Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol

Abstract

Circadian rhythm sleep-wake disorders result from the lack of synchronization between endogenous circadian rhythms and daily environmental or behavioral cycles. Current treatment of circadian rhythm sleep-wake disorders relies on strengthening normal zeitgebers, or temporal cues, through the combination of strict behavioral modification, controlled light exposure, and supplemental melatonin or melatonin receptor agonists. These therapies can be difficult to maintain and are supported with only limited clinical outcome data. The effectiveness of exogenous melatonin, in particular, may be reduced by the patient’s continued production of endogenous melatonin with a temporal pattern that is not conducive to the desired sleep schedule. Here we describe the case of a single, sighted patient with a circadian rhythm sleep-wake disorder who benefited from the combined use of a beta blocker to suppress endogenous melatonin secretion along with the timed administration of exogenous melatonin. We suggest that the positive results obtained justify further study of this mechanism-guided approach.

Citation:

Gehrman PR, Anafi RC. Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol. J Clin Sleep Med. 2021;17(10):2121–2124.

INTRODUCTION

Most humans have an endogenous circadian period that is longer than 24 hours.¹ As a result, our internal clocks require frequent adjustments to best align with the 24-hour day.¹ Circadian rhythm sleep-wake disorders result from the lack of synchronization between endogenous circadian rhythms and daily environmental or behavioral cycles.² Patients with delayed sleep-wake phase disorder, while maintaining 24-hour rhythms, are often unable to fall asleep at a “traditional” bedtime as circadian alertness signals occur later in the evening.^2,3 In contrast, the endogenous clocks of patients with non-24-hour sleep-wake rhythm disorder (non-24 SWRD) “free run” and are not synchronized to a 24-hour cycle.² Periods of relatively good sleep and normal wakefulness occur when endogenous rhythms transiently align with environmental cycles. As rhythms gradually drift out of alignment, nighttime sleep becomes more difficult and daytime sleepiness results.^3,4

Existing circadian rhythm sleep-wake disorder treatments are based on strengthening and adjusting established circadian entrainment signals. In normal physiology, bright light is among the most powerful zeitgebers, time-giving signals that entrain the endogenous clock to the external environment.¹ Indeed, non-24 SWRD is described primarily, but not exclusively, in nonsighted individuals.^2,3 Melatonin, in turn, is a rhythmically produced, pineal hormone that helps synchronize and entrain endogenous rhythms throughout the brain and body.¹ Melatonin feeds back to the suprachiasmatic nucleus, or master circadian pacemaker, to modulate suprachiasmatic nucleus firing activity. While the direct hypnotic effects of melatonin have been debated, its ability to shift circadian rhythms in otherwise normal people is well established.⁵ As a result, daily exposure to bright light and nightly administration of exogenous melatonin or melatonin receptor agonists are used to reinforce entrainment and are recommended therapies for several circadian sleep disorders.^3,4 However, data from patients with advanced sleep-wake phase disorder, delayed sleep-wake phase disorder, shift-work sleep disorder, and non-24 SWRD show melatonin production patterns reflecting the underlying circadian disturbance beginning hours before or after the expected time.^3,4 For example, a study by Gumenyuk and colleagues⁶ demonstrated that well-adapted shift workers have melatonin rhythms consistent with their work schedule, while those with shift-work sleep disorder maintain out-of-phase rhythms inconsistent with nighttime alertness.

The administration of exogenous melatonin in the setting of continued, but aberrantly timed, endogenous melatonin secretion has the potential to result in a relatively flat, or even bimodal, melatonin profile. Such a profile is likely poorly suited to entrain rhythms. A better approach might be to reduce endogenous melatonin while exogenously supplementing melatonin at the appropriate time. This approach is currently employed in the treatment of patients with Smith-Magenis syndrome, a rare genetic disorder associated with inverted melatonin rhythms and nocturnal activity patterns. Therapy entails the suppression of endogenous melatonin secretion with a beta blocker and the restoration of normal melatonin rhythms with the administration of nighttime melatonin. This approach, and the resulting shift from nighttime to daytime activity, has been successfully studied in a small trial and in several subsequent case reports.^7,8 Here we report use of this combination treatment in a sighted patient with a poorly controlled circadian rhythm sleep-wake disorder but without Smith-Magenis.

REPORT OF CASE

A 24-year-old woman presented reporting long-term sleep difficulties. She had been a “night owl” since early childhood with her parents reporting that she “came from a family of night owls” who all just “naturally stayed up late.” However, beginning when she was 14 years of age, she felt her daily schedule began “drifting every day” along with a progressively increasing sleep need and the perception of nonrestorative sleep. She was then home-schooled “so she could sleep when she needed it and follow her body more.” Her sleep schedule became more variable and despite reporting 10–12 hours of nightly sleep, she rarely felt well rested. She developed symptoms of depression that progressively worsened and her change in mood was attributed to her inability to follow a normal schedule and engage in social interactions. When the patient was 16 years old, a school psychologist diagnosed her with attention-deficit disorder. The diagnosis was confirmed that same year by a psychiatrist who also diagnosed the patient with major depressive disorder and started her on bupropion. The patient’s psychiatrist then referred her to a pediatric sleep center. An in-lab polysomnogram, performed when the patient was 16 years old, demonstrated moderate obstructive sleep apnea (by pediatric scoring rules) and she was prescribed continuous positive airway pressure. At the time of our evaluation, the patient reported that continuous positive airway pressure improved neither her sleep schedule nor her self-reported sleepiness. She also described difficulty tolerating continuous positive airway pressure.

She enrolled in college at age 17 years but had trouble making it to her classes, which were almost exclusively scheduled between 10 am and 2 pm. During her sophomore year, her class attendance and performance further worsened and she eventually dropped out after a “possible manic episode.” In the intervening years she underwent several sleep evaluations, including a polysomnogram and multiple sleep latency test that were reportedly “OK.” She had continued to intermittently try continuous positive airway pressure without self-reported benefit.

When she presented to our center at age 24 years, she continued to describe a very variable or rotating sleep schedule, with sleep least likely to occur between 5 pm to 2 am. At the time of her initial evaluation, a 6-week sleep diary, supplemented with the patient’s use of a commercial activity monitor, showed night-to-night variability with a progressive nightly delay. Sleep appeared least likely to occur from ∼5 pm to 1 am (Figure 1A). Her medical history was also notable for environmental allergies with and without episodes of “allergic bronchitis.” Her medications at that time included bupropion XL 150 mg daily and loratadine 10 mg daily as needed for allergy symptoms. In the 2 weeks immediately prior to her initial clinical evaluation, sleep onset time varied from 2 am to 11 am, with final awakenings (for her longest wake period) from 1 pm to 4 pm. Despite her best efforts, she reported only being able to maintain a fixed schedule, even a delayed one, for only ∼2 weeks before “crashing.” Given the inconsistent apnea history, an in-lab polysomnogram was repeated and did not show apnea (apnea-hypopnea index = 1.9 events/h). It was felt that her symptoms were best explained by non-24 SWRD, although it was noted that a combination of extreme delayed sleep-wake phase disorder and poor sleep hygiene might also explain these data.

Figure 1. Self-reported estimates of sleep and wake supplemented with commercial activity monitoring.

(A) Data from a 4-week period prior to active intervention. Sleep is irregular with a general trend for progressive delay consistent with free-running circadian rhythms. (B) Report from a 16-day period after 4 weeks of nighttime melatonin (0.5 mg) and morning bright light. Sleep is somewhat more regular but remains significantly delayed relative to the patient’s desired schedule. (C) Reported data from a 16-day period after 4 weeks of nighttime melatonin (0.5 mg) and daytime metoprolol succinate (50 mg). Sleep is more regular and sleep onset has advanced. A social, weekend delay (trip to New York City) is seen in the middle of the reporting period with a subsequent return to a more advanced schedule. Small “s” and “a” markers = time in bed (number of “s” and “a” markers reflect the total time asleep and awake during these periods as estimated from a commercial device and are provided directly from the patient).

She was instructed to focus on maintaining a fixed wake time of 2 pm and to forgo napping. Supplemental melatonin (0.5 mg) was to be taken at 11 pm with 20–30 minutes of bright light exposure using a commercial light therapy device shortly after awakening at 2 pm. After 1 month the patient reported that her schedule remained stable and no longer drifted night-to-night. We instructed her to advance her wake time by ∼10–15 minutes every week, with wake time, melatonin dose, and light exposure all advanced in tandem. However, after 2 months, the patient reported that she was unable to advance her sleep schedule (Figure 1B). Neither an increase in melatonin dose (1.3 mg) nor a switch to the synthetic melatonin agonist ramelteon led to further improvement.

After an extended discussion with the patient, she was started on metoprolol succinate (slow release) 50 mg upon awakening. She was again instructed to advance her schedule by 15 minutes per week. She reported that these adjustments became easier with the addition of metoprolol. Over the subsequent 2 months she described an increase in daytime energy and concentration along with improved mood. Her rise time advanced until a desired time of 8:30 am (Figure 1C).

She reported consistent use of melatonin, metoprolol SR, and bright light over the next several years with a stable sleep schedule. She returned to college and completed her degree. She continued to follow up at the sleep center, switching to yearly check-ins as her condition remained stable. While we discussed stopping the metoprolol on several occasions, the patient was concerned this would lead to a return of past sleep difficulties. More recently, the patient moved and transferred her care to a sleep physician in her local community. She has now remained on the combination of metoprolol and melatonin for ∼5 years.

The treatment of patients with delayed sleep-wake phase disorder, non-24 SWRD, and other circadian rhythm sleep-wake disorders remains a challenge. Current guidelines recommend a combination of strict behavioral interventions, bright light, and melatonin. However, while these treatments can be difficult for patients, there are limited data documenting their efficacy in clinical populations.³ Effective therapies better targeted to entrain the aberrant rhythms in clinical populations would be of great benefit. Here we present the case of a sighted patient with a circadian rhythm sleep-wake disorder who had poor response to conventional therapy but greatly benefited from the addition of metoprolol.

Beta-selective sympathetic blockers are well-studied, well-tolerated drugs commonly used in the treatment of cardiovascular disease. Sympathetic stimulation of the pineal, via beta-1 receptors, is a key regulator of melatonin synthesis.⁹ The effectiveness of beta blockers in reducing melatonin synthesis has been repeatedly observed since the 1980s.^9,10 In short-duration or single-administration trials, the primary factors determining the effectiveness of melatonin suppression appear to be dose and beta selectivity.¹¹ In the one longer-term (4-week) study, metoprolol (100 mg) appeared to have the most lasting effect, although smaller doses were not evaluated.¹²

We balanced several concerns in selecting a beta blocker. We favored the use of a longer half-life agent that would facilitate once-daily dosing. Given the patient’s history of allergy-related respiratory symptoms, we favored a beta-1 selective agent that would mitigate off-target respiratory side effects and the potential to precipitate an asthma attack. We also preferred more commonly used medications with more exhaustive safety records. Given these criteria we selected slow-release metoprolol succinate, buttressed by the above data demonstrating its persistent ability to reduce melatonin secretion over several weeks. We began with the 50 mg dose to minimize side effects with the plan that we could try an increased dose if required.

Our treatment of this patient with a combination of metoprolol and exogenous melatonin is based on established circadian physiology and is inspired by current recommendations for the treatment of patients with Smith-Magenis syndrome. Yet anecdotal reports like this one cannot justify a change in clinical care. More study is clearly needed. However, the favorable side effect profile and well-established safety record of metoprolol along with our clinical experience in a very small number of patients suggest that this a promising approach.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. Work for this study was performed at the University of Pennsylvania Sleep Center. This study was funded by National Institutes of Health Grants R01AG068577 and R01CA227485 to RCA. The authors report the off-label use of metoprolol succinate, in combination with melatonin, for the treatment of CRSWD. The authors declare no conflicts of interest.

ABBREVIATIONS

non-24 SWRD,

non-24-hour sleep-wake rhythm disorder

SWRD,

sleep-wake rhythm disorder