Sleep-related eating disorder and its associated conditions Yuichi Inoue1,2* 1

Department of Somnology, Tokyo Medical University, and 2Neuropsychiatric Research Institute, Tokyo, Japan

Sleep-related eating disorder (SRED) is a condition characterized by recurrent episodes of eating at the transition from night-time sleep to arousal. SRED patients describe eating in an out-of-control manner with preference for high-caloric foods and sometimes with inedible or toxic items. Level of consciousness during SRED episodes ranges from partial consciousness to dense unawareness typical of somnambulistic episodes. SRED is sometimes associated with psychotropic medication, in particular sedative hypnotics, and other sleep disorders, including parasomnias, narcolepsy, and restless legs syndrome. Night eating syndrome (NES) is another important condition in the disordered night-time eating spectrum showing

hyperphagia episodes at full arousal from nocturnal sleep without accompanying amnesia. NES could be considered an abnormality in the circadian rhythm of meal timing with a normal circadian timing of sleep onset. The two conditions often overlap and possibly share a common pathophysiology. Studies have suggested that central nervous system serotonin modulation may lead to an effective treatment of NES, while the anti-seizure medication topiramate may be an effective SRED treatment.

OTH EATING AND sleeping are influenced by the circadian rhythm, such that sleep usually occurs at night and food intake predominately occurs during the day in humans. In general, sleep is initiated 1–4 h after the last meal, partially depending on one’s lifestyle and sleep duration (7–9 h on average). Thus, night-time for humans is typically characterized by a prolonged period of fasting associated with sleep. Recent advances in sleep and circadian physiology, as well as societal increases in obesity and sleep deprivation, have led to increased interest in the relation between food intake and metabolism in association with sleep and circadian rhythm. In this review we introduce the disease concept of SRED and its clinical

relevance, in which the daily pattern of food intake is dysregulated and uncontrollable eating episodes occur during nocturnal sleep periods.


*Correspondence: Yuichi Inoue, MD, PhD, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Email: [email protected] Accepted 9 December 2014.

Key words: circadian rhythm, hypnotics, night eating syndrome, parasomnia, sleep-related eating disorder.

METABOLIC PHYSIOLOGY DURING SLEEP Despite a lack of food intake, serum glucose level is adequately maintained throughout the nocturnal sleep period in contrast to fasting during sedentary wakefulness, which demonstrates a fall in glucose levels over 12 h.1 The changes in systemic and cerebral glucose utilization during sleep periods help to maintain stable energy stores. The diminished motor activity and decline in brain metabolism during sleep contribute to the decreased glucose utilization in the periphery and brain, respectively.2 A previous study using positron emission tomography (PET) has shown that reduction in glucose utilization in the brain is most marked during deep non-rapid eye

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Table 1. Energy homeostasis during sleep7 Decreased glucose utilization

Impaired glucose tolerance

Appetite suppression

Decreased motor activity Decreased cerebral glucose activity (NREM sleep)

GH secretion at sleep onset Insulin disposal increased

Increased leptin (Satiety hormone)

GH, growth hormone; NREM, non-rapid eye movement.

movement (NREM) sleep, which is more frequent in the first half of the sleep period, and that NREM sleep demonstrates a 40% reduction in glucose metabolism compared to wakefulness.3 On the other hand, glucose utilization in the brain during REM sleep, primarily in the second half of the sleep period, is as high as, and occasionally higher than, periods of wakefulness.3 Glucose tolerance is also impaired to a certain extent during sleep. Under conditions of constant glucose infusion to eliminate confounding mealtiming factors, serum glucose levels become higher during both night-time sleep and daytime naps compared with those during an awakened state. The fact that serum glucose levels increase during a period of nocturnal sleep deprivation also suggests there is a circadian mechanism contributing to the decreased glucose tolerance at night-time.4 Likewise, insulin disposal and growth hormone (GH) secretion help maintain stable glucose levels throughout the sleep period; insulin disposal is increased during the sleep period, helping to maintain elevated glucose levels. Furthermore, GH is released at the onset of the sleep period and increases serum glucose levels by stimulating hepatic gluconeogenesis and inhibiting glucose uptake. Sleep-onset GH secretion is also associated with increases in density of slow-wave sleep, allowing for the promotion of anabolic processes during periods of musculoskeletal and cerebral quiescence. Major hormonal appetite mediators are also modified during the nocturnal sleep period to promote fasting. Among these, leptin, a peptide hormone secreted by adipocytes known to mediate satiety by inhibiting hunger centers in the hypothalamus during states of energy surplus, has a nocturnal rise that correlates with sleep onset.5 On the other hand, ghrelin, which is the initiation signal for feeding that is produced primarily in the stomach in response to fasting and circulates in the blood, shows increased levels during sleep in humans.6 Thus, a balance

between increased ghrelin and increased leptin activity contributes to the maintenance of fasting during sleep. In summary, energy homeostasis is maintained during sleep despite a prolonged fast through alterations in glucose metabolism and appetite regulation, as listed in Table 1.7

CONCEPT AND HISTORY OF SLEEP-RELATED EATING DISORDER AND NIGHT EATING SYNDROME Some cases with bulimia nervosa show nocturnal binging after the last meal, prior to falling asleep. However, the most important conditions during the main sleep period are sleep-related eating disorder (SRED) and night eating syndrome (NES), both of which may be relentless and chronic. The eating and drinking behavior of SRED occurs upon transition from sleep to awake, typically with reduced consciousness. On the other hand, patients with NES have episodes of conscious night eating (eating after awakening from sleep). Due to this difference, some critical reviews of the published work on SRED and NES have suggested that these conditions are situated at opposite poles of a spectrum of disordered eating during the main sleep period. However, recent studies have shown cases where these two disorders coexist; also, there has been some argument about similarities and differences between them. The disease concept of SRED was first introduced in 1991.8 In its early days, there were several reported cases of night-time eating, including the first case showing the link between sleepwalking and night-time eating in a 35-year-old woman with schizoaffective disorder who had episodes of unconscious nocturnal eating in association with psychotropic medications.9 Whyte et al. reported a series of three SRED cases having episodes of eating unpalatable foods, such as raw bacon, often with subsequent amnesia, and polysomnographic (PSG) studies dem-

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onstrated disorders of arousal from deep NREM sleep in these cases.10 Schenck et al. collected a relatively large number of patients with sleep-related eating behaviors, many of whom had PSG evidence for a disorder of arousal, leading the researchers to conclude that SRED is best classified as a parasomnia.8 Along this trend, several sleep researchers have shed light on the relation between problematic night-time eating behaviors and sleep physiology, based on their clinical experience of patients who initially presented to sleep disorder clinics. Consequently, patients who predominantly have an eating episode after nocturnal awakenings, particularly if they have alterations in the level of consciousness during the episode, are diagnosed as having SRED.

bring commonly consumed nocturnal foods into the sleep laboratory so as to facilitate eating behavior. If a patient eats during the PSG study, the concomitant sleep–wake state is then identified, and sleep technologists can assess the level of awareness at the eating episodes and subsequent recall in the morning. Most commonly, eating behavior arises during NREM sleep. One study documented that 44 of 45 nocturnal feeding episodes in 26 patients arose from NREM sleep.12 A high frequency of rhythmic masticatory muscle activity (RMMA) associated with arousal from NREM sleep in SRED has been reported.12 The pathophysiologic link of this sleeprelated RMMA to SRED needs to be elucidated, although the authors proposed a dopaminergic mechanism. One typical feature of SRED includes ‘out-ofcontrol’ or involuntary eating during arousals from sleep with partial or total unconsciousness. Patients with SRED generally arise from sleep and eat within the first 1–3 h after sleep onset. Eating episodes are characterized by rapid ingestion of food with preference for high caloric foods, but patients sometimes report ingesting non-edible or toxic items, such as cigarette butts and preservatives. In addition, these cases may have prolonged episodes with elaborate and sometimes dangerous food preparation.8,13–15 Recently, it has been reported that some SRED patients smoke during or just after eating episodes,16 possibly suggesting a commonality between eating and smoking in that these two are oral-centered behaviors. The level of consciousness during nocturnal eating ranges from full awareness to dense unawareness typical of somnambulistic episodes, and many patients describe themselves as ‘half-

DEFINITION AND CHARACTERISTICS OF SRED Clinicians seeing patients with SRED have the perspective that this disorder includes a combined feature of a daytime eating disorder with parasomnia. That is, SRED patients show compulsive and driven eating with next-morning anorexia and undesirable weight gain, which are the cardinal features of eating disorders. They often exhibit features of parasomnia, especially arousal disorders, such as partial arousals early in the sleep period characterized by confusion, automatic behaviors, and relative unresponsiveness to external stimuli followed by impaired recollection of the behaviors. The diagnostic criteria of SRED in the third edition of the International Classification of Sleep Disorders (ICSD) are shown in Table 2.11 PSG has been used to characterize SRED. At the PSG recording, patients are usually encouraged to

Table 2. Diagnostic criteria of sleep-related eating disorder11 Criteria A–D must be met A. Recurrent episodes of dysfunctional eating that occur after an arousal during the main sleep period. B. The presence of at least one of the following in association with the recurrent episodes of involuntary eating: 1. Consumption of peculiar forms or combinations of food or inedible or toxic substances. 2. Sleep-related injurious or potentially injurious behaviors performed while in pursuit of food or while cooking food. 3. Adverse health consequences from recurrent nocturnal eating. C. There is partial or complete loss of conscious awareness during the eating episode, with subsequent impaired recall. D. The disturbance is not better explained by another sleep disorder, mental disorder, medical disorder, medication, or substance use.

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awake, half-asleep’ during eating episodes. They will also deny hunger during eating episodes, but rather report a drive to eat. Indeed, a precise judgment of the level of consciousness is very difficult, as the judgment is usually made based on the level of the patients’ recollection of the episodes the next morning. Another complicating issue is that the level of awareness can vary within an episode, across episodes within one night (the frequency of episodes can range from once a week to more than 5 times in the same night), and over the longitudinal course (years) of the disorder. In the interviews, some patients report that they come to full alertness during an episode, find themselves eating, finish, and then return to bed. The most common, and often most troublesome, adverse effect of SRED is weight gain due to repeated consumption of high caloric foods during night-time eating episodes;17,18 this symptom is one of the diagnostic features of the disorder in the ICSD-3.11 Another important consequence of SRED is psychological distress due to ‘lack of control’, shame, guilt, and helplessness over night-time eating. Multiple night-time awakening and eating episodes also disrupt sleep, possibly leading to daytime fatigue and elevated daytime sleepiness. Of note, accidents involving falls, burns, and cuts while in search of and preparing food are also a concern, especially in patients who report to have clearly reduced alertness during the behavior episodes.

rare except in the population with eating disorders. However, all these studies predated the current criteria of SRED, and used various operational definitions of the disorder. Future epidemiological studies on SRED should be conducted on the general population using the current ICSD 3rd criteria for the disorder. SRED appears to be more prevalent in women than men, comprising two-thirds to three-quarters of all clinical cases. The female predominance of SRED mimics the higher prevalence rates of daytime eating disorders in women despite a clear difference in pathophysiology between the two disorders. However, the reason for this phenomenon is unclear. The onset of SRED generally ranges between the late teenage years and twenties, and most patients in clinical settings show a chronic course. However, there has been no conclusive information about whether all the affected persons exhibit a chronic course. Studies using PSG have found that patients with SRED are more likely to have concurrent sleep disorders, such as sleepwalking (somnambulism), periodic limb movement disorder (PLMD), restless legs syndrome (RLS), obstructive sleep apnea syndrome (OSAS23,24), and narcolepsy.25 In particular, Schenck et al. reported that 84% of SRED patients in their sample had a history of somnambulism, 13% had RLS, and 10% had OSAS.8,19 Sporadic cases of SRED have been reported with agents, such as tricyclic antidepressants, anticholinergics, lithium, triazolam, olanzapine, risperidone, quetiapine, and sodium oxybate.9,26–29 More recently, SRED has been frequently reported with use of the benzodiazepine receptor agonist zolpidem.14,15

Demographic correlates of SRED The prevalence rate of SRED in the general population is unclear. However, several epidemiological studies have been conducted targeting relatively small and specific populations. Schenck et al. retrospectively studied the prevalence of SRED on a sample of patients who had been referred to a sleep disorder clinic over a 7-year period and found that 0.5% of these patients fulfilled the criteria for SRED.8,19 Winkelman et al. reported that 16.7% of inpatients and 8.7% of outpatients with eating disorders (the prevalence of eating disorder: 4.0– 5.0%20) reported to have behaviors consistent with SRED, which was clearly higher than 4.6% of college students.21 They also reported 3.4% of persons having SRED in an outpatient depression clinic (the prevalence of depression: 4.4–5.0%22) and 1.0% of obese individuals in a weight-loss program. These rates suggest that the presence of SRED is relatively

RELATION BETWEEN SRED AND NES Table 3 shows the current diagnostic criteria for NES.30 There is no uniform classification scheme for night-time eating behaviors. The term ‘night-time eating’ is commonly used by eating disorder researchers to describe both evening hyperphagia (eating after the evening meal, but prior to initial sleep onset) as well as nocturnal eating (eating after an arousal from sleep, but prior to the final morning awakening), while the SRED is used by sleep disorder specialist physicians or researchers to describe amnestic ambulation with eating (sleepwalking-like behavior). Considering this, the researchers of these two fields may use divergent, but occasionally overlapping, ter-

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Table 3. Proposed diagnostic criteria for the Night Eating Syndrome30 I. The daily pattern of eating demonstrates a greatly increased intake in the evening and/or night-time, as manifested by one or both of the following: A. At least 25% of daily food intake is consumed after the evening meal B. At least two eating episodes per week occur upon awakening during the night II. The clinical picture is characterized by at least three of the following features: A. Lack of desire to eat in the morning and/or breakfast is omitted on four or more mornings per week B. Presence of a strong urge to eat between dinner and bedtime and/or during the night C. Sleep onset and/or sleep maintenance insomnia are present four or more nights per week D. Presence of a belief that one must eat in order to get to sleep E. Mood is frequently depressed and/or mood worsens in the evening III. Awareness and recall of evening and nocturnal eating episodes is present IV. The disorder is associated with significant distress and/or impairment in functioning V. The disordered pattern of eating has been maintained for a minimum of 3 months VI. The disorder is not secondary to substance abuse or dependence, a general medical disorder, a medication, or another psychiatric disorder Criteria III, IV, V and VI all have to be satisfied in addition to at least one of the two criteria of item I, and three of the five criteria of item II.

minology that is perplexing and impedes clinical investigation.7 At present, it is unclear whether SRED and NES constitute independent disorders, or should be lumped under the same diagnosis. In short, SRED is dysfunctional nocturnal eating that occurs in an involuntary manner; whereas NES encompasses all eating (dysfunctional and nondysfunctional) that occurs after the evening meal, but prior to the morning awakening (Fig. 1).31 According

to the nosologies identified by these researchers, the major distinctions between SRED and NES include: (i) the level of consciousness during nocturnal eating; (ii) the timing of nocturnal eating; and (iii) the difference in the rate of comorbid sleep disorders between the two disorders. As mentioned above, many patients with typical SRED report being either ‘asleep’ or ‘half-asleep’ during their eating episodes, while those with NES

Night-time eating Amnesia for the event

Partial recall of the event

Full recall of the event

Little arousal from sleep

Half-awake, half-asleep

Total arousal from sleep


• • • • •


Eating episodes after the onset of sleep No apparent daytime food cravings Intake of bizarre items Morning anorexia Comorbid sleep disorders common

• Evening hyperphagia, occasional episodes after the onset of sleep • Food cravings in the evening (post-evening meal) • Intake of normal food items • Morning anorexia

Figure 1. Spectrum of night-time eating.15 NES, night-eating syndrome; SRED, sleep-related eating disorder.

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report being fully awake and aware during the episodes.32 The reduced consciousness during SRED episodes may also account for why some patients with SRED ingest inedible or toxic items and patients with NES do not. Considering this, an item assessing the level of awareness during nocturnal eating was added to the Night Eating Questionnaire, a psychometric scale developed to assess the severity of NES.33 However, the sensitivity or specificity of this item for identifying the presence of unconsciousness during eating episodes is unclear. Interestingly, one report noted full awareness in all 26 SRED patients after episodes of nocturnal eating in a sleep laboratory.12 The timing of nocturnal eating is another key point to distinguish NES from SRED. Theoretically, SRED episodes occur just after awakening from sleep, whereas patients with NES may eat not only before initial sleep onset but also at night-time awakenings. Considering this overlapped timing of eating episodes between these two disorders, the criterion that greater than one-third of all calories are consumed after the evening meal in NES should be more emphasized. In other words, sleep-related awakenings are the cardinal feature of SRED, while a shift in caloric consumption to night-time is the cardinal feature of NES. As indicated above, the frequencies of comorbid sleep disorders, including sleepwalking, PLMS, and OSAS in patients with SRED are quite high. This association is not common in patients with NES. However, thorough evaluation for sleep disorders using PSG has not been conducted on NES patients. Moreover, most of the studies on NES patients specifically excluded the ones suggestive of primary sleep disorders. Thus, it remains inconclusive whether comorbidity of sleep disorders may become an important distinctive marker between NES and SRED. While SRED and NES have been described as independent categories, some features overlap, prompting a proposed continuum of night-time eating behavior.34 In fact, more than half of SRED patients are known to meet the criteria of NES.30 Future studies should facilitate the viewing of NES and SRED as a single continuum.

unfortunately reflects the paucity of knowledge regarding the pathophysiology of parasomnia in general. However, results of previous studies have shown that the mechanism of SRED may be somewhat heterogeneous. Furthermore, some avenues of investigation, including the association of SRED with primary sleep disorders, the studies on circadian variation of neuroendocrinological function, and recent animal genetic knockouts, appear promising.

MECHANISM FOR THE OCCURRENCE OF SRED To date, conclusive information about the underlying mechanism of SRED has not been obtained, and this

SRED as NREM parasomnia As indicated above, SRED occurs as a variant of NREM parasomnia, in which an incomplete dissociation of NREM sleep into wakefulness exists. In the original series of 38 patients, sleepwalking was noted in 23 patients,9 and in another series of 23 patients, 11 were diagnosed with sleepwalking.17 Importantly, sleepwalking without eating often precedes SRED and then once nocturnal eating develops, it often becomes the predominant or even the exclusive sleepwalking behavior. This pattern has led many researchers to consider SRED as a ‘sleepwalking variant disorder’.9 A recent study has shown that patients with SRED shared several clinical commonalities with sleepwalkers, except that childhood eating problems are more frequent in SRED patients.35 Two pathological processes may lead to NREM parasomnia, a sleep–wake boundary dysfunction. First, phenomena that deepen sleep and enhance sleep inertia may promote NREM parasomnia by impairing otherwise normal arousal mechanisms. Second, conditions that cause repeated cortical arousals (sleep fragmentation) may lead to NREM parasomnia.36 In the normal transition from light NREM sleep to wakefulness, consciousness quickly emerges, typically within seconds. However, the speed of the conversion from NREM sleep to wakefulness depends on an intricate combination of factors, including duration of prior wakefulness, current sleep duration, depth of NREM sleep, phase of circadian rhythm, effect of sedating or stimulating medication, and multiple genetic and environmental factors. In particular, the threshold for producing an awakening during deep NREM sleep with continuous slow-wave activity (SWA) is clearly higher than that during light NREM sleep with minimal SWA, and awakenings are typically prolonged in the latter.37 Subsequently, sleep inertia at arousal from deep NREM sleep may become

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strong, being causative of NREM parasomnias. Thus, sleep deprivation, a deep NREM-sleep-promoting condition, can become a risk factor for NREM parasomnias, including SRED and sleepwalking. Likewise, sedative-hypnotic medication acts to increase the threshold for producing an awakening, possibly causing SRED and other NREM parasomnias. Meanwhile, disorders that lead to fragmented NREM sleep precipitate NREM parasomnia by increasing arousal frequency. This theory is supported by a previous study that confusional arousals were experimentally precipitated in the sleep laboratory through sleep deprivation, which promoted SWA, combined with repeated loud noises during deep NREM on the experimental PSG night.38 Considering this, OSAS, PLMD, or orexin-deficiencyinduced disrupted nocturnal sleep39 may promote NREM parasomnias, including SRED by fragmenting NREM sleep. The above-indicated high prevalence of SRED in patients affected with OSAS or PLMD is attributable to the frequent sleep fragmentation associated with increased homeostatic sleep drive caused by intermittent airway collapse or leg movements during sleep.40–42

Circadian neuroendocrinological function Major hormonal appetite mediators are modified during nocturnal sleep periods to promote fasting, and some of them are under the control of the circadian system. Given this, one possible mechanism for NES and SRED is that the circadian rhythm of eating is delayed relative to sleep–awake rhythm. Reports on several SRED cases comorbid with circadian rhythm sleep disorder may support this hypothesis.23,24 Previous studies have demonstrated that sleep onset and offset in NES are similar to those of control subjects.43,44 However, as would be expected in NES, there is a temporal redistribution of daily energy intake with consumption of food both before going to bed and during midnight awakenings. Phase delays in the circadian rhythm of the secretion of hormones, including leptin, insulin, and melatonin, have been demonstrated in patients with NES.33,45 However, as nocturnal awakenings and eating can both influence the underlying neuroendocrine patterns, it is difficult to determine if these physiological alterations are causes or effects of problematic nighttime eating without conducting a longitudinal follow-up study on affected patients after treatment interventions.

Clinical implication of SRED 315

SRED and mental problems SRED may be associated with psychological and psychiatric comorbidities. In the original 1991 case series, 47% of SRED patients had an Axis 1 disorder and many had daytime anxiety about potentially choking or starting fires while asleep.8 A follow-up study noted that 53% of patients described a history of repeated abuse and scores on the Dissociative Experiences Scale approached those typically seen in post-traumatic stress disorder.9 Furthermore, the onset of nocturnal eating is often correlated with psychological stress or withdrawal from substance abuse.9,17,46 Moreover, in a study of 35 patients with nocturnal eating, 14 met the criteria for a depressed mood;12 a separate study noted that patients with SRED endorsed more symptoms of depression and dissociation than those without SRED.21 As indicated above, the prevalence rate of SRED is higher in patients having daytime eating disorders, including bulimia and anorexia.17,18,47 Interestingly, Winkelman reported that more than 40% of his SRED patients had elevated scores on the Eating Attitude Test.21 Taking these into consideration, SRED and daytime eating disorders may share a common psychological background.

SRED and genetic basis Similar to NES and sleepwalking, SRED may have a genetic predisposition. In a case of a 31-year-old woman with SRED, it was reported that her dizygotic twin sister and father were also affected.48 Furthermore, in a PSG study of SRED conducted by Winkelman,17 26% of patients claimed that they had a first-degree relative with a nocturnal eating behavior. In another study series, Winkelman also suggested that approximately 20% of their SRED cases showed familial aggregation of the disorder. Conversely, in a study of 36 subjects with a history of nocturnal eating, only two described similar behaviors in family members.12 Thus, more genetic research would be necessary to determine whether occurrence of SRED depends on an inherited trait. In addition, considering that sleepwalking has been found to exhibit specific HLA Class II gene susceptibilities,49 another form of genetic susceptibility to SRED may involve the HLA system. The use of mutant mouse models is one promising approach to understanding the pathophysiology of SRED. In two intriguing models in which clock genes

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are knocked out, Clock49 or mPer250 knocked-out mice consumed substantially more food during their normally inactive (light) period. When kept on a high-fat diet, they gained a substantial amount of weight. Injections of alpha melanocyte stimulating hormone (MSH), a major effector of appetite control, at the beginning of the light period suppressed the abnormal eating behavior.51 These findings emphasize the requirement of clock genes in appetite control during the inactive period and the potential role of peripherally administered alpha MSH in restoring the night–day eating pattern in individuals with circadian eating disorders, such as NES. Such models should allow an increased understanding of the interrelated roles of the circadian and metabolic system in SRED or NES.52

hypnotics.9,26,27,61–65 The majority of cases with druginduced SRED are related to the medication of zolpidem, a benzodiazepine agonist hypnotic. In the first report on zolpidem-associated SRED, two out of five cases already had intermittent episodes of conscious nocturnal eating prior to starting zolpidem medication. Soon after starting the medication, each patient described amnestic (unconscious) nocturnal eating that disappeared after discontinuation.14 Two reports from Asia also emphasized the strong association between amnestic SRED and zolpidem. The first study targeting 1235 psychiatric outpatients revealed that the combination of zolpidem and antidepressants posed the greatest risk for the presence of SRED.62 In the second study, two-thirds of sleepwalkers frequently taking zolpidem had episodes of SRED.66 When reviewing zolpidem-associated SRED cases, most of them had amnestic SRED episodes possibly due to the amnestic action of the drugs, although reduced awareness with subsequent amnesia is not a required diagnostic criterion for SRED in the current ICSD. As for the mechanism of SRED in these cases, disinhibition of eating behavior in persons who are potentially at risk for nocturnal feeding brought about by enhanced gamma amino butyric acid (GABA) activity at GABA-A receptors due to taking sedating hypnotics is likely. With regard to this, Tsai et al.67 reported that the AUG at the GABA α1 receptor subunit gene confers a high risk of zolpidem-induced complex sleep behaviors, including sleepwalking and SRED, if the enhanced GABAergic activity is involved in the mechanism of drug-induced SRED and this condition could not be specific to zolpidem medication. Considering that SRED frequently occurs when patients take supratherapeutic doses of zolpidem,15,68,69 any kinds of hypnotics with high potency or high dose may cause SRED. Future investigations should focus more on this issue.

SRED and RLS Nocturnal food ingestion in SRED can be characterized as restless eating. At this point, SRED bears a similarity to the motor symptoms of RLS. RLS is a relatively common disorder affecting 5–10% of the Caucasian population53,54 and 2–4% of the Japanese population.55 As with SRED, the prevalence of RLS is higher in women. Some researchers have suggested that dopaminergic dysfunction is involved not only in the mechanism of RLS,56 but also in smoking and binge eating.56,57 Previously, two studies revealed a >30% prevalence rate of SRED in RLS patients.58,59 The following two possibilities should be considered for this phenomenon: one is that the presence of SRED is related to an underlying dopaminergic dysfunction in RLS, and the other is that eating behavior is merely a ‘killing time’ behavior.60 However, one report showed a clearly higher prevalence rate of SRED in RLS patients than in patients with psychophysiological insomnia, who were more likely to have prolonged nightly awakenings (>5 min) compared to RLS patients, suggesting nocturnal eating associated with RLS was not merely a ‘killing time’ behavior.21,59 Although future pathophysiological studies on this issue are desirable, dopaminergic dysfunction may play a role in the mechanism of SRED, especially in patients with RLS.

Hypnotic medication and SRED Several early studies noted that nocturnal eating was associated with sedating psychotropic medications, including antipsychotics, antidepressants and

TREATMENT OF SRED As adequate medical guidance related to treatment of SRED is lacking, many individuals with the disorder attempt multiple kinds of ‘home remedies’, such as limiting the amount and type of food in their house and locking the refrigerator and cabinets, often with little success. However, some pharmacological or non-pharmacological approaches give SRED sufferers more hope.

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Pharmacological treatment for SRED or NES has been created based on the effectiveness on either daytime eating disorders or disorders often comorbid with these night-time eating disorders (e.g. RLS or PLMD). Treatment of sleep disorders that cause sleep fragmentation, such as RLS, PLMD, or OSAS, may be of value for the treatment of SRED, possibly by reducing the number of arousals from sleep that may drive nocturnal eating episodes. In particular, RLS may predispose individuals to nocturnal eating, as it produces fragmented sleep and the inability to stay in bed when awakened. Indeed, Schenck et al. found that dopaminergic agents were effective in 52% (14/27) of their cases with SRED, five of whom had RLS or PLMD.19 A randomized, double-blind, placebo-controlled crossover study of pramipexole (up to 0.36 mg per day, 3 weeks each for active drug and placebo) on 11 SRED subjects demonstrated improvement in nocturnal activity monitored with actigraphy and ‘the number of self-reported good nights of sleep per week’.70 However, in that study, eating outcomes related to SRED showed no improvement and no weight loss was observed. Clonazepam, a benzodiazepine derivative, is reportedly effective in some SRED cases having a history of sleepwalking.19 However, considering the increased risk of SRED among BZD hypnotic users in previous reports,15,68,69 the first step of the treatment for patients in whom SRED appears after starting or escalating doses of BZD is to taper the drug. Furthermore, clonazepam treatment is thought to be contraindicated in such cases. Topiramate, a globally used anticonvulsant, was originally found to produce weight loss in treatment trials for epilepsy and bipolar disorders. Reportedly, the drug reduced binge episodes in binge-eating patients.71,72 Winkelman reported that 68% of 25 patients with SRED were responders (mean daily dose of 135 mg/day), as measured by the Clinical Global Impression of Improvement (CGI-I73). Although substantial weight loss was observed in over one-quarter of responders, nearly half of the responders discontinued the medication after a mean of 12 months due to side-effects, including dullness, paresthesia, and daytime sleepiness. On the other hand, in our experience on Japanese SRED patients, 25–50 mg/day doses of topiramate treatment were quite tolerable for a long time, but the rate of clear responders to the treatment remained less than 40%.81 Thus, topiramate cannot become a promising

treatment for all SRED patients. In addition, it is unclear how topiramate works to decrease night-time eating episodes; however, it was hypothesized that the drug acts as an anorexigenic agent, either through glutamatergic antagonism or serotonergic agonism.24 In addition, topiramate has been reported to stimulate insulin release and increase insulin sensitivity, both of which may contribute to appetite regulation and weight loss.74,75 Treatments that are employed to manage daytime eating disorders may be beneficial for SRED. Among these, sertraline, a selective serotonin reuptake inhibitor (SSRI), has received much attention because both open-labeled and double-blind, flexible-dose studies (up to 200 mg sertraline) have demonstrated substantial benefit for patients with NES.43,76 In the report by O’Reardon et al., reduced nocturnal eating episodes by over 80% (from 8.3 to 1.6 episodes per week) and substantial weight loss were observed in patients given sertraline.76 Recent studies have also shown that escitalopram, a different SSRI, is effective for the treatment of NES.77,78 Considering the pathological commonality between SRED and NES, SSRI are expected to become an important treatment candidate, although no treatment trial with SSRI on SRED has been conducted to date. Because the pathological mechanism of NES includes the aspect of circadian rhythm disorder as implicated above, some chronobiological treatments have been tested. Friedman et al.79 reported two NES cases comorbid with depression that were successfully treated with 2 weeks of exposure to bright light therapy (10 000 lx) for 30 min early in the morning. Milano et al.80 also reported that agomelatine, an antidepressant analogue of melatonin, was effective in a case with NES and depression; the use of agomelatine reduced the number of nocturnal awakenings with food intake and improved the mood. Future clinical trials of these chronobiological treatments for SRED cases, especially comorbid with delayed sleep phase syndrome, are necessary.

CONCLUSION SRED combines features of both sleep and eating disorders, such that individuals eat during partial or complete arousal from sleep. Patients who seek medical assistance are likely to show a chronic course with near-nightly eating episodes and suffer from a variety of daytime consequences brought about by

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the disorder. Currently, as the mechanism of the disorder shows heterogeneous properties, treatment is directed towards the underlying sleep disorders when present, or otherwise involves the empiric use of topiramate or SSRI. SRED and NES share similarities both in clinical manifestations and disease mechanism. Thus, a uniform screening questionnaire encompassing both SRED and NES should be developed for clinical and research purposes. Furthermore, coordination among sleep physiology, obesity, and eating disorder researchers is desirable for investigating the pathophysiology and for developing adequate treatment of these disorders.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Number 25515009. The author has nothing to disclose.

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Sleep-related eating disorder and its associated conditions.

Sleep-related eating disorder (SRED) is a condition characterized by recurrent episodes of eating at the transition from night-time sleep to arousal. ...
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