A Novel Disease Condition Presenting with Insomnia and Hypersomnia Asynchronization Part 3

Potential Therapeutic Approaches

Basic Principles

For synchronization of the biological clock to a 24-hour cycle, exposure to morning light and avoidance of nocturnal light are essential. Therefore, lack of these two behaviors will result in asynchronization. Moreover, light-induced adrenal gene expression and corticosterone release have been demonstrated [136]. Under normal conditions, steroid secretion is greatest in the morning.

In addition to light and social factors [124], food [137] is known to affect the circadian clock. The dorsomedial hypothalamic nucleus was determined to be a putative food-entrainable circadian pacemaker in mice, and oscillation of this pacemaker was found to persist for at least 2 days, even when mice received no food during the expected feeding period following establishment of food-entrained behavioral rhythms [62]. Regular mealtimes, as well as participation in social activities, are likely to prevent asynchronization.

A daytime nap is known to result in favorable performance [138]. However, evening-type adolescents were reported to nap more frequently during school days than other chronotypes [44], although improved school performance after an afternoon 15-minute-nap was reported in a Japanese high school [139]. Further studies are needed to determine whether napping affects asynchronization.

Nevertheless, to prevent asynchronization, the social promotion of favorable sleep hygiene is important [140, 141].

Conventional Approaches

Light therapy

Light therapy has been shown to effectively treat patients with depression [142, 143] and seasonal affective disorder [144]. It has been recommended that patients with seasonal affective disorder initially receive morning light shortly upon awakening [68]. In patients with winter depression (seasonal affective disorder), one week of bright, morning light (2500 lux) treatment produced significantly greater remission rates (53%) than evening (38%) or midday (32%) treatment [145]. A clinical trial [68] that administered 5 weeks of bright, morning light therapy (10000 lux, 60 minutes) to chronic (> 2 years) major depression outpatients resulted in a remission rate of 50%, while the control group showed only minor improvements. Light therapy also reduced depression scores in patients with fibromyalgia [146].

The effects of light therapy on chronic fatigue syndrome have, however, been controversial [147, 148]. As described previously, exposure to at least 3 hours daylight per day was suggested to produce favorable effects on burnout patients [109], and light therapy was used to treat patients with shift work and jet lag disorders [149]. However, in animals and humans, short nights attenuate both evening light-induced circadian phase delays and morning light-induced circadian phase advances [150, 151]. In addition, circadian clocks advance phases by inducing earlier waking time and bedtime, while circadian clocks delay phases by pushing waking and bedtime later [152, 153]. Although these light effects should be clues for treating patients with early phase asynchronization, attenuation of light-induced circadian phase delays during short nights results in decreased light therapy effects on individuals suffering from jet lag and night workers engaged in a nocturnal life with a long nocturnal photoperiod (= short nights) [151].



There is insufficient evidence to assess the safety and efficacy of hypnotic medication for delayed sleep phase disorder [154]. Data encompassing the safety and efficacy of hypnotics with other types of circadian rhythm sleep disorders are scant [154]. In addition, the effects of hypnotics on shift work disorder patients are inconsistent [149]. However, the use of hypnotics for jet lag-induced insomnia is a rational treatment and is consistent with standard recommendations for treating short-term insomnia. The efficacy of benzodiazepines on patients with fibromyalgia, together with non-steroidal anti-inflammatory drugs, has been inferior to amitriptyline [155]. In addition, ultra-short- or medium-acting hypnotics have been used in children with chronic fatigue syndrome [148], and are widely used to treat insomnia in depression patients [156]. It is likely that appropriate use of hypnotics should be taken into consideration for the management of asynchronization.


The efficacy of antidepressants has been reported in depression, as well as chronic fatigue syndrome [103] and fibromyalgia [117, 155]. These agents could also be promising for treating depressive tendencies in asynchronization patients. However, because asynchronization are likely to be involving serotonin depletion, the use of selective serotonin reuptake inhibitors or serotonin and norepinephrine-reuptake inhibitors as the first agent of choice for treating asynchronization needs further studies.

Melatonin and its Agonists

The effects of melatonin in patients with delayed sleep phase disorder and free-running disorder have been established [154]. Afternoon or evening melatonin administration would be expected to shift rhythms earlier, thereby correcting pathological phase delay. Appropriately timed melatonin administration has been shown to entrain totally blind individuals with free-running disorder. Melatonin or melatonin agonists might benefit daytime sleep in night workers through their hypnotic, as well as phase-shifting, effects [149]. Melatonin, administered at the appropriate time, can reduce symptoms of jet lag and improve sleep following travel across multiple time zones [149]. Melatonin is also effective treatment for some patients with chronic fatigue syndrome [104], as well as pain associated with fibromyalgia [118]. Interestingly, agomelatine, a compound with melatonin receptor agonist properties, has been reported to exert an antidepressant effect superior to selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors [157]. However, because melatonin is not regulated by the U.S. FDA, there are a variety of preparations, and its usefulness has been limited [158].

In a 4-year-old boy diagnosed with Smith-Magenis syndrome, Carpizo et al. reported treatment with a beta (1)-adrenergic antagonist in the morning (to suppress diurnal melatonin secretion) and melatonin in the evening (to generate nocturnal melatonin peak), which resulted in improved sleep quality, as evaluated by polysomnographic methods [159]. This approach could be beneficial for asynchronization patients that exhibit altered diurnal melatonin secretion.

Vitamin B12

Vitamin B12 has been shown to enhance light pulse-induced phase shifts and thus augment entrainability of the circadian clock to light in rats [160]. In fact, high-dose vitamin B12 (3 g/day) proved to be effective in childhood chronic fatigue syndrome patients with free-running disorder [148]. An association between low vitamin B12 status and depression in elderly individuals has been suggested [161]. Because vitamin B12 deficiency causes decreased remethylation of homocysteine and is, therefore, most likely contributing to increased homocysteine levels, Regland et al. [162] measured homocysteine and vitamin B12 levels in cerebrospinal fluid of patients that fulfilled criteria for both fibromyalgia and chronic fatigue syndrome. They measured increased homocysteine concentrations, as well as a correlation between vitamin B12 levels and clinical variables. In other words, decreased vitamin B12 levels resulted in more severe clinical conditions. However, a recent review suggested that vitamin B12 was not an effective treatment for delayed sleep phase disorder [154]. Also, vitamin B12 was not recommended for treating jet lag or shift work disorders [149].

Physical activity

Physical activity is associated with an antidepressant effect in clinical depression [163]. Exercise leads to improved physical and mental health in fibromyalgia patients [164] and was shown to re-time circadian rhythm in individuals suffering from jet lag or shift work [165]. In patients with chronic fatigue syndrome, graded exercise therapy was shown to be valuable in randomized controlled trials [166]. Exercise induces these effects not only through the serotonergic systems, which is activated by rhythmic movements, such as gait, chewing, and respiration [90], but also through other molecules, such as brain-derived neurotrophic factor [91]. Physical activity or exercise could be potentially used to relieve asynchronization. Each morning in Japan, we have a 10-minute radio program of gymnastic exercises with piano accompaniment. This set of exercises is very familiar to almost all people in Japan, especially those older than twenty years of age. The efficacy of these exercises should be re-evaluated for physical and mental health.


To resynchronize the circadian clock with the desired 24-hour cycle, chronotherapy has been used in patients with circadian rhythm sleep disorder. This approach assumes that the circadian clock cycle of the majority of people is longer than 24 hours. In a case of delayed sleep phase, a successive delay of sleep onset by 3 hours each day, over a 5 -6-day period, is required to achieve desired sleep onset [167]. This shift should be rigidly adhered to establish a set sleep-wake schedule and proper sleep hygiene practice. However, the potential confounding effects of light exposure at inappropriate circadian times might limit the effectiveness and practicality of this approach [168].

Alternative Approaches

The following are potential approaches to manage asynchronization, although the diagnostic standards and methodology, in terms of applicability, remain to be determined.


Kampo medicine is a traditional Japanese herbal medicine that originated from traditional Chinese medicine. Examples for prescription are listed in Table 4 [169-171]. In addition to these prescriptions, Kanbaku-taisou-to (72) (the value in parentheses is the standardized number for prescription in Japan) and Yoku-kan-san (54) is the author’s preference for patients with early-phase asynchronization and presumed elevated sympathetic nerve activity. I also use Dai-saiko-to (8) to treat insomnia due to hypertension or tinnitus. In patients with depression [172] and fibromyalgia [173], Kampo or traditional Chinese medicine have been commonly used. 

Table 4. Presumable Kampo prescriptions for asynchronization.

weakness in the lower extremities

systemic hypofunction and/or coldness

glow ing (or heat sensation in the palm or foot)


aggressiveness or


depressive tendency




fatigue after acute infection

fatigue syndrome

Rokumi-gan (88), Hochu-ekki-to (41), and Sho-Saiko-to (9) [169]

chronic fatigue syndrome

Ninjin-yoei-to (108)[169][170]


(7) [171]

Sinbu-to (30) or Ougiken-chu-to

(98)and Ninzin-to (32) [171]

Rokumi-gan (87) [171]

Zyuzen-taiho-to (48)

and/or Ninjin-yoei-to (108) [171]

or insomnia Kihi-to (65) or fatigue Hochu-ekki-to (41) [171]

Saiko-keishi-to (10) [171]

child patients with school refusal

Rokumi-gun (87) [171]

Seisho-ekki-to (136) [171]

Saiko-karyu-kotuborei-to (12) [171]

Kami-shouyou-san (24) [171]

Zyuzen-taiho-to (48)

and/or Ninjin-yoei-to (108) [171]

or insomnia Kihi-to (65) Hochu-ekki-to (41) [171]

Number in the parenthesis is the standardized number for prescription in Japan.

Rhythmic Movements

As described in the former section, exercise could produce favorable effects on depression [163], fibromyalgia [164] jet lag, shift work [165], and chronic fatigue syndrome [166], presumably not only through the activation of serotonergic system [90] but also by the induction of other molecules [91]. Among rhythmic movements which activate serotonergic system [90], gait must be a part of exercise. In this section, rhythmic movements other than gait -respiration and chewing- will be introduced.

Qigong is an ancient, oriental, mindful exercise [174], also described as a mind-body, integrative exercise or traditional Chinese medicine intervention that is used to prevent and cure ailments, as well as to improve health and energy levels [175]. Qigong (or ch’i kung) refers to a wide variety of traditional "cultivation" practices that involve movement and/or regulated breathing [176]. Qigong has recently been designated as an alternative therapy to help meet the increasing demand of non-pharmacologic modalities for achieving bio-psycho-social health in patients suffering from anxiety [174] or pain [177]. Although the meta-analyses to date have been based on low-quality studies and small numbers of hypertensive participants, Qigong and Zen meditation have been shown to significantly reduce blood pressure [178].

Tanden breathing involves slow breathing (range of 0.05-0.15 Hz) into the lower abdomen, and was found to affect cardiac variability, which is controlled by the autonomic nervous system [179]. Although rhythmic respiration has been reported to activate serotonergic activity [90], Arita and Takahashi [180] preliminarily determined that tanden respiration also elevates serotonergic activity. Chewing has also been reported to activate the serotonergic system [90, 181]. This behavior could be used to manage asynchronization by deliberately activating serotonergic activity.

Locomotion is a sort of rhythmic movements. Failed locomotion (crawling) during infancy (lack of interlimb coordination between upper and lower extremities) has been reported to be due to hypofunctioning serotonergic and/or noradrenergic neurons [182]. This results in postural atonia by disfacilitating postural augmentation pathways and/or disinhibiting the postural suppression pathway and preventing locomotion [183]. Forced-crawl training has been described as relieving symptoms resulting from low serotonergic activity [184].

Direct Contact

An older generation Japanese pediatrician [185] was quoted to say, "Holding a baby in the arms ("dakko" in Japanese) is the most effective tranquilizer for a baby." Although therapeutic touch is now receiving attention as a method to manage anxiety disorders, including depression [186], dakko is a typical and classic daily behavior that involves direct contact between caretakers and youngsters. With the rapid spread of various types of media, including mobile phones, one concern is that direct contact between people is rapidly diminishing. In fact, concurrent television exposure is reported to correlate with fewer social skills [187]. In addition, hugging and intimate, face-to-face conversations are expected to be promising in the effort to manage and/or prevent asynchronization.

Control of the Autonomic Nervous System

To provide adequate cues for the circadian clock, morning activation of the sympathetic nervous system and evening stimulation of the parasympathetic system might be helpful to manage asynchronization. In Japan, some pediatricians recommend scrubbing the skin with a dry towel or cold water in the morning to train the autonomic nervous system in patients with orthostatic dysregulation [188]. However, this approach has not been covered in the recently published guideline [189].

Pulse Light

In addition to the removal of stimuli that induce singularity effects, adequate stimuli (light pulse at CT 9-15 (transition from subjective day to night) [59]) could also reverse singularity. Further studies are needed to identify adequate stimuli for reversing circadian singularity behavior in asynchronization.


Many young people in Japan suffer from daytime sleepiness and nocturnal insomnia, and are persistently tired and inactive. This review focused on the association between nocturnal lifestyle and biological clock disorders, as well as the melatonergic and serotonergic systems. However, involvement of dopamine [190] and opioid peptides [101] are also possible. A novel clinical concept – asynchronization – has been proposed, and a similar basic concept -singularity – was also introduced.

In this review, studies that recommended morning-type behavior to reduce behavioral/emotional problems were introduced [28, 47, 52]. Ayurveda, an ancient system of health care that is native to the Indian subcontinent, suggests that, in addition to good conduct, thought, diet, interpersonal dealings, physical activity, early rising, and early bedtimes are good for a healthy life [191]. Ekken Haibara wrote in his essay, Youzyoukun (1713), that one should awake early in the morning and avoid late bedtime to live a healthy life [192]. Byoukesuchi (Hirano, 1832), a topic describing medical practices for the home, stated that one should go to bed early at night and awake before dawn for a healthy life [193]. Thus both traditional wisdoms and recent researches recommend morning-type behavior, and this article reviewed the possible background mechanisms for the favorable effects on physical and mental health.

Senior high school students in Korea are reported to go to bed (0:54 on school nights) [194] later than those in Japan (0:06 [11] or 23:50 [12]). Although Chinese senior high school students in Hong Kong went to bed earlier (23:24) than those in Japan, it was concluded that they did not receive sufficient sleep [195]. Many young people not only in Japan but also in the other countries might be potential patients with asynchronization. In addition, some NEET (Not in Employment, Education, or Training) [196] individuals might also suffer from asynchronization.

Now we are living in the society with 24-hour activity. I am afraid that this type of society might produce unfavorable effects on the SCN. A quarter of the world’s population is subjected to a 1 hour time change twice a year (daylight saving time; DST) [197]. DST is now known to disturb normal seasonality seen in sleep timing assessed by mid-sleep times [197]. In addition, at the beginning of DST (=spring), the rates of traffic accidents [198] and the attacks of myocardial infarction [199] are reported to increase. I wonder we should be more careful on the property of the biological clock. I hope a novel concept of asynchronization to contribute to noticing the significance of the SCN, and to helping patients suffering from circadian disruptions.

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