**6. If you decide the patient has a circadian rhythm sleep-wake disorder, how should the patient be managed?**

#### **6.1 Advanced sleep-wake phase disorder (ASWPD)**

Bright light therapy in the early evening is the primary treatment for ASWPD, with the goal to delay the circadian phase so it is better aligned to desired sleep and wake times [5, 9]. Patients should use a bright light that filters out ultraviolet rays (2,500 to 10,000 lux) for 1-3 hours per day, starting at the time when they first experience sleepiness in the evening (usually around 7-9 pm). This should be done to gradually delay bedtime by 1-2 hours each day until desired times are met (**Figure 5**).

There is no strong evidence to support pharmacologic therapy in ASWPD. Melatonin in the morning can theoretically shift the clock to a later phase, however the sedating effect of melatonin often limits morning use. Early morning hypnotics to resume sleep can lead to daytime grogginess and hangover effect and thus are generally discouraged.

#### **Figure 5.**

*For individuals with advanced sleep–wake phase disorder (ASWPD), bright light therapy should be given for 1-3 hours per day in the evening starting at the time of sleepiness. This will gradually shift the sleep time until the desired schedule is met.*

#### **6.2 Delayed sleep-wake phase disorder (DSWPD)**

Management of DSWPD consists of *behavioral modifications* to realign one's circadian system with desired sleep–wake times, and concurrent *melatonin* use and *light* therapy. Easily modifiable behaviors should be targeted first. These behaviors include avoiding daytime naps, eliminating excessive use of caffeine and/or alcohol, reducing stimulating activity, and minimizing light (particularly blue light) exposure 2 hours prior to bedtime.

For those who fail to respond to behavioral therapies alone, timed melatonin can supplement these behavioral modifications. One reasonable approach would be to take melatonin daily, approximately 3-5 hours prior to desired sleep time [5]. Doses may vary from 0.5-5 mg, though it is best to use the lowest effective dose. Melatonin dose and timing can be strategically adjusted based on clinical response. Relapse tends to occur in high rates (80-90%) once melatonin is discontinued [3, 5].

Morning light therapy can be coupled with the above interventions. Commercial light boxes that either contain a broad spectrum of white light or narrow spectrum of blue light (2,000-10,000 lux) should be used every morning between just after typical wake-up time, with gradual advancing of the sleep–wake time until the desired time is reached [5, 9]. Care should be taken to avoid light exposure earlier than 2-3 hours before the habitual wake up time because light prior to the core body temperature minimum may cause further delays in circadian phase (**Figure 6**).

**Figure 6.**

*For individuals with delayed sleep–wake phase disorder (DSWPD), treatment can consist of low-dose melatonin (to be taken ~3-5 hours prior to desired sleep time), along with phototherapy in the morning upon awakening. This combination can cause gradual advancement in sleep phase.*

#### **6.3 Irregular sleep–wake rhythm disorder (ISWRD)**

Treatment of ISWRD involves using behavioral strategies to restructure an individual's daily routine, and to optimize sleep hygiene to better consolidate sleep times and improve daytime alertness. It is important to create a cognitively enriched and socially interactive environment during the day to maintain alertness and prevent excessive napping. At night, measures should be taken to reduce noise and light, and to prevent sleep disturbances caused by other factors (e.g., nocturia).

#### *Circadian Rhythm Disorders DOI: http://dx.doi.org/10.5772/intechopen.99816*

Light therapy remains the most effective intervention during the day. Exposure to 3,000-5,000 lux of light for at least 2 hours in the morning has been shown to improve daytime alertness, reduce napping, and consolidate nightly sleep [5].

Melatonin can also be used for management of ISWRD, though positive results with melatonin use are less consistent than with treatment of other CRSWDs. Melatonin doses of 1-5 mg can be used 30 min prior to bedtime to facilitate sleep, and melatonin is more effective if used in conjunction with light therapy [3, 5]. Controlled-release formulation can be more effective than immediate release in this specific patient population with ISWRD.

#### **6.4 Non-24 sleep-wake rhythm disorder (N24SWRD)**

Treatment for N24SWD includes attempting to re-synchronize the circadian pacemaker using behavioral approaches and pharmacologic therapy. Education regarding proper sleep hygiene and maintenance of regularly scheduled timing of meals, social activities and physical exercise is important.

Tasimelteon, a melatonin agonist with affinity for the MT1 and MT2 receptors, is Food and Drug Administration (FDA) approved for use in N24SWD [5]. Melatonin can also be used to achieve gradual re-alignment. Higher doses (3-10 mg) may be given 1-2 hours prior to the desired bedtime for the first month. Entrainment usually occurs within 5-10 weeks, after which low-dose melatonin (0.5-1 mg) should be maintained to prevent relapse [5, 7].

Less robust evidence exists for bright light therapy, though it has been shown to be effective in sighted individuals with N24SWD and can be used in the early morning after awakenings.

#### **6.5 Shift work sleep-wake disorder (SWD)**

Management of SWD should first start with changes to work schedule, if possible, with adjustments to sleep hygiene. A regular daytime sleep schedule that can be followed, even during non-working days, is recommended to promote stability to the circadian system. This can be organized around an individual's personal schedule, but should ideally incorporate at least a 5 to 6-hour block of uninterrupted sleep. The sleep environment should be optimized to reduce sound, light, unfavorable temperatures and other factors that can interfere with sleep. Light blocking window shades can be used, and a temperature setting between 65 and 70 degrees Fahrenheit is optimal.

While at work, individuals can use continuous exposure to high-intensity light (2,000-10,000 lux) for as little as four 20-minute periods during the first part of the nigh [8] t. Use of blue light-blocking goggles in the morning and general avoidance of morning light help the circadian rhythm remain adapted to the shift work schedule. Additionally, short naps (<45 minutes) prior to the start of the work shift are a low-risk intervention that can be used to promote wakefulness during the shift.

If these behavioral measures fail, medication therapy is the next step. Modafinil (200 mg) and armodafinil (150 mg) are FDA approved for shift work disorder and can be used during the first part of the night [5, 8]. Small doses of caffeine (100-250 mg, equivalent to a small cup of coffee) can also be used during the first part of the night. Short-acting hypnotics such as zolpidem and zaleplon can be used to promote sleep during the daytime; use of hypnotics must be introduced cautiously to prevent nocturnal grogginess (during work hours). Exogenous melatonin 30 min prior to desired bedtime can be used, although the evidence for this is poor [5].

#### **6.6 Jet lag disorder (JLD)**

The treatment strategy depends on the length of trip, number of time zones traveled, and direction of travel [9]. Trips less than 3 days are usually too short to create problematic jet lag symptoms. Treatment planning is best done in anticipation of travel.

For eastward travel on trips longer than 3 days and up to 7 time zones, a strategy using timed light exposure and melatonin can help advance the circadian rhythm (making natural bedtime and wake time earlier) to the new time zone. Bright light therapy can be started up to 3 days prior to departure to start the advancing process. Individuals should wake up about 1 hour prior to usual wake-up time and expose themselves to bright light for at least an hour. Upon arrival at destination, strategic light exposure throughout the afternoon and light avoidance during the early morning can help with this circadian realignment. The specific timing of light exposure is based on when the patient's habitual core body temperature minimum (CBT-min) occurs, which is usually 3 hours before habitual wake-up time. Light exposure after the CBTmin causes circadian phase advancement, whereas light exposure before the CBT-min causes a circadian phase delay and is thus counterproductive for eastward travel [8].

Timed melatonin (3-5 mg) taken at the desired destination bedtime can be used concurrently with prescribed light exposure. Melatonin should first be taken on the evening of arrival and continued for up to 5 days. Hypnotics have been used by patients during travel, but these medications can lead to impaired daytime performance, and thus are generally not recommended for management of JLD. Caffeine can help mitigate daytime sleepiness. Other stimulants (e.g. modafinil, armodafinil) can offset daytime sleepiness though these medications are not FDA approved for JLD. For eastward travel that crosses more than 8 time zones, it is often easier to pursue a circadian phase delay, rather than a circadian phase advance, to mitigate symptoms of JLD. This approach generally involves seeking out early morning light at the destination and avoiding light exposure in the afternoon.

Westward travel requires a delay in the circadian rhythm (later bed times and wake times) to adjust to the destination time zone. It is advised to seek bright light before the calculated CBT-min at the destination (based on the home time zone). For example, if one's habitual wake up time in Boston is 8 am Eastern Standard Time (EST), the habitual CBT-min will be at 5 am EST. If that individual travels to Westward to Hawaii (5-hour time zone delay), the CBT-min will occur at midnight EST, thus bright light exposure should be given prior to that time. Melatonin or hypnotics are generally not required in JLD associated with westward travel.

Resources such as www.jetlagrooster.com and the British Airways jet lag advisor [10] can help individuals plan light and melatonin exposure including in preparation for travel.

#### **7. How do patients generally respond to treatment? What other considerations exist for patients with circadian rhythm disorders?**

Treatment of circadian rhythm sleep wake disorders can often be challenging, and requires an individualized and multimodal approach, incorporating behavioral strategies such as directed light exposure, and appropriately timed melatonin. Overall effectiveness can be improved by combining these measures with chronotherapy, which gradually and progressively shifts the circadian clock.

Patients tend to respond well initially, however often require significant personal investment to maintain their newly desired schedule, and relapse to prior sleep schedule is not uncommon. It is essential to have the support of family, friends, teachers and coworkers to establish and maintain a sustainable new sleeping schedule.

#### *Circadian Rhythm Disorders DOI: http://dx.doi.org/10.5772/intechopen.99816*

When treating circadian rhythm sleep wake disorders, it is important to optimize the treatment of other comorbid medical conditions, especially psychiatric and mood disorders. This is especially true in adolescents and older patients. The importance of addressing sleep hygiene and one's sleep environment cannot be overstated as a critical component of treatment.

The treatment of CRSWDs remain a challenge, in part because of the scarcity of large, multicenter placebo-controlled trials using phototherapy and pharmacotherapy. However there have been recent rapid advances in our understanding of the genetics of circadian rhythm regulation, which may lead to improved diagnostic tools and treatments. For example, technology involving DNA manipulation has been used to generate Cry1/Cry2 knockout animals to further study the expression of specific genes on circadian function [11]. This opens up avenue for new therapeutic approaches in many disorders, specifically neuropsychiatric conditions, associated with circadian rhythm disturbance.

## **8. Conclusions**

Circadian rhythm disorders are common conditions that occur as a result of misalignment between an individual's intrinsic time-keeping system, and extrinsic cues. There are usually multifactorial contributions, including genetic influences, and behaviorally induced elements. Effective treatment approaches largely revolve around strategically timed melatonin and phototherapy to shift one's sleep phase to a more desired time. Consultation with a sleep medicine clinician may be helpful if symptoms persist, or to clarify a suspected circadian rhythm disorder.

#### **Acknowledgements**

The authors wish to acknowledge faculty at the Northwestern University Center for Circadian & Sleep Medicine, and the UCLA Sleep Disorders Center for their significant contributions towards our training and sleep medicine education.

## **Author details**

Ajay Sampat1 \* and Armand Ryden2

1 UC Davis Department of Neurology, Sacramento, CA, USA

2 VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

\*Address all correspondence to: acsampat@ucdavis.edu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
