Chronotherapy refers to treatments for depression, mania, or both, that focus on changing sleep and wakefulness patterns. This blog post provides an update of this important area.
Background
The International Society of Bipolar Disorders (ISBD) task force on chronobiology and chronotherapy published a comprehensive review of chronotherapy techniques and their effectiveness in bipolar disorder in 2019. This article summarizes the findings in the review, which is available free online (see references below).
The Biology of Internal Clocks
The basic science of chronobiology is the study of biological rhythms, biological timekeeping systems, and their effects on human health and disease. Chronotherapies are techniques that affect these rhythms.
The master clock in the suprachiasmatic nucleus (SCN) is made up of cells which rhythmically oscillate. These cells are regulated by inputs from the retina (light) and other parts of the brain (daily routines, social interaction) (see figure).
This oscillation is driven by a set of transcription factors, CLOCK and BMAL, that promote the read‐out of the core CLOCK genes, Per1, Per2, Cry1, and Cry2, whose protein products exert negative feedback control on the transcription process (See figure below). This autoregulatory transcription‐translation feedback loop, which is governed by dozens of CLOCK genes, naturally repeats over a nearly 24‐hour period. This is the internal timekeeping system. The system depends, however, on input to stay aligned with the outside world, because it does not quite oscillate every 24 hours.
The input to the circadian system consists of light and non‐light factors, (these inputs are called zeitgebers or time‐givers). These factors adjust the timing (phase) and amplitude of the SCN neuronal oscillations. While light is the strongest zeitgeber in humans, non‐photic elements such as the timing of exercise, eating, social interaction, work, and sleep also modulate SCN activity. The combined effect of these zeitgebers is to constantly adjust the timing (ie, to shift the phase or phase‐shift) of the near‐24‐hour human circadian period to more precisely conform to the exact 24‐hour period of the geophysical day.
There is evidence to suggest that people with mood disorders may be particularly prone to disruption in the internal clock system and thus may need stronger zeitgebers in order to have healthy circadian rhythms.
Thus, several therapies have been developed that affect the clock system. Broadly, these therapies can be grouped as follows…
- Bright Light Therapy (LT)
- Dark Therapy (DT)
- Treatments Using Sleep Deprivation (SD)
- Melatonergic Agonists (MA)
- Interpersonal Social Rhythm Therapy (IPSRT)
- Cognitive Behavioral Therapy adapted for BD (CBTI-BP)
Bright Light Therapy
Bright Light Therapy was the result of two significant discoveries in the 1980’s. One discovery was that changes in the timing of circadian rhythms could have an antidepressant effect. The second discovery was that bright light suppressed melatonin production and set the timing of circadian rhythms in humans. Before this discovery it was thought that circadian rhythms in humans were mostly regulated by social factors.
Initially, Bright Light Therapy studies examined people with seasonal mood disorders, but in 2016 several studies began to show that BLT was effective in treating people with non-seasonal mood disorders.
Meanwhile, the nature of effective light therapy was defined more clearly.
The intensity duration timing and color of the light were found to be essential for effective bright LT. Light has to come from a broad visual field (typical light devices measure 12 inches by 14 inches) and the light source needs to be mounted above the eyes to target inferior retinal photorecepters. Light devices should provide 7,000 to 10,000 lux to the eyes at a distance of approximately 12 – 15 inches. Internal clocks are most affected by blue light, although single wavelength blue light devices still lack long‐term clinical and safety outcomes data; hence, UV–filtered bright white light is still recommended in clinical guidelines.
Bright Light Therapy means exposure to 10,000 lux full spectrum, ultraviolet filtered light, from a device that is wider than a light bulb and is mounted above the eyes, at about 12-15 inches from the face, and visible from both eyes.
The evidence is good that LT is very effective. Four articles provided sufficient data to estimate the strength of the treatment. These estimates of treatment effect suggested robust effects from morning or midday bright light; the Number Needed to Treat (NNT) for remission ranged from 2.17 to 3.17 and for response ranged from 1.61 to 2.86. With seasonal bipolar depression, bright light produced a large treatment effect (Cohen’s d = 1.485).
What does this mean? An NNT of around 2 for response to a treatment is practically unheard of in clinical trials of medications. (NNT is a measure of how many people would have to receive a treatment for you to be sure that one would have the desired effect, and thus a smaller number is better). A review (Suttajit) of all the studies on quetiapine for bipolar depression, which is one of the most effective medication treatments, found a NNT of 6 for response.
Light therapy appeared to be 3 times as effective as quetiapine which is a standard treatment for bipolar depression.
Adverse effects appear to be mild. The most worrisome one (switching someone into hypomania or mania) appears to be relatively rare… In four of the studies, no switches were reported with bright LT (338 patient‐weeks of exposure) or control treatment, whereas in one study hypomanic switches occurred in 4 of 18 patients (144 patient‐weeks exposure) treated with bright light compared to 2 of 20 patients (160 patient‐weeks exposure) with sham treatment.
Treatments with Sleep Deprivation
The therapeutic potential of sleep deprivation (SD) was discovered by German psychiatrists. Johann Christian August Heinroth was the first physician to recognize, use, and write about the relationship between melancholia and sleep restriction in the early 19th century. After a gap of almost 150 years, the finding was rediscovered by Walter Schulte who published the first modern report on the beneficial effect of sleep deprivation on mood in 1966. After that, several case reports and case series were added to the literature, and these suggested that the antidepressant effects were rapid (within the first day and a half) and led to improvements in mood in roughly 2/3rds of patients with unipolar and bipolar depression, but also associated with a rapid relapse in 85% of those with an initial response after recovery sleep.
The challenge was to find a way of preserving the improved mood. Follow up studies suggested that the benefit could be prolonged if bright light therapy, lithium, or pindolol was added after the sleep restriction.
Ultimately, the field has focused on two approaches that combine sleep restriction with therapies that help the patient shift sleep to an earlier cycle – going to bed earlier and waking up earlier when sleep is resumed.
- One Week Sleep Restriction. Probably the best studied approach involves a week of active treatment in three cycles – a night of total sleep deprivation (TSD) and then a night of full sleep recovery.
- Triple Chronotherapy. This is an approximately four-day procedure that uses one night of TSD accompanied by light therapy and sleep phase advance.
Surprisingly there are no studies comparing the effects of both treatments.
In addition, although the earlier studies included bipolar as well as unipolar patients with depression, adequate controlled trials have not been done on either One Week Sleep Restriction or Triple Chronotherapy.
Dark Therapy (or Blue Blocking Therapy)
If bright light can treat depression, it seemed logical to wonder if dark therapy (avoiding light exposure) could treat mania.
A series of case series suggested that this was the case. But obviously placing people in total darkness is not easy to do when they are manic.
In 2001 a new light receptor in the retina was discovered and turned out to be responsible for mediating the effects of light on the master clock. This receptor only responds to light in the wavelengths between 420 and 600 nanometers and optimally responds to blue light within that range.
Scientists demonstrated that orange and red light had NO effect on the central clock. Individuals exposed only to that light had the same dysregulated circadian rhythms as people in the dark.
Scientists then tried treating people who were manic by giving them glasses that blocked all blue light
A preliminary trial of blue blocking (amber) glasses showed that it was possible to treat people who were manic on an outpatient basis with this approach and this led to a randomized inpatient trial by Henriksen and colleagues. In this study, patients using control lenses experienced a slow
reduction in mania rating scores over the first week, while the blue-blocking lenses were associated with much steeper reduction in scores, There was a large effect size of 1.86.
At this point, we have a handful of studies of Blue Blocking Therapy for mania. They all support its value, and there have been no significant adverse effects but the small number of patients studied suggests some caution in relying on the data. On the other hand, all of the studies found large effect sizes which suggests that there may well be something to this approach.
Melatonin
Since melatonin is the key neurotransmitter in the brain’s clock center, studies were done using melatonin in patients with mood disorders.
Although one should be cautious in interpreting the results of these studies, because they used widely varying doses and frequencies of administration of melatonin, this review finds little support for the adjunctive use of melatonin or its agonists in the acute treatment of either mania or bipolar depression.
Psychotherapies
Two types of psychotherapy have been developed that focus on regulating the clock system.
INTERPERSONAL SOCIAL RHYTHM THERAPY
IPSRT is a manualized treatment, developed by Ellen Frank and colleagues, that addresses interpersonal problems and disrupted social rhythms with the intent of stabilizing underlying biologic processes. In IPSRT, therapists utilize the Social Rhythm Metric (SRM) to monitor and improve the regularity of five daily activities over 20 weeks (as an acute intervention) or monthly (as a maintenance treatment): time of out of bed, first contact with another person, start of daily activity, dinner, and time to bed. Patients learn to identify potential sources of rhythm disruption in their lives, both planned and unplanned, and develop strategies to maintain rhythm integrity, despite routine-disrupting events. Although focus on the sleep-
wake cycle is an essential component of IPSRT, this intervention takes a more global approach to standardizing daily routines. For instance, patients may be encouraged to seek employment characterized by more fixed hours, seek out a partner to help them stay on track for fixed exercise times, or select classes that meet at times consistent with their chronotype.
There is evidence from RCTs to support efficacy of IPSRT in hastening recovery from a depressive episode and in increasing time to recurrence over two years of maintenance treatment. Indirect evidence (superiority trials that show similar outcomes for two active treatments) suggests that IPSRT is comparable to active treatments such as quetiapine and specialist care for acute bipolar depression.
COGNITIVE BEHAVIORAL THERAPY FOR INSOMNIA ADAPTED FOR BIPOLAR DISORDERS (CBTI-BP)
As part of a program of research into insomnia and psychiatric disorder, Harvey and colleagues postulated that treating comorbid sleep and/or circadian disturbances may ameliorate the mood symptoms of BD. They further proposed that cognitive behavioral therapy for insomnia (CBT-I) would be an appropriate basis for such treatment, and developed a variant of CBT- I modified for BD (CBTI-BP).
CBTI-BP aims to improve mood, sleep and functioning in people with BP,
by adding to CBT-I elements of motivational interviewing, interpersonal and social rhythm therapy, and chronotherapy ( for example regularizing sleep and wake times, daily timing of meals and exercise). CBTI-BP involves 8 weekly sessions of 50-60 minutes; an individualized case formulation is developed in the first session, which determines the weighting given to prescribed elements of behavioral and cognitive modules completed by all participants.
In the one study to date of CBTI-BP produced benefits for mood relapse post- acute treatment amongst inter-episode patients with comorbid insomnia disorder, with the benefit being statistically significant for hypomania/mania relapse and a trend towards improvement of both depression and manic symptoms. Effect sizes were moderate for mood, and moderate-large for insomnia; no significant adverse events or mood switches attributable to the intervention were recorded.
Summary
Bright Light Therapy delivered in the morning (up until noon) appears to be a very effective treatment of bipolar depression with few side effects.
Sleep Deprivation therapies are rapidly effective but by themselves lead to transient improvement in mood. However, combining sleep deprivation with a therapy to shift sleep cycles earlier (early to bed and early to rise) has promise in the acute and maintenance treatment of bipolar depression.
Blue Blocking Therapy shows considerable promise in treating bipolar mania, with no apparent adverse effects.
Melatonin does not have significant evidence of efficacy in treating bipolar mood disorders.
Two psychotherapies that focus on strengthening circadian rhythms seems to help bipolar mood disorders.
For More Information
Other ways of strengthening circadian rhythms
References
Gottlieb, JF, Benedetti, F, Geoffroy, PA, et al. The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. Bipolar Disord. 2019; 21: 741–773. https://doi.org/10.1111/bdi.12847
Suttajit S, Srisurapanont M, Maneeton N, Maneeton B. Quetiapine for acute bipolar depression: a systematic review and meta-analysis. Drug Des Devel Ther. 2014;8:827–838. Published 2014 Jun 25. doi:10.2147/DDDT.S63779
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