The profound effect of circadian timing and sleep on physical and mental health is well-known, including adverse metabolic and cardiovascular effects, depression, and learning impairment.1-3 Circadian rhythm sleep-wake disorders may develop when wakefulness and sleep patterns conflict with the timing of one’s biological clock.

Melatonin and other melatonin receptor agonists have demonstrated efficacy in the treatment of these disorders in both pediatric and adult populations.4 In a review published in July 2020 in Sleep Medicine Clinics, the authors discussed the use of these agents in patients with intrinsic circadian rhythm sleep-wake disorders.4

While other drugs such as hypnotics and alerting medications may also be used as “chronobiotics”  (ie, agents that can shift central circadian timing and improve sleep), they are not discussed in the current review because of the lack of clinical trials investigating their use for these indications.

Based on available evidence, the American Academy of Sleep Medicine (AASM) clinical guidelines recommend strategically timed melatonin or other melatonin receptor agonists for delayed sleep-wake phase disorder (DSWPD) in children and adults, irregular sleep-wake rhythm disorder (ISWRD) in children and adolescents with neurologic disorders, and non-24 sleep-wake disorder in blind adults.5


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For adults with DSWPD, the recommendation is based on 3 studies that used 1 of 2 fast release methods. One was a 0.3 mg or 3 mg fast release taken 1.5 to 6.5 hours before baseline dim light melatonin onset [DLMO] for the first 2 weeks and then advanced 1 hour earlier in the following. The second was a 5 mg fast release taken between 7 PM and 9 PM, advanced by ~1-hour following the first week.6-8

For children and adolescents with DSWPD, the recommendation is based on 3 pediatric studies that used a 0.15 mg/kg fast release taken 1.5 to 2.0 hours before habitual bedtime in children aged 6 to 12 years with no comorbidities, or a 3 mg or 5 mg fast release taken at 6 PM or 7 PM for those with psychiatric comorbidities.9-11

In pediatric patients with ISWRD with neurologic disorders, the recommendation is based on 1 study involving a 2 to 10 mg fast release taken ~30 minutes before the patient’s planned bedtime.12

Lastly, regarding adults with non-24 sleep-wake disorder, the recommendation is based on 3 studies used either 10 mg taken 1 hour before the patient’s preferred bedtime, or 0.5 mg or 5 mg taken at 9 PM.13-15

“Given that accurate objective measures of sleep and circadian timing are not currently easily accessible, treatment success is best judged by symptom improvement,” according to review coauthor Helen J. Burgess, PhD. Dr Burgess is now a professor in the Department of Psychiatry and codirector of the Sleep and Circadian Rhythms Research Laboratory at the University of Michigan in Ann Arbor (she was employed by Rush University Medical Center in Chicago, Illinois, at the time of publication).

Dr Burgess noted that data derived from wearable technology, such as heart rate, body temperature, and activity levels, will eventually be validated against polysomnography and DLMO and may lead to easy accessibility to accurate sleep and circadian rhythm data. The main diagnostic challenge is the lack of a simple method to measure endogenous circadian timing in humans. Dr Burgess and her colleagues are investigating the use of a home DLMO kit to address this need.

More studies are needed, Dr Burgess argues,  regarding the etiology of circadian rhythm sleep disorders and  optimal treatment approaches. Concerning the latter, Burgess discussed that the   “the biggest challenge is that treatment usually needs to be applied every 1 to 3 days to keep the clock in the desired place.” “There is usually no simple one-time treatment. Patients need to implement a lifestyle change, just as they need to do with exercise and nutrition.”

We interviewed Alicia J. Roth, PhD, a clinical health psychology fellow specializing in Behavioral Sleep Medicine at the Cleveland Clinic’s Sleep Disorders Center in Ohio, to learn more about the management of circadian rhythm sleep-wake disorders.

What is the current state of treatment for circadian rhythm sleep-wake disorders?

Dr Roth: There are several types of circadian rhythm sleep-wake disorders. The most prevalent are Advanced Sleep-Wake Phase Disorder (ASWPD) and DSWPD.

The most recent AASM clinical practice guidelines review of research evidence (both randomized trials and observational studies) show that both timed melatonin use and light therapy are the only treatments with consistent efficacy for DSWPD.5 For DSWPD, light therapy would take place after awakening. Melatonin use should be in the early evening, usually 4 to 5 hours before desired bedtime, and in small doses (0.5 mg-3 mg appear to be the optimal doses — it is not “the higher the better” in the case of melatonin). For ASWPD, only light therapy has consistent efficacy in the research, and it would be administered in the early evening.

However, in practice we also apply behavioral sleep strategies in conjunction with light therapy or melatonin use. For example, for DSWPD we gradually advance the bed and wake times 15 to 30 minutes earlier every week, while also administering melatonin earlier and using light in the morning. Other behavioral strategies we use are strategic timing of eating, exercise, and other activities and stimulus control measures — for example, “don’t go to bed until sleepy” and “get out of bed when awake.” Sleep medications such as hypnotics and benzodiazepines are not typically recommended for circadian rhythm sleep-wake disorders.

How should treatment response be assessed with these therapies, and what are some key safety considerations?

Dr Roth: The effectiveness of treatment should always be assessed against the patient’s goals and expectations. Patients with circadian rhythm disorders have a variety of goals. For DSWPD, it could be a teenager who wants to be able to join school at second period instead of missing the entire day. It could be a young adult who desperately needs to conform to a 9-to-5 job setting. So, there isn’t a one-size-fits-all schedule. Ultimately the questions are:  Are you functioning at the times you want or need to function, and are you functioning well?

We have a running joke in our clinic that we rarely see patients with ASWPD because an early-bird schedule is desirable in our society. However, having DSWPD typically affects the ability to work and go to school —and really to function within the parameters of society — so these individuals typically seek help.

Safety considerations are always drowsiness in dangerous situations such as driving. We recommend to all of our patients that if they are too drowsy to drive, to not drive or pull over. This may be especially relevant to DSWPD patients in the morning or ASWPD in the late afternoon or early evening.

What should be the focus of future research regarding this topic?  

Dr Roth: There is a dearth of literature showing the efficacy of behavioral methods to treat circadian rhythm disorders, as evidenced in the AASM practice parameters. There is also a psychological toll of having a circadian rhythm disorder, especially DSWPD. These individuals are often stigmatized as being lazy because of their late schedule and have difficulty in school or work performance. There is a definite need to explore the cognitive themes for these patients and how best to address them.

Finally, the acute and long-term effects of the COVID-19 pandemic on persons with circadian rhythm disorders will be interesting to investigate. Several sleep labs across the world are already working on these projects. In our clinics, we are seeing people with circadian rhythm disorders function better with stay at home orders and work from home scenarios because they are free to be on their own schedule. This was especially evident for teenagers with DSWPD when school transitioned to the home environment.

References

1. Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106(11):4453-4458.

2. Levandovski R, Dantas G, Fernandes LC, et al. Depression scores associate with chronotype and social jetlag in a rural population. Chronobiol Int. 2011;28(9):771–778.

3. Wright KP Jr, Hull JT, Hughes RJ, Ronda JM, Czeisler CA. Sleep and wakefulness out of phase with internal biological time impairs learning in humans. J Cogn Neurosci. 2006;18(4):508-521.

4. Burgess HJ, Emens JS. Drugs used in circadian sleep-wake rhythm disturbances. Sleep Med Clin. 2020;15(2):301-310.

5. Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2015;11(10):1199-1236.

6. Mundey K, Benloucif S, Harsanyi K, Dubocovich ML, Zee PC. Phase-dependent treatment of delayed sleep phase syndrome with melatonin. Sleep. 2005;28(10):1271-1278.

7. Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med. 2001;63(1):40-48.

8. Rahman SA, Kayumov L, Shapiro CM. Antidepressant action of melatonin in the treatment of delayed sleep phase syndrome. Sleep Med. 2010;11(2):131-136.

9. van Geijlswijk IM, van der Heijden KB, Egberts AC, Korzilius HP, Smits MG. Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT. Psychopharmacology (Berl). 2010;212(3):379-391.

10. Smits MG, van Stel HF, van der Heijden K, Meijer AM, Coenen AM, Kerkhof GA. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003;42(11):1286-1293.

11. Van der Heijden KB, Smits MG, Van Someren EJ, Ridderinkhof KR, Gunning WB. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry. 2007;46(2):233-241. 

12. Wright B, Sims D, Smart S, et al. Melatonin versus placebo in children with autism spectrum conditions and severe sleep problems not amenable to behaviour management strategies: a randomised controlled crossover trial. J Autism Dev Disord. 2011;41(2):175-184.

13. Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med. 2000;343(15):1070-1077.

14. Hack LM, Lockley SW, Arendt J, Skene DJ. The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms. 2003;18(5):420-429.

15. Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J. Melatonin administration can entrain the free-running circadian system of blind subjects[. J Endocrinol. 2000;164(1):R1-R6.