Abstract
Study Objectives:
The objective of this study was to determine the efficacy of ramelteon in treating abnormal eating behavior in patients with sleep-related eating disorder and/or night eating syndrome.
Methods:
We retrospectively reviewed the medical records of patients with sleep-related eating disorder/night eating syndrome at the Yoyogi Sleep Disorder Center from November 2013 to November 2018. We categorized patients as ramelteon treatment responders when the frequency of nighttime eating per week decreased to less than half of that before treatment.
Results:
Forty-nine patients were included in the analysis. The mean frequency of eating behavior (per week) (standard deviation) at baseline and post-ramelteon treatment was significantly different, at 5.3 (2.2) and 3.2 (3.0), respectively (P < .001). Twenty-one patients (42.9%) were classified as responders. Adverse events, all of which were mild daytime somnolence, were observed in 5 patients. There were significantly more individuals using benzodiazepine derivatives and Z-drugs before treatment and those with coexisting delayed sleep-wake phase disorder in the responder group than in the nonresponder group (P < .001 and P < .05, respectively). The mean benzodiazepine derivatives and Z-drugs dose significantly decreased from baseline to post-ramelteon treatment within the responder group (P < .05). This trend was not observed in the nonresponder group. Meanwhile, the sleep midpoint of patients with sleep-related eating disorder/night eating syndrome and delayed sleep-wake phase disorder did not significantly change after treatment.
Conclusions:
Our results indicate that ramelteon is a candidate treatment for sleep-related eating disorder/night eating syndrome. The effects of ramelteon might have occurred primarily through the reduction in benzodiazepine derivatives and Z-drugs rather than through the improvement in sleep-wake rhythm dysregulation.
Citation:
Matsui K, Kuriyama K, Kobayashi M, Inada K, Nishimura K, Inoue Y. The efficacy of add-on ramelteon and subsequent dose reduction of benzodiazepine derivatives/Z-drugs for the treatment of sleep-related eating disorder and night eating syndrome: a retrospective analysis of consecutive patients. J Clin Sleep Med. 2021;17(7):1475–1483.
Keywords: ramelteon, sleep-related eating disorder, night eating syndrome, insomnia, delayed sleep-wake phase disorder, benzodiazepine, nocturnal eating
BRIEF SUMMARY
Current Knowledge/Study Rationale: A few studies have reported the efficacy of chronobiological therapies on sleep-related eating disorder and night eating syndrome. However, the efficacy of ramelteon in treating these disorders has not yet been confirmed in a large sample.
Study Impact: Of the 49 patients included, 21 were deemed to have responded to the ramelteon treatment. Our results suggest that ramelteon is more likely to be effective when used as an alternative to benzodiazepine derivatives or Z-drugs.
INTRODUCTION
Sleep-related eating disorder (SRED) is characterized by involuntary food ingestion during sleep with partial or total amnesia, and is therefore categorized as a parasomnia.1–3 Night eating syndrome (NES), an eating disorder, is also characterized by eating behavior during the sleep period; however, NES episodes can be remembered the next morning.4,5 In addition, a dissociation of the circadian rhythms of feeding and the sleep-wake cycle is thought to be the mechanism underlying NES.6–8 Despite these differences, SRED and NES often coexist, and it is sometimes difficult to distinguish between the 2 disorders.9,10 To date, there have been several reports of the efficacy of selective serotonin reuptake inhibitors (SSRIs) for the treatment of SRED and NES.11–15 Particularly for NES, randomized controlled trials have revealed the efficacy of sertraline and escitalopram, with a responder rate of 60%–70% when evaluated using the Clinical Global Impressions Improvement scale.13,14 For SRED, there have been several reports on the efficacy of topiramate16–18; however, the low tolerability of this drug may be a cause for concern.9,17
Meanwhile, a recent study from our group has indicated that NES may be associated with a delayed sleep-wake rhythm.19 This condition is typified by delayed sleep-wake phase disorder (DSWPD), which is a circadian rhythm sleep-wake disorder (CRSWD) that is characterized by difficulty both falling asleep at night and waking up in the morning.3 The pathophysiology of CRSWD is considered to be a desynchronization between the circadian sleep-wake rhythm and the light/dark cycle.3,20,21 The feasible endogenous markers of the circadian rhythm in humans that can be measured in clinical situations include serum and salivary melatonin levels and core body temperature.22–26 However, the relationship between NES and profiles of these circadian markers is still controversial,7,27,28 and there has been no report on the diurnal change in melatonin secretion or core body temperature, per se, in patients with SRED. Recently, however, there have been some case reports of treatment success using melatonin and/or a melatonin receptor agonist (agomelatin), both in patients with SRED and patients with NES.29–31 Moreover, a pilot study in a small number of patients reported that bright-light therapy, which is thought to shift circadian phases,32 was effective for the treatment of NES.33 However, the efficacy of chronobiological treatment for SRED or NES is not yet fully understood, and the relationship between changes in the sleep-wake rhythm and abnormal eating behavior in the context of chronobiological treatment has not been investigated. Given that ramelteon, a melatonin receptor agonist, is thought to modulate sleep-wake rhythms,34,35 we hypothesized that ramelteon may contribute to the improvement in SRED/NES symptoms, as well as the amelioration of sleep-wake rhythms. The aim of this study was to investigate changes in SRED/NES symptoms following ramelteon treatment and to determine whether ramelteon treatment efficacy on eating behavior depends on treatment-associated changes in sleep-wake rhythms. In addition, since ramelteon is a potential alternative to benzodiazepine derivatives and Z-drugs (BZDs), both of which can aggravate nighttime eating behavior,36,37 we investigated changes in BZD dosage by comparing the dosage before and after starting ramelteon treatment in patients taking BZDs.
METHODS
Participants and procedure
The medical records of all patients who were diagnosed as having SRED and/or NES at the Yoyogi Sleep Disorder Center from November 2013 to November 2018 were retrospectively reviewed. Patients’ clinical symptoms were evaluated up to the last visit or at the end of ramelteon administration before January 2019, when the medical records survey was conducted. SRED was diagnosed using the International Classification of Sleep Disorders, third edition,3 and NES was diagnosed according to the criteria proposed by Allison et al,4 based on thorough clinical interviews by board-certified sleep-disorder psychiatrists or neurologists. Patients with SRED/NES who had been treated with ramelteon and whose nighttime eating frequency could be checked before and after starting the medication were included in the analyses. Before using ramelteon for the treatment of SRED/NES, consent for off-label use was obtained from all patients. Patients who had used ramelteon for less than 4 weeks were excluded from the analysis. In addition, patients who were already using ramelteon at the start of the observation, or in whom other agents targeting SRED/NES were initiated within 4 weeks before the administration of ramelteon, were excluded.
The following data were collected from patients’ clinical records: demographic information (age at the start of ramelteon treatment, sex, and body mass index), self-reported onset age of SRED/NES, frequency of eating behavior, status of cigarette smoking and habitual alcohol consumption, usual sleep-onset time and waking up time, presence/absence of morning anorexia, a current dietary restriction, history of somnambulism in one’s childhood, coexisting sleep disorders (diagnosed by board-certified sleep-disorder neuropsychiatrists), coexisting self-reported mental disorders, duration of ramelteon treatment (months), medications used during the observational period, and possible adverse events due to ramelteon. The frequency of nighttime eating behavior and habitual sleep schedules were evaluated at the start of ramelteon administration and at the end of the therapeutic period. The ramelteon dose ranged from 1 mg to 8 mg. Patients administered with any therapeutic doses were included in this study. In patients for whom nocturnal polysomnography was performed, obstructive sleep apnea (apnea-hypopnea index ≥ 5 events/h) and periodic limb movement disorder (periodic limb movement index ≥ 15) were thoroughly investigated and defined as coexistent sleep disorders. If BZDs were used both at the time of diagnosis and during the period of ramelteon administration, then SRED/NES was defined as possibly BZD-related. The daily amount of BZDs used before and after ramelteon administration was converted into the diazepam-equivalent dose.38 To evaluate the efficacy of ramelteon in SRED/NES treatment, we defined ramelteon treatment responders as those who exhibited a decrease in the frequency of nighttime eating per week to less than half of that before treatment; this included the definitions of “moderate to marked response” and “remission with the study drug” described in previous studies.16,39 In patients in whom other treatment medications for SRED/NES were added to ramelteon, the frequency of nighttime eating before the addition was used for the analysis. The Ethical Committee of the Neuropsychiatric Research Institute approved this study protocol.
Statistical analyses
The frequency of nighttime eating behavior was compared between baseline and post-ramelteon treatment using Mann-Whitney U tests. Demographic variables (age, sex, and body mass index), length of disease morbidity, dietary restrictions (yes/no), childhood history of somnambulism (yes/no), possibly BZD-related (yes/no), coexisting sleep disorders (DSWPD [yes/no], CRSWDs other than DSWPD [yes/no], and other sleep disorders [yes/no]), coexisting mental disorders (yes/no), use of other treatment medication for SRED/NES (yes/no), and habitual sleep schedules (sleep-onset time, waking up time, and the midpoint between sleep onset and waking time [sleep midpoint]) at baseline and after ramelteon treatment were compared between the responder and nonresponder groups using chi-square tests for categorical variables and Mann-Whitney U tests for continuous variables. In patients with possible BZD-related SRED/NES, the BZD doses before and after ramelteon treatment were compared using Mann-Whitney U tests. To assess the sleep-wake rhythms in patients with SRED/NES with DSWPD, the differences in habitual sleep schedules between baseline and post-ramelteon treatment and between the responder and nonresponder groups were also compared using Mann-Whitney U tests. Statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS, version 22.0J; SPSS Inc., Tokyo, Japan), and the significance level was set at a 2-tailed α-level of 5%.
RESULTS
Seventy consecutive patients were treated with ramelteon for SRED/NES during the study period. After excluding 9 patients who had already received ramelteon before their diagnosis, 11 patients whose nighttime eating frequency before or during ramelteon treatment could not be determined, and 1 patient who received ramelteon concurrently with topiramate, 49 patients were included in the subsequent analyses. Forty-five patients met the diagnostic criteria for SRED,3 41 met the diagnostic criteria for NES,4 and 37 met the criteria for both. Forty-two patients underwent nocturnal polysomnography, and their polysomnographic diagnoses supported the presence of their coexisting sleep disorders. All patients had an apnea-hypopnea index of less than 30 events/h and a periodic limb movement index of less than 30. Of the 49 patients, 28 (57.1%) were female. The patients’ mean age (standard deviation [SD]) was 36.2 (8.3) years, with a mean body mass index (SD) of 24.0 (4.8) kg/m2, and a mean duration of SRED/NES morbidity (SD) of 6.7 (5.7) years. Comorbid psychiatric disorders were present in 13 patients, but no patients had an eating disorder, including anorexia nervosa and bulimia nervosa, or a history of alcohol or other substance use disorders. Four patients had restless legs syndrome; however, symptoms were mild in all patients and none of them received medication for restless legs syndrome symptoms. Twenty-one patients (42.9%) were judged as having possible BZD-related SRED/NES. The BZDs used by patients with SRED/NES in this study included brotizolam (n = 1), clonazepam (n = 3), eszopiclone (n = 3), etizolam (n = 1), flunitrazepam (n = 8), loflazepate (n = 3), triazolam (n = 3), zolpidem (n = 6), and zopiclone (n = 2). Other concurrent treatment medications for SRED/NES, including SSRIs and topiramate, were used in 13 patients (sertraline for 7 patients, escitalopram for 3 patients, and topiramate for 5 patients). The dose of ramelteon was 4 mg/d or less in 35 patients and 8 mg/d in 14 patients. The mean (SD) duration of ramelteon treatment was 11.7 (13.8) months (range: 1–67 months). Adverse events, which were mild daytime somnolence in all patients, were observed in 5 patients, all of whom discontinued ramelteon due to this adverse event and a lack of efficacy. No patients had a clear exacerbation of insomnia after ramelteon administration. The demographic and clinical features, coexisting sleep disorders (including CRSWDs), coexisting mental disorders, concomitant medications, treatment outcomes, and adverse events are shown in Table 1. Overall, there was no significant difference in habitual sleep schedules between baseline and post-ramelteon treatment (Table S1 (13KB, pdf) in the supplemental material).
Table 1.
Demographic and clinical data of patients with SRED/NES treated with ramelteon (n = 49).
| Values | |
|---|---|
| Age at the investigation, mean ± SD (range), y | 36.2 ± 8.3 (23–59) |
| Female, n (%) | 28 (57.1) |
| Body mass index, mean ± SD (range), kg/m2 | 24.0 ± 4.8 (17.2–41.2) |
| Length of disease morbidity, mean ± SD (range), y | 6.7 ± 5.7 (0–23) |
| Habitual alcohol consumption, n (%) | 5 (10.2) |
| Habitual smoking, n (%) | 19 (38.8) |
| Morning anorexia, n (%) | 41 (83.7) |
| Dietary restrictions, n (%) | 8 (16.3) |
| Childhood history of somnambulism, n (%) | 10 (20.4) |
| Possibly BZD-related, n (%) | 21 (42.9) |
| Coexisting CRSWDs, n (%) | |
| DSWPD | 15 (30.6) |
| Shift-work disorder | 3 (6.1) |
| Non–24-hour sleep-wake disorder | 1 (2.0) |
| Coexisting other sleep disorders, n (%) | |
| OSA | 6 (12.2) |
| RLS | 4 (8.2) |
| PLMD | 1 (2.0) |
| Coexisting mental disorders, n (%) | |
| Major depressive disorder | 8 (16.3) |
| Bipolar disorder | 3 (6.1) |
| Schizophrenia | 1 (2.0) |
| Panic disorder | 1 (2.0) |
| Concomitant medication for SRED/NES, n (%) | |
| SSRIs | 10 (20.4) |
| Topiramate | 5 (10.2) |
| Any of the above | 13 (26.5) |
| Dose of ramelteon (per d), n (%) | |
| ≤ 4 mg | 35 (71.4) |
| 8 mg | 14 (28.6) |
| Duration of ramelteon treatment, mean ± SD (range), mo | 11.7 ± 13.8 (1–67) |
| Responder,a n (%) | 21 (42.9) |
| Adverse events | |
| Daytime somnolence, n (%) | 5 (10.2) |
| Habitual sleep schedules at baseline, mean ± SD (range),b h:min | |
| Sleep-onset time | 0:50 ± 1:28 (22:00–5:30) |
| Waking-up time | 7:07 ± 1:52 (4:00–15:00) |
| Sleep midpoint | 3:58 ± 1:33 (2:00–10:15) |
| Habitual sleep schedules after ramelteon treatment, mean ± SD (range),b h:min | |
| Sleep-onset time | 0:35 ± 1:31 (22:00–6:30) |
| Waking-up time | 7:21 ± 1:43 (5:00–15:00) |
| Sleep midpoint | 3:58 ± 1:33 (2:00–10:45) |
aDefined as participants in whom the frequency of sleep-related eating became < 50% after ramelteon treatment. bFour patients who were not on a fixed sleep schedule (3 with shift-work disorder and 1 with non–24-hour sleep-wake disorder) were excluded from the analysis. BZD = benzodiazepine derivatives and Z-drugs, CRSWD = circadian rhythm sleep-wake disorder, DSWPD = delayed sleep-wake phase disorder, NES = night eating syndrome, OSA = obstructive sleep apnea, PLMD = periodic limb movement disorder, RLS = restless legs syndrome, SD = standard deviation, SRED = sleep-related eating disorder, SSRI = selective serotonin reuptake inhibitor.
The mean (SD) frequency of eating behavior per week significantly decreased from baseline to post-ramelteon treatment: 5.3 (2.2) and 3.2 (3.0), respectively (P < .001). SRED disappeared in 18 out of the 45 patients with SRED, including 5 in the nonresponder group. However, 2 patients with SRED developed night eating episodes without amnesia that did not exist at baseline, while no patients in the non-SRED group exhibited new SRED episodes after ramelteon administration. Among the 49 patients, 21 were categorized as responders and 28 as nonresponders. Of the 13 patients who did not respond to the other medication, including SSRIs and topiramates, 5 (38.4%) responded to ramelteon treatment. Of the 6 patients who had used zolpidem, all 4 patients who discontinued zolpidem after receiving ramelteon were categorized as responders. There were significantly more individuals with possible BZD-related SRED/NES in the responder group (15 out of 21, 71.4%) than in the nonresponder group (6 out of 28, 21.4%) (P < .001). Also, there were significantly more individuals with coexisting DSWPD in the responder group (10 out of 21, 47.6%) than in the nonresponder group (5 out of 28, 17.9%) (P < .05). Within the responder group, the waking-up time after ramelteon treatment was significantly latercompared with baseline, with a mean (SD) of 7:34 (0:56) vs 7:10 (2:12) hours:minutes, respectively (P < .05; Table 2). Age, sex, body mass index, length of disease morbidity, the presence of dietary restrictions, a history of somnambulism in one’s childhood, coexisting CRSWDs other than DSWPD, other coexisting sleep disorders (including obstructive sleep apnea, restless legs syndrome, and periodic limb movement disorder), coexisting mental disorders, habitual sleep schedules at baseline, and sleep-onset time or sleep midpoint after ramelteon treatment were not significantly different between the 2 groups (Table 2).
Table 2.
Patient characteristics: responder vs nonresponder groups (n = 49).
| Respondera (n = 21) | Nonresponder (n = 28) | Pb | |
|---|---|---|---|
| Age at the time of investigation, mean ± SD, y | 38.1 ± 9.3 | 34.8 ± 7.4 | .188 |
| Female, n (%) | 11 (52.4) | 17 (60.7) | .560 |
| Body mass index, mean ± SD, kg/m2 | 25.4 ± 5.3 | 22.9 ± 4.1 | .079 |
| Length of disease morbidity, mean ± SD, y | 7.6 ± 6.6 | 5.9 ± 4.9 | .489 |
| Dietary restriction, n (%) | 2 (9.5) | 6 (21.4) | .265 |
| Childhood history of somnambulism, n (%) | 5 (23.8) | 5 (17.9) | .609 |
| Possibly BZD-related, n (%) | 15 (71.4) | 6 (21.4) | < .001 |
| Coexisting CRSWDs, n (%) | |||
| DSWPD | 10 (47.6) | 5 (17.9) | .025 |
| CRSWDs other than DSWPDc | 0 (0.0) | 4 (14.3) | .071 |
| Coexisting sleep disorders,d n (%) | 6 (28.6) | 5 (17.9) | .374 |
| Coexisting mental disorders,e n (%) | 8 (38.1) | 5 (17.9) | .112 |
| Concomitant medication for SRED/NES,f n (%) | 5 (23.8) | 8 (28.6) | .709 |
| Habitual sleep schedules at baseline, mean ± SD, h:min | |||
| Sleep-onset time | 0:54 ± 1:21 | 0:46 ± 1:35g | .400 |
| Waking-up time | 7:11 ± 1:23 | 7:03 ± 2:14g | .161 |
| Sleep midpoint | 4:03 ± 1:09 | 3:54 ± 1:51g | .249 |
| Habitual sleep schedules after ramelteon treatment, mean ± SD, h:min | |||
| Sleep-onset time | 0:24 ± 1:11 | 0:44 ± 1:46g | .917 |
| Waking-up time | 7:34 ± 0:56 | 7:10 ± 2:12g | .027 |
| Sleep midpoint | 3:59 ± 0:57 | 3:57 ± 1:57g | .268 |
aDefined as participants in whom the frequency of sleep-related eating became < 50% after ramelteon treatment. bChi-square test (categorical variables) or Mann-Whitney U test (continuous variables). cIncluding shift-work disorder (n = 3) and non–24-hour sleep-wake disorder (n = 1). dIncluding OSA (n = 6), RLS (n = 4), and PLMD (n = 1). eIncluding major depressive disorder (n = 8), bipolar disorder (n = 3), schizophrenia (n = 1), and panic disorder (n = 1). fIncluding sertraline (n = 7), escitalopram (n = 3), and topiramate (n = 5). gFour patients who were not on a fixed sleep schedule (3 with shift-work disorder and 1 with non–24-hour sleep-wake disorder) were excluded from the analysis. BZD = benzodiazepine derivatives and Z-drugs, CRSWD = circadian rhythm sleep-wake disorder, DSWPD = delayed sleep-wake phase disorder, NES = night eating syndrome, OSA = obstructive sleep apnea, PLMD = periodic limb movement disorder, RLS = restless legs syndrome, SD = standard deviation, SRED = sleep-related eating disorder, SSRI = selective serotonin reuptake inhibitor.
BZD doses before and after ramelteon administration in patients with possible BZD-related SRED/NES are shown in Figure 1. Within the responder group, the mean (SD) BZD dose was significantly higher at baseline than post-ramelteon treatment: 9.7 (5.7) mg and 3.9 (4.9) mg, respectively (P < .01). Within the nonresponder group, the mean (SD) BZD dose at baseline and post-ramelteon treatment was 12.8 (13.7) mg and 7.8 (6.1) mg, respectively, with no significant difference between groups (P > .05). Of the 15 patients who had coexisting DSWPD, 10 patients, including 7 responders, were identified as having possible BZD-related SRED/NES. In these patients, the mean (SD) BZD dose tended to be higher at baseline than post-ramelteon treatment—9.3 (6.5) mg and 6.1 (6.3) mg, respectively—but this difference was not significant (P > .05). Of the 13 patients who did not respond to other medications, including SSRIs and topiramate, 6 (including 4 responders) were identified as having possible BZD-related SRED/NES. In these patients, the mean (SD) BZD dose was higher at baseline than post-ramelteon treatment—12.9 (13.5) mg and 3.8 (3.9) mg, respectively—but this difference was also not significant (P > .05). Of the 18 patients with SRED whose night eating behavior with amnesia disappeared after treatment with ramelteon, 13 were identified as having possible BZD-related SRED. Among these patients, the mean (SD) BZD dose was significantly higher at baseline than post-ramelteon treatment: 12.7 (10.1) mg and 4.1 (4.9) mg, respectively (P < .01). All 5 patients who discontinued BZDs were categorized as responders, but 1 patient still occasionally had SRED symptoms after the intervention.
Figure 1. Doses of BZDs in patients with possible BZD-related sleep-related eating disorder/night eating syndrome.
The mean (SD) dose at baseline and post-ramelteon treatment in the responder group was 9.7 (5.7) mg and 3.9 (4.9) mg, respectively. The mean (SD) dose in the nonresponder group was 12.8 (13.7) mg and 7.8 (6.1) mg, respectively. *Mann-Whitney U test. BZD = benzodiazepine derivatives and Z-drugs, SD = standard deviation.
The distribution of ramelteon treatment responders/nonresponders in the possible BZD-related SRED/NES group and non–BZD-related group is shown in Table S2 (13KB, pdf) in the supplemental material. Among patients with possible BZD-related SRED/NES and DSWPD (n = 10), 7 patients (70%) responded to ramelteon treatment. Even in patients with non–BZD-related SRED/NES and DSWPD (n = 5), 3 patients (60%) responded to ramelteon treatment. As for the sleep-wake schedule of patients with SRED/NES and DSWPD, there was a significant difference in sleep-onset time between baseline and post-ramelteon treatment within the responder group (mean [SD] value of 2:00 [0:32] and 1:09 [0:53] hours:minutes, respectively; P < .05), but not in waking-up time or the midpoint. Within the nonresponder group, there was no significant difference in sleep-onset time, waking-up time, or sleep midpoint between baseline and post-ramelteon treatment (Table 3). Overall, sleep schedules appeared to be delayed in the nonresponse group compared with the response group, which suggested that DSWPD was more severe in the nonresponse group; however, the sleep-onset time, waking-up time, and sleep midpoint were not significantly different between the 2 groups (all, P > .05).
Table 3.
Habitual sleep schedules before and after ramelteon treatment in patients with SRED/NES and DSWPD.
| Respondera (n = 10) | Nonresponder (n = 5) | |||||
|---|---|---|---|---|---|---|
| Baseline | Post-Ramelteon Treatment | Pb | Baseline | Post-Ramelteon Treatment | Pb | |
| Sleep-onset time, mean ± SD, h:min | 2:00 ± 0:32 | 1:09 ± 0:53 | .015 | 2:54 ± 1:55 | 2:54 ± 2:38 | > .99 |
| Waking up time, mean ± SD, h:min | 7:57 ± 1:17 | 8:15 ± 0:51 | .631 | 9:48 ± 3:34 | 9:48 ± 3:34 | > .99 |
| Sleep midpoint, mean ± SD, h:min | 4:59 ± 0:45 | 4:42 ± 0:45 | .436 | 6:21 ± 2:42 | 6:21 ± 3:05 | > .99 |
aDefined as participants in whom the frequency of sleep-related eating became < 50% after ramelteon treatment. bMann-Whitney U test. DSWPD = delayed sleep-wake phase disorder, NES = night eating syndrome, SD = standard deviation, SRED = sleep-related eating disorder.
DISCUSSION
This is the first case series to report the outcome of treatment for SRED and NES with ramelteon and the subsequent reduction in BZD doses. In our study, there was a significant decrease in the self-reported nighttime eating behavior after administration of the ramelteon, and 21 of 49 patients (42.9%) were categorized as responders. Even in the 13 patients who did not respond to SSRIs or topiramate, 5 patients (38.4%) responded to the ramelteon treatment. Considering this, ramelteon treatment, together with a reduction in BZD dose, may be worth trying, even when other drugs are not sufficiently effective. Polypharmacy of psychotropic drugs has been reported to be associated with SRED in psychiatric outpatients37; however, our results could not clarify whether ramelteon was effective in patients with SRED/NES with comorbid psychiatric disorders who were on multiple psychotropic medications. Moreover, while it has been reported that other sleep disorders, such as obstructive sleep apnea, restless legs syndrome, and periodic limb movement disorder, can trigger SRED,1 the effect of ramelteon was less clear in the patients who were comorbid with these disorders in the present study. Mild daytime somnolence, observed in 5 patients (10.2%), was the only adverse effect of ramelteon. Thus, the use of ramelteon to treat SRED/NES is a relatively reasonable option given that topiramate is more likely to cause adverse effects, with more than 80% of patients experiencing them.17,18
We should also emphasize that there were larger number of patients with possible BZD-related SRED/NES in the responder group. Of note, in the responder group, the dose of BZDs was significantly reduced after the ramelteon treatment. The dose of BZDs was also significantly reduced in patients whose night eating behavior with amnesia disappeared after the treatment. There have been several reports of SRED being induced by BZDs, especially in the case of zolpidem.36,37,40 In the present study, all patients who were able to discontinue zolpidem showed a decrease in night eating behavior, which is consistent with the results of previous open-label trials.41 Meanwhile, our previous epidemiological study indicated that drug-induced SRED can also be induced by long-acting BZDs.36 That study also suggested that there is a possible association between BZD dose and SRED, which could explain the relationship between BZD dose reduction and the improvement in abnormal eating behavior in the present study. Given that we did not examine the severity of insomnia symptoms before and after the ramelteon treatment, it is not clear whether ramelteon contributed to the improvement in insomnia symptoms. However, ramelteon might help reduce the BZD dose without worsening insomnia symptoms, thereby contributing to the improvement in SRED/NES. Considering this, drugs other than ramelteon, such as orexin receptor antagonists, trazodone, and doxepin, all of which have sedative effects and few adverse effects of appetite stimulation,42 may also be effective treatments for SRED/NES as alternatives to BZDs. Indeed, a patient in whom trazodone was effective for SRED/NES has been previously reported.43 In addition, nonpharmacological interventions for insomnia, especially cognitive-behavioral therapy, which has been shown to be effective in reducing BZDs,44 might be effective for SRED/NES. The effects of these interventions on SRED/NES should be clarified in future prospective intervention trials.
Patients in this study had a relatively high rate (30.6%) of coexisting DSWPD. Interestingly, there were significantly more patients with comorbid DSWPD in the responder group than in the nonresponder group. This finding is in line with previous reports that chronobiological treatment was effective for the treatment of SRED and/or NES.24–26,28 However, for the patients with SRED/NES and DSWPD in this study, there was no significant treatment-related change in sleep midpoint; therefore, it is unlikely that the improvement in DSWPD secondarily led to the improvement in night eating behavior. Patients with SRED/NES with comorbid DSWPD in the present study mostly had severe difficulty falling asleep, which was associated with the disorder at the baseline. Nevertheless, our results failed to support the hypothesis that ramelteon improves SRED/NES through a normalization of sleep-wake rhythms.
There was no difference in sleep habits between the responder and nonresponder groups at baseline; however, waking time was significantly later in the responder group after ramelteon treatment compared with baseline. Moreover, for the patients with SRED/NES and DSWPD, a significant decrease in sleep-onset time after ramelteon treatment was observed in the responder group. These results could indicate that a prolongation of habitual sleep time contributes to the amelioration of SRED/NES symptoms. Given that nonrapid eye movement parasomnias are exacerbated by sleep deprivation,45,46 the extended sleep duration may be associated with symptom improvement. However, the association between short sleep duration and NES or SRED is still controversial19,47,48 and should be examined in future studies.
The current study has several limitations that should be considered. First, the amount of food intake after dinner (ie, evening hyperphagia) was not evaluated in the patients with NES in this study. Therefore, we might have overlooked some of the typical patients with NES. In addition, no severity scale, such as the Night Eating Questionnaire,49 was used, there was no assessment of calories ingested, and there were no pre– and post–body-weight assessments. Second, the participants in this study were from a single institution, and so the results cannot be generalized to all patients with SRED and/or NES. To address this, future prospective multicenter randomized controlled trials are needed. Third, there was a lack of information about clinical factors that could potentially affect SRED/NES, such as the precise amount of daily alcohol ingestion and the severity of daily psychological stress. In addition, the present study might not have adequately evaluated SRED/NES induced by transient dosing of BZDs. Furthermore, there is the possibility that we missed minor adverse events. Finally, the sleep-onset time and waking-up time were determined from medical records that were based on participants’ self-reports, and we did not measure objective circadian rhythm markers such as actigraphic findings or salivary melatonin secretion profiles. In addition, we did not assess sleep variables such as sleep latency or wake after sleep onset. Future studies should measure circadian markers and insomnia symptoms both objectively and using self-reported measures.
In conclusion, ramelteon is a possible candidate for the treatment of SRED/NES, especially when DSWPD co-occurs with it and/or BZDs are used. The present findings indicate that the use of ramelteon and the subsequent reduction in BZD dose may reduce nighttime eating behavior, even when the abnormal eating symptoms are refractory to other treatments. Given the possibility that a reduction in BZDs contributes to an improvement in night eating behavior, medications other than ramelteon and nonpharmacological therapies for insomnia should be considered for SRED/NES treatment. Future studies should examine whether the reduction in BZDs improves night eating behavior, and how BZDs can be reduced in patients with SRED/NES.
DISCLOSURE STATEMENT
All authors have read and approved this manuscript. Work for this study was performed at Japan Somnology Center. This study was supported by the JSPS KAKENHI Grant-in-Aid for Young Scientists (no. 19K17098). Kentaro Matsui has received speaker’s honoraria from Eisai, Meiji Seika Pharma, Mochida Pharmaceutical, MSD, Otsuka Pharmaceutical, and Yoshitomi Pharmaceutical. Kenichi Kuriyama has received speaker’s honoraria from Eisai, Eli Lilly, Janssen Pharma, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Tsumura, and Yoshitomi Pharmaceutical; he has received research/grant support from Eisai, Kao, Pfizer, PMC, Meiji Seika Pharma, MSD, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, and Takeda Pharmaceutical. Ken Inada has received speaker’s honoraria from Eisai, Eli Lilly, Janssen, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Mochida, MSD, Novartis, Otsuka, Shionogi, Sumitomo Dainippon Pharma, and Yoshitomiyakuhin; he has received research/grant support from Mitsubishi Tanabe Pharma and MSD. Katsuji Nishimura has received speaker’s honoraria from Chugai Pharmaceutical, Eisai, Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis, Otsuka Pharmaceutical, Shionogi, and Takeda Pharmaceutical; he has received research/grant support from Eisai, Mebix, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Tsumura. Yuichi Inoue has received speaker’s honoraria from Eisai and MSD; he has received research/grant support from Eisai, Koike Medical, and Philips Japan; and he has received funding for clinical trials from Idorsia Pharmaceuticals. Mina Kobayashi reports no conflicts of interest.
SUPPLEMENTARY MATERIAL
ACKNOWLEDGMENTS
The authors thank Nia Cason, PhD, from Edanz Group (https://en-author-services.edanz.com/ac), for editing a draft of this manuscript.
ABBREVIATIONS
- BZD
benzodiazepine derivatives and Z-drugs
- CRSWD
circadian rhythm sleep-wake disorder
- DSWPD
delayed sleep-wake phase disorder
- NES
night eating syndrome
- SD
standard deviation
- SRED
sleep-related eating disorder
- SSRI
selective serotonin reuptake inhibitor
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