disorder) [172] | |
● Increased depressive symptoms are associated with more pronounced misalignment between melatonin, temperature and sleep-wake rhythms [173] | |
Depression in youth | ● Subjective sleep-wake complaints |
Difficulty falling asleep and staying asleep [174] | |
Difficulty waking up in the morning [175] | |
● Macro and microarchitecture of sleep | |
● Biological rhythms | |
Higher levels of ‘eveningness’ preference [70] | |
Lower circadian amplitude [185] | |
Late-life depression | ● Macro and microarchitecture of sleep |
Lower increase in REM sleep duration [136] | |
Otherwise similar features to that seen in adult depression, but more pronounced [136] | |
● Biological rhythms | |
Increased early morning awakenings [188] | |
Abnormal melatonin levels [189] | |
High prevalence of abnormal blood pressure circadian rhythms [190] | |
Bipolar disorders | |
● Insomnia often occurring before and during manic episodes [196] | |
● Insomnia or hypersomnia often occurring before and during depressive episodes [196] | |
● Macro and microarchitecture of sleep | |
● Disturbed biological rhythms | |
Short circadian period [203] | |
Diurnal variations in the direction of mood cycle switch [206] | |
Possibly enhanced disturbances in thyrotropin rhythms [207] | |
Seasonal affective disorder | ● Disrupted sleep |
● Disrupted biological rhythms | |
Seasonal pattern of changes in symptoms [218] | |
Increased sensitivity of melatonin to light in the winter and decreased sensitivity in the summer [219] | |
Dysthymia | ● Similar features to that seen in major depression expressed to a lesser degree [220] |
Typical and atypical forms of depression
Loss of circadian hormonal patterns in depressive disorders
Common genetic factors in circadian systems and risk of mood disorders
Disturbances in melatonin secretion in mood disorders
The challenge of bipolar depression
The importance of internal desynchrony
Clinical studies of young people with major depressive disorders
Monitoring the 24-hour sleep-wake and activity cycle
Measurement system | Key features | Proposed use |
---|---|---|
Self-report | Prolonged reporting (for example, two weeks or more) of sleep timing, latency, quality and duration, daily mood, daytime physical activity | - Identification of insomnia, dysfunctional sleep and circadian-rhythms. |
Cross sectional questionnaires of sleep quality, excessive daytime sleepiness, fatigue, presence of sleep disordered breathing and circadian rhythms; | - Characterization of the sleep-wake cycle. | |
Smart phone technologies now allow daily recording of sleep schedules and disturbances, as well as daytime physical activity patterns | - Assessment of treatment response. | |
Polysomnography | Laboratory or ambulatory monitoring of nocturnal sleep | - Differential diagnosis of various sleep disorders. |
- Characterization of sleep macro/microarchitecture. | ||
Actigraphy | Indirect measure of the sleep-wake cycle especially convenient for multiday ambulatory assessment | - Identification of insomnia, dysfunctional sleep and circadian rhythms. |
At least one week of monitoring, (including weekdays and weekends) | - Characterization of the sleep-wake cycle. | |
Key differentiation of patterns of sleep onset, offset, daytime activity and napping | - Assessment of treatment response. | |
Some monitors can simultaneously record patterns of light exposure and estimate energy expenditure | ||
Melatonin assays | Dim light melatonin onset protocol in controlled laboratory settings or at home | - Characterization of circadian rhythms |
- Assessment of treatment response. | ||
From saliva, urine or blood | - Can support diagnosis of some circadian rhythm sleep disorders | |
Core body temperature monitoring | 24-hour recording in controlled laboratory settings | - Characterization of circadian rhythms |
- Assessment of treatment response | ||
From ingested wireless probe or rectal probe | - Can support diagnosis of some circadian rhythm sleep disorders | |
Cortisol assays | 24-hour recording | - Characterization of circadian rhythms |
From saliva, urine or blood | - Assessment of treatment response | |
Vigilance monitoring | 24-hour recording in controlled laboratory settings | - Characterization of circadian rhythms |
- Psychomotor Vigilance Task (PVT) | - Assessment of treatment response | |
- Wake EEG | ||
- Multiple Sleep Latency test | ||
The PVT or similar tasks are now available on smart phone applications | ||
Cardiovascular monitoring | Continuous or repeated measures of blood pressure and heart rate parameters across 24 hours in controlled laboratory settings | - Characterization of circadian rhythms |
- Assessment of treatment response |
Markedly delayed sleep phase in young people with depression
Therapeutic approaches focused on correction of sleep-wake and circadian disturbance in major depression
Therapeutic approach | Target and rationale |
---|---|
Psychoeducation | ● Understanding sleep-wake and circadian regulation mechanisms and the processes through which sleep and circadian disturbances can be initiated and maintained |
● Linking changes in sleep quality, quantity and 24-hour sleep-wake cycles to onset and relapse of mood disorders | |
● Promoting awareness of how daytime and nighttime behaviors and environmental factors influence sleep-wake and circadian rhythms (that is, sleep hygiene) | |
N.B. These interventions are not considered to be efficient when used by themselves, but can be helpful in conjunction with other cognitive-behavioral interventions | |
● Identifying and adjusting dysfunctional beliefs contributing to the maintenance of sleep difficulties | |
● Understanding the influence of perceptions on sleep quality and daytime functioning | |
● Establishing realistic expectations about sleep | |
● Learning techniques to prevent evening/nighttime ruminations | |
● Stimulus Control Therapy | |
Aiming to reestablish positive associations between the bedroom and sleeping by: a) keeping the bedroom solely for sleep and sexual activities; and b) leaving the bedroom if awake for more than 15 minutes | |
● Bed Restriction Therapy | |
Using sleep pressure to enhance sleep consolidation by: a) limiting the sleep opportunity window to the habitual time spent asleep; and, b) increasing this window progressively as sleep efficiency (that is, ‘total sleep time’/‘time in bed’) improves | |
● Rescheduling | |
Progressive delay/advance of the sleep-wake and light–dark cycles | |
● Regularization of wake-up times (emphasizing the importance of keeping the same wake-up times on weekends) | |
● These techniques provide patients with simple therapeutic tools that can subsequently be used independently in case of relapse | |
● Can induce acute antidepressant effect | |
● Can be used prior to sleep-wake rescheduling to facilitate sleep-wake phase shifting | |
● May be useful to hasten and potentiate the response to phototherapy or cognitive-behavioral therapy | |
N.B. Caution is warranted as sleep loss can trigger mania/hypomania episodes in patients with unipolar or bipolar depression | |
Intensive Sleep Retraining [292] | ● While being monitored with polysomnography over a 25-hour protocol, patients are repeatedly given short sleep opportunities, each time being awoken shortly after achieving sleep (the progressive increase of sleep pressure is believed to facilitate multiple experiences of rapid sleep onset) |
● This novel conditioning technique may be especially promising for patients with depression and sleep/circadian disturbances because of the combined effects of acute partial sleep deprivation and subsequent improvement of sleep onset and other sleep parameters | |
N.B. Caution is warranted as sleep loss can trigger mania or hypomania episodes | |
Social rhythms therapy for bipolar disorder [265] | ● Integrated behavioral, interpersonal and psychoeducational therapy focusing on: |
- Regularizing daily activity rhythms (that is, eating, sleeping, leisure/work activities, social meetings) | |
- Managing biological or psychosocial factors susceptible of dysregulating biological rhythms | |
● Based on a model of bipolar disorder in which a genetic predisposition to circadian disturbances contributes to bipolar symptoms | |
● Techniques commonly used for insomnia include: progressive muscle relaxation, diaphragmatic breathing, autogenic training and imagery training | |
● Exposure to bright light (especially in the short blue to green wavelengths) has antidepressant and chronobiotic effects | |
● To advances circadian rhythms: | |
Morning exposure to bright light and evening exposure to dim light | |
● To delay circadian rhythms: | |
Evening exposure to bright light and morning exposure to dim light | |
● Extended exposure to darkness can reduce manic symptoms in bipolar disorders | |
● Actimeters with light sensors can be used to monitor adherence | |
Hypnotics/Sedatives | ● In those with delayed circadian rhythms, can be used in the short-term to help realign the sleep phase to a regular schedule |
Stimulant-wakefulness agents | ● In those with daytime fatigue, low energy, reduced locomotor activity and daytime sleeping can been used to increase the wake period |
● Modafinil, a unique wakefulness agent, has been proposed as a treatment for bipolar disorder – including bipolar depression | |
● Often result in longer-term correction of sleep-wake cycle and circadian phase after recovery from depression – assumed via monoamine related mechanisms | |
● Traditionally result in REM-sleep suppression and in the short-term may disturb sleep architecture | |
● Those with more obvious noradrenergic properties have been used (with daytime or morning administration) to also promote daytime activity and arousal and help reduce subjective fatigue | |
● Those with classical serotoninergic properties, when given at night, may increase arousal and wakefulness. While serotoninergic inputs to the SCN are expected to increase wakefulness, selective serotonin reuptake inhibitors (SSRIs) have not proved to be very useful in the management of more prolonged fatigue states compared with either nighttime sleep-promoting agents or daytime stimulants | |
● Inhibits GSK-3β, a kinase involved in the circadian regulation of the SCN | |
● Modulates circadian rhythms (possibly by lengthening the circadian period or delaying endogenous rhythms) | |
● Can enhance the therapeutic effects of combined sleep deprivation and phase advance in people with bipolar disorders | |
● Known to decrease retinal sensitivity to light and could possibly influence melatonin’s sensitivity to light | |
● Can advance sleep onset in those with delayed sleep phase syndrome | |
● Could possibly improve the sleep-wake rhythm and prolong sleep in elderly people with advanced sleep phase syndrome (insufficient empirical data) | |
● Reduce sleep onset latency and improve sleep efficiency (most consistent effects in elderly insomniac) | |
N.B. Not recommended for children and adolescents under 18 years of age because of insufficient safety data (MIMS online) | |
● Direct effects on sleep onset with potential additional effects via other monoamine related mechanisms | |
● Can reduce sleep onset latency and increase sleep duration in patients with insomnia | |
● Could possibly be used to phase shift endogenous melatonin rhythms | |
● Could possibly improve subjective sleep and increase sleep consolidation and SWS in patients with major depression | |
● Can advance endogenous rhythms in older adults | |
N.B. Not recommended for children and adolescents under 18 years of age because of insufficient safety data (MIMS online) |
Available circadian-based interventions
Pharmacological approaches to sleep-wake and circadian systems
Melatonin-based therapies
Phase advance as a therapeutic strategy
Planning a mood disorder intervention based on sleep and circadian therapies
A. Initial clinical assessment and enrollment to two weeks of systematic assessment | |
---|---|
1. Clinical assessment of depression | Assessment for key features indicative of circadian-dependent mood disorders including: |
● Positive family history of mania or circadian rhythm sleep disorders | |
● Diurnal or seasonal sensitivity | |
● Easy destabilization by changes in time-zones or changes in regular sleep pattern | |
● Non-restorative sleep | |
● Daytime fatigue | |
● Difficulty falling asleep | |
● Late morning rising or waking up early in the morning | |
● Oversleeping | |
● Overeating or weight gain | |
● Screen for other sleep disorders, such as restless legs syndrome or sleep apnea | |
2. Evaluation of key sleep and circadian phenotypes | Self-report/self-monitoring over two-weeks (see Figure 4) using smart phone or paper-pencil, particularly focusing on: |
● Chronotypes on morningness-eveningness scales | |
● work/schooldays and weekend schedules | |
● Duration of sleep | |
● Waking from sleep | |
● Pre-sleep hyperarousal symptoms | |
● Night sweats – raised temperature during sleep | |
● Timing and level of daytime physical activity | |
● Atypical circadian mood variations | |
Objective measures including: | |
● Two-weeks of continuous actigraphy/sleep diaries | |
● Dim light melatonin onset assays | |
B) Information and treatment planning sessions | |
1. Psychoeducation with regards to the human sleep and circadian systems | Key elements include: |
● Explanation of the biology of the human clock | |
● Illustration of the normal 24-hour cycle in sleep and activity and synchronization with hormonal, immune, body temperature and other key physiological elements | |
● Emphasis on setting the clock through morning rising, appropriately timed light exposure, regularity of activity cycles, daytime physical activity, bedtime schedules and nighttime practices | |
● Linking to eating behavior and risks to obesity and metabolic function | |
2. Set specific behavioral elements | Key decisions include: |
● Set sleep offset time (or schedule for gradual phase advance/delay relative to current waking time) with special care to avoid sleep loss induced mania/hypomania episode in people at risk for bipolar disorder | |
● Set daily activity schedules | |
● Emphasize morning light exposure (natural or through specific devices with special care to avoid bright light induced mania/hypomania in people at risk for bipolar disorder) | |
● Discuss regular sleep onset time expectations | |
● Set sleeping conditions relative to light exposure and temperature | |
3. Introduce self-report or objective measurement techniques for this period | Key elements include (see Figure 4): |
● Daily monitoring of actual sleep onset /offset, sleep duration and sleep quality | |
● Continuous recording of actual daytime physical activity | |
● Daily mood and fatigue monitoring ● Monitoring of substance use and eating behavior ● Monitoring of other behaviors that could adversely affect sleep including excessive or poorly timed napping | |
C) Review progress at two weeks | |
Key elements are: | |
● Adherence to sleep offset time, light exposure and degree of actual physical activity | |
● Evaluate changes in daily mood, fatigue, sleep quality | |
D) If inadequate clinical progress: | |
Consider: | |
● Adherence and planning issues | |
● Adjunctive strategies to be considered: | |
- Earlier/later or augmented light exposure | |
- Melatonin supplementation with careful planning of ingestion time | |
E) Review progress at four weeks | |
If inadequate clinical progress: | Consider: |
● Adherence and planning issues | |
● Adjunctive strategies to be considered: | |
- Melatonin-based antidepressant strategies | |
- Other conventional antidepressant strategies | |
- Alternative daytime stimulant or nighttime sedation strategies | |
F) Review progress at six- to eight-weeks |