Circadian Interventions as Adjunctive Therapies to Cognitive-Behavioral Therapy for Insomnia

INTRODUCTION

Cognitive-behavioral therapy for insomnia (CBTI) is effective for many individuals who suffer from insomnia; however, a nontrivial proportion of patients who complete treatment will not achieve full remission.¹ Thus, identification of treatment targets for therapies administered adjunctively to CBTI can enhance treatment outcomes. Although attention is paid in CBTI to the role of the circadian system in the pathogenesis of insomnia, the primary therapeutic components are largely focused on behavioral modifications that do not directly target the circadian system. Thus, integrating specific circadian-focused interventions adjunctive to CBTI may enhance treatment outcomes for patients whose insomnia is associated with circadian misalignment.

Circadian rhythms are the 24-hour physiologic and behavioral manifestations of the internal master circadian pacemaker, located in the suprachiasmatic nucleus.² Alertness, sleepiness, and the propensity for sleep are key circadian rhythms. Insomnia, a sleep disorder characterized by difficulty falling asleep, staying asleep, and/or early morning awakenings,³ is linked to dysregulation of circadian rhythms.⁴ Although the exact pathophysiology of insomnia remains unknown, evidence implicates the circadian system as an important pathway in the development and maintenance of chronic insomnia.^5,6 For example, a mismatch between the behavioral timing of sleep and the circadian timing of sleepiness/alertness—that is, attempting to sleep at the wrong circadian time—can cause insomnia.⁷

The types of insomnia symptoms reported by the patient can provide clues about whether, and how, circadian rhythms may be contributing to sleep difficulties and aid clinical decision making about whether to integrate a circadian-based therapeutic with CBTI. For example, patients who report primarily early morning awakenings and experience sleepiness in the early evening may have a circadian rhythm timed to be abnormally early (circadian phase advance).^8,9 Conversely, patients who report primarily difficulty falling asleep with sleepiness in the morning hours may have a circadian rhythm timed to be abnormally late (circadian phase delay).¹⁰

This article reviews the role of the circadian system in sleep, circadian dysregulation in insomnia, and practical applications of circadian interventions adjunctive to CBTI, with a focus on bright light therapy, strategically timed dim light and blue-blocking glasses, and exogenous melatonin. It discusses adjunctive circadian-based interventions for patients whose insomnia may be influenced by circadian misalignment as suggested by presentation and clinical interview, but who do not meet full diagnostic criteria for a circadian rhythm sleep-wake disorder. For a more in-depth review of implementation of CBTI in patients who meet full diagnostic criteria for a circadian rhythm sleep-wake disorder, the authors recommend the chapter by Evans and Hasler in Adapting Cognitive Behavioral Therapy for Insomnia.¹¹

REGULATION OF SLEEP

The sleep-wake cycle is regulated by the complex interaction between 2 specific systems: the sleep homeostatic system (Process S) and the circadian system (Process C).¹² Briefly, Process S is a homeostatic process whereby the drive for sleep accumulates throughout wakefulness and diminishes during sleep. Process C is determined by the master circadian clock, which produces a circadian rhythm of arousal/sleepiness. The circadian rhythm of arousal/sleepiness across the 24-hour day can be impacted by a variability in the intrinsic circadian period length resulting in a behavioral preference for morning or eveningness (morning larks and night owls, respectively).¹³ External zeitgebers (timegivers) also play an important role in entraining the circadian rhythm. The light-dark cycle is the most potent zeitgeber,¹⁴ but other relevant external inputs to the circadian clock include social activity, feeding, and physical activity.^15,16 Markers of the timing of process C include core body temperature and melatonin rhythms; falling body temperature and rising melatonin levels herald sleep, whereas rising body temperature and falling melatonin levels presage wake.¹⁷ To sleep well, the behavioral timing of sleep must be aligned with Process C and Process S—that is, sleep is attempted when both the homeostatic drive for sleep and circadian rhythm of sleepiness are high.

Sleep is inhibited by Process C at specific times, even when the homeostatic drive (Process S) for sleep may be high, via an alerting signal. A 2- to 3-hour forbidden zone for sleep occurs in the early evening (about 1 to 4 hours before habitual sleep onset time); the propensity for sleep is low at this time.¹⁸ For someone who typically falls asleep around 11 p.m., the forbidden zone for sleep would occur from 6 to 9 p.m. In the morning, a wake-up zone facilitates awakening, approximately between 8 and 11 a.m. for someone who goes to bed around 11 p.m.¹⁸ These zones hold particular relevance for insomnia; an individual who has delayed (ie, late) circadian timing but attempts to sleep during the forbidden zone will have difficulty falling asleep. An individual who has advanced (ie, early) circadian timing but attempts to sleep through the wake-up zone will have difficulty with sleep maintenance/early awakening.

CIRCADIAN DYSREGULATION IN INSOMNIA

Sleep-Onset Insomnia

Difficulty falling asleep accompanied by morning sleepiness/fatigue, in the absence of difficulty with sleep maintenance and early morning awakenings, may indicate a subtype of insomnia—sleep-onset insomnia—linked to a delayed circadian rhythm. This type of insomnia is often observed in younger adults who have difficulty sleeping on a schedule dictated by their work/social obligations. Adults with sleep-onset insomnia have a later time of melatonin onset compared to adults without insomnia.^10,19–21 An investigation of sleep and circadian timing in adults with insomnia revealed that adults with insomnia attempted to fall asleep at the same clock time as good-sleeping controls, but their circadian clocks were delayed by more than 1 hour on average.¹⁰ More specifically, in this study, good-sleeping controls attempted to fall asleep 3 hours and 10 minutes after their melatonin onset occurred, whereas participants with insomnia went to bed 2 hours 13 minutes after melatonin onset; the patients with insomnia were trying to fall asleep during their forbidden zone, during which sleep onset latency will be prolonged.¹⁰ Sleeping in on the weekends (ie, a later wake time on the weekends relative to weekdays) can cause a circadian phase delay and contribute to an increased length of time to fall asleep at the start of the week.²²

Early Morning Awakening Insomnia

Insomnia characterized by waking up too early with an inability to resume sleep and sleepiness/fatigue in the early evening, in the absence of difficulty falling asleep, may indicate a subtype of insomnia—early morning awakening insomnia—linked to an advanced circadian rhythm. This type of insomnia is most frequently observed in older adults who may report that they inadvertently doze off or fall asleep on the couch or recliner in the early evening and subsequently wake up too early in the morning. Compared with good sleepers, adults with early morning awakening insomnia have significantly earlier circadian timing as indicated by earlier body temperature and melatonin rhythms.^9,18 Their sleep period is also timed such that a considerable portion overlaps with the wake-up zone.⁹

APPLYING CIRCADIAN INTERVENTIONS ADJUNCTIVE TO COGNITIVE-BEHAVIORAL THERAPY FOR INSOMNIA

Interventions that target the circadian system and are most readily adjunctively administered to CBTI include strategically timed bright light, strategically timed dim light, and melatonin (Table 1). Here the authors briefly discuss relevant physiology for each intervention while maintaining a focus on clinical implementation. For a thorough overview of the impact of light and melatonin on human circadian physiology, the reader is referred to Emens and Burgess.²³

Table 1.

Summary of circadian interventions by insomnia subtype

Circadian Intervention
	Bright Light: Intensity	Bright Light: Dose and Timing	Dim Light AND/OR Blue-Blocking Glasses	Melatonin
Sleep onset insomnia	10,000 lux light box OR light glasses	30–60 min at scheduled wake time	90–120 min before scheduled bedtime	0.5 mg taken 5 h before habitual sleep onset time
Early morning awakening insomnia	2500 lux light box	In evening, ending between 0–3 h before scheduled bedtime	From bedtime through 1 h after scheduled wake time	Not indicated

The specific implementation of each intervention depends on the patient’s insomnia subtype. An important caveat to circadian-based interventions is that if the interventions are not timed correctly, they may actually worsen the patient’s sleep. Thus, careful attention to the patient’s sleep timing and the timing of the interventions is important; Fig. 1 summarizes the timing for each intervention relative to the sleep period by insomnia subtype.

Fig. 1.

Summary of timing of circadian interventions relative to the sleep period by insomnia subtype = bright light therapy; dim light or blue-blocking glasses; melatonin 0.5 mg.

Although the authors outline suggestions for when to begin each circadian intervention relative to the first session of CBTI to maximize efficacy, there are no contraindications to adjunctive administration of CBTI. Some elements of CBTI (ie, strict time in bed scheduling with maintenance of a consistent wake time throughout treatment) will enhance implementation of the circadian interventions. Indeed, time in bed restriction may help to realign the behavioral timing of sleep and the circadian propensity for sleep. Specifically, in a small study of adults with insomnia, after 2 weeks of sleep restriction therapy (ie, time in bed restriction) patients attempted sleep later, while their circadian timing remained the same—meaning they attempted sleep at a more appropriate circadian time.²⁴

Strategically Timed Bright Light Exposure

As the most potent zeitgeber,¹⁴ strategically timed bright light exposure is a powerful tool to help patients move their circadian rhythms earlier or later to realign their circadian timing with their desired sleep time. A recent meta-analysis supports the role of light therapy for treatment of insomnia, although it is important to note that the number of studies focused specifically on patients with insomnia are limited, and effect sizes were relatively small, confirming its utility as an adjunctive, but not stand-alone, insomnia therapy.²⁵ Importantly, light intensity mediated treatment outcomes in this meta-analysis, such that larger treatment effects were observed in studies using brighter light (ie, higher lux).²⁵

The impact of light therapy on circadian timing depends on the time at which light therapy is administered, described in a phase response curve to light (Fig. 2).²⁶ As shown in the phase response curve, exposure to bright light in the hours before habitual sleep onset (starting about 4 hours before) will delay (move later) circadian phase. Conversely, exposure to bright light in the morning (starting about 2 hours before habitual wake time) will advance (move earlier) circadian phase. Note that if morning light is timed too early (that is, more than 2 hours before habitual wake time), it can exacerbate a circadian phase delay and lead to lengthening of the sleep onset.

Fig. 2.

Phase response curves to light and melatonin. (From Emens JS, Burgess HJ. Effect of light and melatonin and other melatonin receptor agonists on human circadian physiology. Sleep Med Clin 2015;10(4):435–453; with permission.)

Bright Light Therapy Considerations

Device selection

Various light therapy devices are commercially available, and guidance should be provided to patients regarding the specific features to assist them in selecting an effective device. Historically, light therapy was delivered by light boxes. More recently, wearable devices (eg, light therapy glasses) have emerged as an effective treatment option^27–29 with the distinct advantages of mobility and portability. The circadian system is most sensitive to blue-green light (wavelength between 470 to 525 nm^30–32), and devices that emit light in this wavelength can offer effective therapy at dimmer settings than broad-spectrum light; wearable devices often use light in this wavelength.³³ An ideal wearable device will project light upwards from below the eye, so the supraorbital ridge does not block the light.

Patients interested in a light box should look for a broad-spectrum or blue-green light-emitting box that emits between 2500 and 10,000 lux; patients with early morning awakening insomnia may find benefit on the lower end of this range (ie, 2500 lux), whereas patients with sleep-onset insomnia should look for a box with higher lux (ie, 10,000 lux). Patients who use a light box can be instructed to measure and cut an appropriate length of string (typically 2 feet) to be taped to the box to make sure they are sitting at the correct distance from the box.²³ In their clinical practice, the authors have found that wearable light therapy glasses offer the most practical way for patients to receive bright light therapy, as they can carry out much of their morning routine and engage in activities such as watching television, or working on a computer or tablet, while receiving effective therapy.

Side effects and contraindications

The most common side effects of bright light therapy are headache, eyestrain, nausea, and agitation, but these often spontaneously remit within 1 to 2 weeks of use.^34,35 The dose can be adjusted (eg, reduced to 30 or even 15 minutes) as needed to address side effects. Contraindications for bright light therapy include certain medical conditions (eg, epilepsy/seizure, lupus or other medical conditions associated with photosensitivity, retinal pathology, or retinal surgery) and use of photosensitizing medications. Individuals with a history of mania/hypomania or bipolar disorder may use light therapy but must be closely monitored to prevent possible recurrence of mania/hypomania triggered by overexposure to light, which is rare but serious should it occur.³⁵ In their clinical experience, the authors have found that bright light therapy for insomnia is typically well-tolerated without significant side effects or adverse events.

Bright Light Therapy for Sleep-Onset Insomnia

Incorrectly timed bright light therapy can worsen a circadian phase delay and exacerbate difficulty falling asleep. When integrating light therapy with CBTI, patients should maintain a consistent wake time throughout the course of therapy. The authors recommend waiting to initiate light therapy until the second CBTI treatment session, generally only after the patient has maintained a consistent wake time across both weekdays and weekends, and physicians are confident in the patient’s ability to continue this; sleeping in on the weekends can contribute to light therapy overlapping with the phase delay portion of the phase response curve on weekdays. Emphasizing the importance of maintaining a consistent wake time, even on weekends, when undergoing morning light therapy, and providing the rationale for this instruction, can enhance the patient’s adherence.

Once the patient is ready to begin light therapy, he or she should be instructed to use light therapy device for 30 to 60 minutes as close to their scheduled wake time as possible, ideally starting no later than 30 minutes after their scheduled wake time. Patients should be instructed to delay starting light therapy until their scheduled wake time if they wake earlier. The length of treatment may depend on what the patient’s morning schedule allows; although 60 minutes will elicit a more robust treatment response, 30 minutes is often more pragmatic and sufficient to improve sleep.^36,37

Bright light therapy for early morning awakening insomnia

Patients whose insomnia is primarily characterized by early morning awakenings can use light therapy in the evening to delay circadian timing.^8,38 Treatment for patients with early morning awakening insomnia can be started at the first session of CBTI, as there is little risk of exacerbation of a circadian phase advance with light administration in the evening before bedtime, and light therapy can assist with the patient staying awake until their scheduled bedtime. Patients can be instructed to use light therapy in the evening, ending at their bedtime, or ending up to 3 hours before their scheduled bedtime. The authors typically initially schedule light therapy to end 1 hour before scheduled bedtime, and then adjust the timing based on how the patient responds. If the patient develops difficulty falling asleep, light therapy should be ended earlier (eg, 1.5 to 3 hours before bedtime). If they report persistence of early morning awakenings, light therapy can be extended later. In some instances, patients may need to be exposed to bright light right until their bedtime. As bedtime is often adjusted to be earlier throughout CBTI to accommodate extension of time in bed as the patient experiences sleep consolidation, the timing of light administration should be adjusted earlier accordingly.

Strategically Timed Dim Light and Blue-Blocking Glasses

Strategically timed dim light

In addition to timing exposure to bright light, ensuring patients are in dim light at the correct circadian time can enhance circadian phase delay or phase advance. This can be started in the first session of CBTI. During scheduled dim light periods, patients should remain in dim lighting conditions—50 lux or less.³⁹ The authors instruct patients to use just enough light to see during their scheduled dim light period; ideally, light-emitting devices (smartphones, tablets, computer screens) would not be used during time.⁴⁰ Depending on the time of year and the patient’s latitude, patients may have to employ light-blocking curtains or window coverings to minimize exposure to sunlight during the dim light period. Patients may watch television on an actual television set during this time, ideally with all other light sources turned off.⁴¹ Patients who find it necessary to use a light-emitting device (eg, smartphone, tablet, computer) during their dim light period may use the device, provided the device is dimmed to the lowest possible setting, or the patient can wear blue-blocking glasses.⁴⁰

Blue-blocking glasses

Blue-blocking glasses filter out blue-green wavelength light and therefore limit ocular exposure to wavelengths of light most impactful to the circadian system; they are effective in preventing light from suppressing melatonin production.⁴² Their use can improve insomnia symptoms.^43,44 Patients should be advised to select glasses that block short wavelength light (approximately 100% of blue light), provide as much coverage around the eye area as possible (eg, wraparound lenses), and have tinted lenses (orange, amber, or brown), as clear lenses marketed as blue-blocking do not block enough blue light to be effective.⁴⁵ Patients can use the glasses during their scheduled dim light period if they are not able to be in dim light, or if they choose to use a light-emitting device during this time, especially if they are not able to dim the light-emitting device.

Patients with sleep-onset insomnia should be instructed to be in dim light (or use blue-blocking glasses) starting a least 90 minutes before their scheduled bedtime; this can be extended up to 120 minutes for patients who are able to be in dim light for longer, or for whom 90 minutes is not effective. They should remain in dim light until their scheduled wake time; if they need to follow stimulus control instructions during the night, they should follow the same dim light procedures as they would before bed. The authors have patients set a daily alarm on their smartphone during the first treatment session for the start of their dim light period to remind them to dim the lights or put on the blue-blocking glasses; some smartphones can be programmed to set a specific daily wind-down time before bedtime, which can serve as a dim light reminder.

Patients with early morning awakening insomnia should be instructed to implement dim light procedures throughout their scheduled time in bed period, particularly when they wake earlier than their scheduled wake time (ie, remain in dim light until their wake-up alarm) to avoid potentially exacerbating their early morning awakenings with morning light exposure. Ideally, patients with this type of insomnia would also avoid bright light exposure for the first hour after their scheduled wake time when possible. Strategies to facilitate this include wearing dark sunglasses if patients must be outdoors (eg, commuting to work) within an hour of their scheduled wake time, and avoiding light-emitting devices during this time. Blue-blocking glasses can be worn as needed. In some instances, patients with early morning awakening insomnia require a more limited dim light period before bedtime (dim light starting less than 60 minutes before bedtime), or they should avoid a dim light period before bed altogether, particularly if they are inadvertently falling asleep during the dim light procedures before bedtime.

Exogeneous Melatonin

Exogenous melatonin, an over-the-counter supplement, can be helpful in reducing sleep onset latency in insomnia but is not likely to be beneficial for sleep maintenance or early morning awakenings.^46–48 Melatonin can be used as a both hypnotic and as a zeitgeber.⁴⁹ The authors focus on its use as a zeitgeber to advance circadian phase. As a zeitgeber, melatonin has its own phase response curve (see Fig. 2); administration in the late afternoon until about 2 hours before habitual sleep onset time will advance circadian phase, whereas administration timed within 2 hours of habitual sleep onset time through the morning hours will delay circadian phase.^50,51 As with the light response curve, this means that taking melatonin at the wrong time (too close to habitual sleep onset time) can exacerbate a circadian phase delay.

It is important to tell patients that the dosing instructions for melatonin found on the bottle (indicating that the patient should take it 30 to 60 minutes before bed) are for use of melatonin as a soporific and should be disregarded. Patients who have difficulty falling asleep and are interested in using melatonin as adjunctive to CBTI should be instructed to use a small dose (0.5 mg) of melatonin taken 5 hours before their typical sleep onset time. The authors prefer use of a small dose of melatonin (0.5 mg) based on work showing similar phase shifting effects between smaller (0.3 to 0.5 mg) and larger (3.0 mg) doses to maximize efficacy while minimizing soporific effects and the possibility of overlap with the phase delay portion of the phase response curve.^51,52 As 0.5 mg of melatonin may not be commercially available, the authors tell patients to purchase 1 mg tablets and cut them in half. During the treatment session, the authors have patients set a daily alarm on their smartphone for their scheduled melatonin administration time, as many forget to take melatonin at the desired time without the reminder alarm. Melatonin may be used in conjunction with bright light therapy for sleep-onset insomnia; the combination may enhance circadian phase advances.⁵³

Side effects and contraindications for melatonin

Melatonin is not regulated by the US Food and Drug Administration, and the actual melatonin content in the tablet may vary from the label on the bottle.⁵⁴ Although extended-release formulations are available, the authors do not recommend them, as they may lead spillover of melatonin into the phase delay period.⁵⁵ Although melatonin is widely used and available over-the-counter, it may cause side effects and negatively interact with frequently used medications and common medical conditions (see https://naturalmedicines.therapeuticresearch.com for a comprehensive list of possible interactions and possible side effects). The most common side effects of melatonin include drowsiness, headache, dizziness, and nausea.⁵⁶ Because of the potential for drowsiness, patients should not use alcohol, or operate a motor vehicle or heavy machinery while taking melatonin until they know how they respond to low-dose afternoon melatonin. Relative contraindications for melatonin include diabetes, hypertension, clotting/bleeding disorders (including warfarin therapy), seizures/epilepsy, pregnancy/attempting conception, and breastfeeding because of interactions with these conditions, drugs used to treat these conditions, and an unknown safety profile for fetuses and in breastfeeding.⁵⁶ Melatonin may interact with many prescription medications, supplements, and medical conditions. The most commonly used medications that may interact with melatonin include antihypertensives, immunosuppressants, antidiabetes drugs, and anticoagulant/antiplatelet medications.⁵⁷ Although melatonin may reduce blood pressure in healthy individuals, it may increase blood pressure in patients taking antihypertensive medications, and it reduces the effectiveness of some antihypotensive medications in animal studies.⁵⁷ Caution is recommended when taking melatonin in combination with antidiabetes drugs because of some evidence that suggests that melatonin may impair glucose metabolism.⁵⁷ Melatonin may interfere with immunosuppressive therapy by stimulating immune function, increase the risk of seizure activity when taken with drugs that lower the seizure threshold, and have antiplatelet effects that increase the risk of bleeding with anticoagulant/antiplatelet therapies.⁵⁷ Moreover, melatonin has only been studied in short-term trials; larger-scale randomized controlled trials of longer duration are needed to establish the long-term safety of melatonin.

SUMMARY

The circadian system plays an important role in the regulation of the sleep-wake cycle. Dysregulation of circadian rhythms, or misalignment between the behavioral timing of sleep and the circadian propensity for sleep, can contribute to the development and maintenance of insomnia, even in the absence of a frank circadian rhythm sleep-wake disorder. Patients who present with specific subtypes of insomnia (ie, sleep-onset insomnia or early morning awakening insomnia) most closely linked to circadian rhythm dysregulation may benefit from circadian interventions administered adjunctively to CBTI. Specific interventions to consider include bright light therapy, strategically timed dim light, and exogenous melatonin. However, careful attention must be paid to the timing of these interventions to ensure their success. Further, although overall evidence supports the use of these interventions in insomnia, there is a need for trials testing adjunctive administration of circadian interventions within a course of CBTI to determine best practices for implementation.

KEY POINTS.

• The insomnia subtypes of sleep onset insomnia and early morning awakening insomnia are associated with delayed and advanced circadian rhythms, respectively.

• Adjunctive circadian interventions for sleep onset insomnia include morning bright light therapy, scheduled dim light in the evening, and low-dose melatonin administered in the late afternoon/early evening.

• Adjunctive circadian interventions for early-morning awakening insomnia include evening bright light therapy and scheduled dim light in the morning.

• Clinical trials are needed to test adjunctive administration of circadian interventions within a course of cognitive-behavioral therapy for insomnia to inform best practices.

CLINICS CARE POINTS.

• Patients who present with sleep-onset insomnia may be prescribed bright light therapy in the morning in conjunction with dim light in the evening before bed to aid in advancing circadian phase.

• A small dose (0.5 mg) of melatonin taken in the late afternoon (approximately 5 hours before habitual sleep onset time) may help advance circadian phase in patients who have sleep-onset insomnia.

• Bright light in the evening before bedtime in conjunction with dim light for 1 hour after scheduled wake-up time may improve sleep in patients with early morning awakenings by delaying their circadian phase.

• Blue-blocking glasses can improve insomnia by reducing light exposure during scheduled dim light periods.