Night Eating Syndrome - Springer Link

CNS Drugs 2005; 19 (12): 997-1008 1172-7047/05/0012-0997/$34.95/0

THERAPY IN PRACTICE

 2005 Adis Data Information BV. All rights reserved.

Night Eating Syndrome Diagnosis, Epidemiology and Management John P. O’Reardon,1 Andrew Peshek1 and Kelly C. Allison2 1 2

Division of Mood and Anxiety Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA Weight and Eating Disorders Program, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997 1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998 2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998 2.1 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999 3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000 4. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000 4.1 Recognition in the Clinical Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000 4.2 Rationale for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 4.3 Naturalistic Treatments in the Community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 4.4 Modulation of the Serotonin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002 4.4.1 Case Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002 4.4.2 Clinical Trial of Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003 4.4.3 Possible Therapeutic Mechanism of SSRIs in Night Eating Syndrome . . . . . . . . . . . . . . . . 1004 4.5 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005 4.6 Psychological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006 5. Medication Selection and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007

Abstract

Night eating syndrome (NES) is an eating disorder characterised by the clinical features of morning anorexia, evening hyperphagia, and insomnia with awakenings followed by nocturnal food ingestion. The core clinical feature appears to be a delay in the circadian timing of food intake. Energy intake is reduced in the first half of the day and greatly increased in the second half, such that sleep is disrupted in the service of food intake. The syndrome can be distinguished from bulimia nervosa and binge eating disorder by the lack of associated compensatory behaviours, the timing of food intake and the fact that the food ingestions are small, amounting to repeated snacks rather than true binges. NES also differs from sleep-related eating disorder by the presence of full awareness, as opposed to parasomnic nocturnal ingestions. NES is of importance clinically because of its association with obesity. Its prevalence rises with increasing weight, and about half of those diagnosed with it report a normal weight status before the onset of the syndrome. The recognition and effective treatment of NES may be an increasingly important way to treat a subset of the obese population. Treatment of the syndrome, however, is still in its infancy. One clinical trial has reported efficacy with the SSRI sertraline. Other

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treatments, such as the anticonvulsant topiramate, phototherapy and other SSRIs, may also offer future promise.

1. Background Night eating syndrome (NES) represents a novel eating disorder, which, despite its original description in the scientific literature 50 years ago,[1] is still little recognised or treated in the clinical setting. However, the rising importance of obesity as a public health problem in developed countries and the apparent links between NES and obesity, as described in this article, clearly warrant both greater clinical awareness of the syndrome and further research into its aetiology and possible treatment. 2. Diagnosis NES was first described in the 1950s among a subset of obese persons seeking weight loss treatment.[1,2] This original work noted that the subgroup with NES had little morning hunger, evening hyperphagia, and initial insomnia or difficulty falling asleep. It was also noted that these symptoms seemed to worsen with stress and were possibly alleviated with removal of the person from the stressful environment.[1] The presence of NES was predictive of a poor weight loss outcome in these early studies. Little attention was paid to NES in the research community until the advent of the obesity epidemic. Additionally, the lack of specific diagnostic criteria limited investigations. The original description of NES by Stunkard et al.[1] required ≥25% of the daily caloric intake occur after the evening meal, initial insomnia ≥50% of the time and morning anorexia. In 1996, Stunkard and colleagues revised the definition to require ≥50% of the daily caloric intake after 7pm, trouble getting to sleep or staying asleep, and morning anorexia.[3] Further criteria were added in 1999, as a result of sleep and food diary data reported in a controlled study,[4] namely: nighttime awakenings (≥1 episode per night), with full alertness and frequently accompanied by ingestion of snacks; the presence of symptoms for a duration of ≥3 months; and the absence of bulimia nervosa and binge eating disorder. Initial insomnia was not mentioned in this revision.[4] Distress has not been in 2005 Adis Data Information BV. All rights reserved.

cluded in any of the above diagnostic criteria, although the association between NES and stress and depressed mood has been described consistently.[1,2,4-8] Other studies have employed varying degrees of the core criteria: evening hyperphagia (including variation in its timing and the percentage of the daily caloric intake), nocturnal ingestions and morning anorexia (for review see de Zwaan et al.[5]). While there is not yet consensus on an absolute set of diagnostic criteria, the core feature that clearly emerges across all definitions is the delay in the circadian pattern of eating.[6] In the largest study to date of NES, we examined the patterns of food intake (using data derived from food diaries) and sleep (based on motion actigraphs worn by the subjects and diary records of the timing and duration of sleep) in overweight subjects with NES (n = 46) and an overweight control group (n = 43).[6] Timing of sleep onset, offset and total sleep duration (despite frequent awakenings in the NES group) did not differ significantly between the groups. Ignoring for a moment the effects of the awakenings on sleep continuity in the NES group, the basic sleep rhythm of the individuals with NES was identical to that of matched controls. In simple terms, they went to bed at night and got up in the morning at the same time as subjects in the control group, and their sleep duration was about the same. Similarly, the total caloric intake over a 24-hour period did not differ significantly between the groups (2314.4 ± 748 kcal vs 2420 ± 748 kcal), but the timing or distribution of food intake did. As indicated in figure 1, the energy intake in the NES group was lower during the first 8 hours (6am–2pm; p < 0.01), no different in the middle 8 hours (2pm–10pm) and higher in the final 8 hours (10pm–6am; p < 0.01) compared with the control group. In essence, the timing of the sleep rhythm (despite the disruption of awakenings) appears preserved in NES, whereas the timing of food intake is delayed. NES may be an important clinical example, CNS Drugs 2005; 19 (12)

Night Eating Syndrome

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1400

NES group Control group

Caloric intake (kcal)

1200

*

1000 800 600 400 200

*

0 6am−2pm

2pm−10pm

10pm−6am

Time Fig. 1. Caloric intake in 8-hour increments in overweight patients with (n = 46) and without (n = 43) night eating syndrome (NES).[6] Note that food intake was lower during the first part of the day and higher during the night in the NES group compared with the control group (reproduced from O’Reardon et al.,[6] with permission). * = p < 0.01.

possibly the first in humans, of a dissociation of the rhythms of eating and sleeping. Associated features of NES include significant co-morbid psychopathology and links with stress. Depressed mood is a frequent finding in NES in several studies.[4,7,9,10] The pattern of depressed mood in NES may also be distinct in some individuals, with mood falling in the evening and throughout the nighttime (assessed through mood ratings made at each ingestion), the opposite pattern to that typically experienced in classic or melancholic depres-

sion. Those with NES also report significantly greater scores on the Beck Depression Inventory and Zung Depression Scale than controls.[6,7] Additionally, in obesity clinics, self-esteem is lower[7] and symptoms of anxiety are higher[8] among those with NES than in persons without NES. Finally, Birketvedt et al.[4] established a link between abnormal neuroendocrine patterns and NES. Serum cortisol level was elevated among individuals with NES, consistent with this being a stressrelated disorder. Additionally, the usual rises of both melatonin and leptin levels at night were blunted among those with NES, suggesting that these hormones were not serving their usual functions, at this time, of maintaining sleep and suppressing hunger, respectively. However, this study had a small sample size and a rigid specified eating schedule, which was not typical of the food intake of those with NES. More studies are needed to confirm these findings. 2.1 Differential Diagnosis

Not all patients who complain of nighttime eating are experiencing NES. Other possibilities to be considered include sleep-related eating disorder (SRED), other eating disorders, such as bulimia nervosa or binge eating disorder with symptoms manifesting at night, or simply a non-normative eating pattern. Table I highlights clinical features of NES that help to distinguish it from SRED and other eating disorders.

Table I. Clinical features that help distinguish night eating syndrome (NES) from the eating disorders, bulimia nervosa and binge eating disorder (BN/BED), and the parasomnia, sleep-related eating disorder (SRED) Clinical features

BN/BED

NES

SRED

Morning anorexia

Usually no

Yes

Yes

Evening hyperphagia

No

Yes

No

Daytime food cravings

Yes

Yes (evening only)

No

Binges

Yes

No (snacks)

No (bizarre food items)

Nocturnal ingestions

Rarely

Yes

Yes

Awareness of nocturnal eating episodes

Yes

Yes

Clouded

Amnesia for events

No

No

Yes

Polysomnographic study

Normal

Low sleep efficiency

Sleep disorder found (e.g. sleep apnoea, restless legs, sleep walking)

Treatment

CBT Sertraline SSRIs Other SSRIs (?) Topiramate Topiramate (?) CBT = cognitive behavioural therapy; ? indicates suggested.


Treat sleep disorder Dopamine agonists Topiramate

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At first glance, NES and SRED may seem similar, but there are important differences.[11-16] SRED often occurs alongside other sleep disorders, such as periodic leg movement disorder, restless legs syndrome and obstructive sleep apnoea, whereas NES does not. Unusual food combinations and non-food items are often consumed in SRED,[17] whereas in NES, regular food items, often those that are craved but not consumed during the day, are eaten. SRED is a parasomnia and is often regarded as an atypical form of sleepwalking, in which there is a lack of conscious awareness associated with episodes of nocturnal eating, although other sleep disorders such as obstructive sleep apnoea and restless legs syndrome and certain medications, such as zolpidem, are also known to promote SRED.[15] NES differs from bulimia nervosa and binge eating disorder because the food is not consumed in large quantities and there are typically no compensatory behaviours. In NES, the disorder lies more in the altered timing of the food intake and its disruption of normal sleep, than in the amount of food consumed at one sitting. Finally, food intake may occur at an unusual or unexpected time in some individuals without NES or an eating disorder. In this instance, food intake is not associated with distress and tends to be elective rather than compulsive. Eating behaviour in the evening and nighttime occurs on a spectrum, and for some individuals to eat late in the evening or even get up at night to eat may represent a subcultural or family variant. A study examining eating patterns in adolescent girls aged 9–19 years found that occasional episodes of night eating were common, but that multiple episodes in a single week were much rarer (by a factor of ten).[18] We have also observed clinically in patients with NES that the pattern may start out at a low level in response to some stressor, but then become entrenched and more clearly pathological over time. It should also be borne in mind that while night-shift workers are known to be at risk for weight gain, a diagnosis of NES is not indicated in this instance as the nocturnal eating is a situationbound or situation-specific behaviour.[19] 3. Epidemiology The prevalence of NES is estimated at 1.5% in the general population,[20] 6%[21] to 14%[7] in obesity  2005 Adis Data Information BV. All rights reserved.

O’Reardon et al.

clinics and 8%[22,23] to 42%[24] in pre-operative bariatric surgery patients in the US. Such a wide range of estimates is most certainly influenced by varying assessment methods (e.g. survey vs interview) and diagnostic criteria. However, in general, these results suggest that NES is more prevalent with increasing adiposity. Because NES occurs commonly among the obese and has been reported to interfere with weight loss attempts,[1,7] it may be a useful target for treatment in a subgroup of the overweight/obese population. NES has also been reported in 15% of persons seeking treatment for binge eating disorder.[3] NES also occurs in persons with normal weight (body mass index [BMI] = 18.5–25 kg/m2).[4,25] Marshall et al.[25] indicated that half of the overweight persons presenting with NES reported being normal weight before the onset of night eating, suggesting that NES may be a pathway to excess weight and obesity. NES appears to be more common in women than men, but it is not infrequent in men. In the largest study of NES to date, described in section 2,[6] 30% of the NES group were male. Additionally, Grilo and Masheb[26] reported that 8.8% of men and 9.2% of women with binge eating disorder experienced nocturnal ingestions at least half of the time, suggesting similar prevalence rates across genders. A recent study in two centres in the US (at the University of Minnesota and the University of Pennsylvania) reported quite a high prevalence rate of NES in a general outpatient psychiatric clinic population, with 16.5% meeting criteria based on questionnaire and interview data, thus further supporting the link between NES and psychiatric co-morbidity.[27] The average BMI in the NES-positive group was 33.0 (± 9.3) compared with 27.4 (± 6.9) in the psychiatric clinic outpatients without NES, suggesting that overweight and obese patients in that setting may be at quite a high risk of having NES. 4. Management 4.1 Recognition in the Clinical Setting

How should a clinician approach treatment of NES? The first practical step is to improve recognition of the syndrome. Due to a lack of physician CNS Drugs 2005; 19 (12)


awareness, combined with embarrassment or even shame on the part of the patient, NES is frequently a hidden diagnosis. As the prevalence of NES rises steadily with increasing weight it makes sense to question obese individuals about symptoms of night eating. Two simple screening questions can be quite effective in this regard (i) “Do you get up at night to eat?”; and (ii) “Are you troubled by overeating in the evening or at night?” It should be noted that these questions would also screen for SRED and followup questions regarding the level of alertness/awareness would be necessary in order to distinguish between the disorders. The Night Eating Questionnaire (NEQ)[25,28] is a sensitive screening measure that may also be helpful in detecting symptoms of the syndrome, and it should be followed by a clinical interview for confirmation of diagnosis.[29] Psychiatric clinic patients who are overweight or obese may also represent a population at risk for the syndrome (section 3).[27] 4.2 Rationale for Treatment

Individuals with the NES are clearly distressed by it and frequently seek help for the disorder from their physicians. Their distress appears to be a combination of dissatisfaction resulting from obesity and dysphoria from the perceived loss of control over eating in the late evening and night. Findings from Marshall et al.[25] suggest that obesity follows NES in about half of the patients presenting for treatment, although no causal studies have been reported. Aranoff et al.[30] have also suggested that the displaced circadian rhythm of eating and preference for energy-dense foods at night may contribute to obesity. Some individuals with NES view their nocturnal eating in particular as shameful and will attempt to conceal it from friends and family members. Others are distressed by the sleep disturbance and the associated fatigue and the feeling of sleep deprivation during the following day. Finally, about 70% of those diagnosed with NES in our study cohort[6] reported some significant degree of depressed mood, sometimes accompanied by a diurnal swing with worsening in the evening. Currently, there is very little guidance from the literature as to the most appropriate treatment of NES, as research on treatment is very much in its  2005 Adis Data Information BV. All rights reserved.

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infancy. No placebo-controlled studies have been published, and there has only been one open-label, unblinded clinical trial.[9] Nevertheless, the prevalence of the syndrome, with its associated distress and links to obesity, warrants careful evaluation of potential treatment strategies. 4.3 Naturalistic Treatments in the Community

Currently, most physicians are unaware of the possibility of NES as a diagnostic entity, and not surprisingly patients with NES report largely mixed results from their attempts at treatment in the community. We collected reports on previous attempts at treatment in the community in the Philadelphia area from 23 subjects prior to their entry into an NES treatment trial.[9] These data are of interest primarily because they indicate what treatments patients with NES are likely to undertake in the community setting. As indicated in table II, there had been a total of 83 medication exposures (3.6 per patient). Perhaps reflecting a lack of physician recognition of the syndrome, the most common type of medication class utilised was over-the-counter herbal or natural remedies (30 exposures). No herbal remedy was reported to be very effective (table II). There is a suggestion that kavain yielded benefit when used, but the number of exposures (three) was very small (table II). On the other hand, melatonin, which was by far the most common natural agent tried (15 of 30 total exposures), did not appear to work adequately when used in an over-the-counter formulation (table II). In the absence of an adequate clinical trial, it is impossible to know whether this might be due to low bioavailability of the over-the-counter formulations of melatonin used or, alternatively, that melatonin may not be as effective as might have been expected (i.e. as a consequence of low levels of nocturnal melatonin secretion in patients with NES[4]). The other class of medications used frequently by patients in the community was antidepressants (25 exposures), but with no clear benefit. Hypnosedatives were also reported to be of no benefit, implying that NES is not simply an issue of a sleep disruption, but is more accurately construed as an eating disorder that partially manifests itself at night. Overall, attempts at treatment in the community were disappointing for the large majority of patients CNS Drugs 2005; 19 (12)

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Table II. Treatment of night eating syndrome in the community setting. Medication exposures and outcomes in 23a patients prior to receiving sertraline in a clinical trial (reproduced from O’Reardon et al.,[9] with permission) Medication

Antidepressants (total)

Total

Outcome (no. of exposures)

medication exposures

moderately effective

no change in night eating symptoms

25

2

23

21

2

19

Venlafaxine

1

0

1

Nefazodone

1

0

1

Buproprion

2

0

2

16

0

16 13

SSRIsb

Hypnosedatives (total) Zolpidem

13

0

Diphenhydramine

3

0

3

Anorectics (total)

8

4

4

Sibutramine

3

0

3

Fenfluramine/phentermine

4

4

0

Dexamfetamine Herbal medicines (total) Melatonin

1

0

1

30

7

23

15

2

13

Valerian root

3

2

1

Kavain

3

3

0

St. John’s Wort

4

0

4

Tryptophan

3

0

3

Ephedrine

1

0

1

Pyrrolizidine alkaloids

1

0

1 3

Others (total)

4

1

Antipsychotics

2

0

2

Benzodiazepines

2

1

1

83

14

69

Total reports a

Forty-six patients completed an initial structured interview; however, 23 patients did not report taking any medication and are thus excluded from the table.

b

Includes nine exposures to sertraline.

with NES, with only 17% of medication exposures (14 of 83) resulting in some reduction of NES symptoms. However, our population sample was drawn from individuals undergoing assessment and characterisation of their NES, with the possibility of subsequent participation in a trial of sertraline therapy. Thus, this sample might under-represent those individuals who did, in fact, obtain a satisfactory response to treatment with medication in the community. 4.4 Modulation of the Serotonin System 4.4.1 Case Reports

A number of NES case reports and series have been published, which, while inconclusive by their nature, nevertheless suggest potential therapeutic  2005 Adis Data Information BV. All rights reserved.

mechanisms and may be pointers for future clinical trials. In one case series of seven patients, benefit was reported after treatment with dexfenfluramine, a serotonin releaser.[31] In a single case, remission of NES symptoms was reported in a 51-year-old obese female, also experiencing non-seasonal, recurrent, major depressive disorder, following 14 sessions of phototherapy.[32] NES returned with the cessation of treatment, while her depression remained in remission. Phototherapy is also known to be of benefit in the treatment of seasonal affective disorder (SAD). In SAD, studies have been performed using a research paradigm called tryptophan depletion, which is a research method in which the ingestion of an amino acid drink causes an acute depletion of serotonin stores in the brain. Tryptophan depletion reCNS Drugs 2005; 19 (12)


sults in a return of symptoms for patients with SAD who have responded to phototherapy. This implies that the therapeutic effects of phototherapy on mood, in terms of underlying neurobiology, rest, at least in part, on augmenting the serotonin system centrally.[33] Thus, both of the abovementioned reports in patients with NES[31,32] suggest that the serotonergic system in the CNS can be beneficially modulated in NES. A recent case series from Japanese investigators further suggests that serotonin mechanisms may be important in the treatment of NES.[34] In this study, four female subjects with complaints of nocturnal eating were assessed. One subject had a diagnosis of bipolar disorder preceding the onset of NES and was taking lithium (200–400 mg/day), whereas the others did not have any concomitant psychiatric disorders. All were evaluated medically at baseline and had normal laboratory, brain magnetic resonance imaging and EEG studies. Three of the four subjects had an overnight polysomnogram, during which night eating episodes were observed following awakening from non-rapid eye movement (NREM) sleep. All were described as fully aware during their nocturnal eating and had no subsequent amnesia of their behaviour. This is of importance clinically, as it helps to distinguish NES from SRED. The most striking feature in these four cases was the unusually rapid response to SSRI medications. Three of the subjects responded robustly to paroxetine (20–40 mg/day) with resolution of NES symptoms within 2 weeks. The fourth subject had a similar response to a low dosage of another SSRI fluvoxamine (25 mg/day) within 3 weeks. When SSRIs are used to treat other psychiatric disorders, in both clinical trials and routine clinical practice, the onset of effect may be expected to commence by 2 weeks, but it is rare to see a full remission of symptoms in that time frame. 4.4.2 Clinical Trial of Sertraline

A clinical trial with the SSRI sertraline in a sample of 17 obese individuals with NES has recently been reported from the University of Pennsylvania.[9] An SSRI medication was selected for the trial based on evidence of SSRI efficacy in reducing compulsive eating in binge eating disorder.[35] The subjects were all obese (BMI >27 kg/m2) and in 2005 Adis Data Information BV. All rights reserved.

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cluded 12 women (aged 46 ± 9.0 years; BMI = 39.3 ± 5.9 kg/m2) and five men (aged 50 ± 5.6 years; BMI = 31.6 ± 5.5 kg/m2) who met NES criteria following a semi-structured diagnostic interview and review of symptoms reported on the Night Eating Questionnaire.[25] Subjects with a lifetime diagnosis of psychosis or bipolar disorder were excluded, as were those who had a current major depressive disorder judged to be severe based on criteria in the Structured Clinical Interview for the DSM-IV. Existing psychotropic medication was washed out prior to study entry, and no psychotropic medication, other than sertraline, was allowed during the 12-week trial. Sertraline was titrated, as required, during the biweekly visits to a maximum dosage of 200mg daily. The mean final dosage was 188mg daily. Twelve patients completed the study. As depicted in figure 2, highly significant (p < 0.01) improvements in NES outcome measures from baseline to study end were observed in the intent-to-treat population (n = 17). The rate of awakenings (with getting up out of bed) decreased from two per night per patient at baseline to 0.8 per night after 12 weeks’ treatment with sertraline. The rate of nocturnal ingestions de-

60

51.4

Baseline Week 12

50 40

* 25.7

30 20 10

14.3 * 5.9

10.8 * 3.7

* 4 2.6

0 Awakenings (no. per wk)

Nocturnal Caloric intake ingestions after evening meal (no. per wk) (% of total daily kcal)

CGI-I score

Fig. 2. Primary outcome measures for the intent-to-treat population (n = 17) in a clinical trial[9] of sertraline in patients with night eating syndrome (reproduced from O’Reardon et al.,[9] with permission). Results are expressed as mean values ± standard error. Awakenings refers to where subject woke up and got out of bed. CGI-I = Clinical Global Impression of Improvement scale; * = p < 0.01 vs baseline.

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creased by two-thirds from 1.5 to 0.5 per night. Selfreported caloric intake after the evening meal decreased by about half from 51.4% to 25.7% of daily caloric intake. About half of the intent-to-treat population (8 of 17) and 67% (8 of 12) of those who completed the study responded to treatment (score ≤2), as measured by the Clinical Global Impression of Improvement (CGI-I) scale, a measure of global and categorical outcome. Five patients (29%) entered remission with sertraline therapy. Of particular note in the subgroup with the most robust response, namely those achieving remission, was the finding of a significant decrease in weight over the course of the study (–4.8 ± 2.6kg, p < 0.05). If patients whose symptoms remitted while receiving sertraline were excluded, the remainder of the sample (n = 12) did not lose weight, but rather had a modest gain (+0.6 ± 5.4kg). The modest weight loss detected in some patients in this study suggests that successful treatment of NES might contribute to the control of associated obesity. Weight loss, however, occurred only in a minority of the full sample, although it is often the primary reason for obese patients with NES to seek treatment, rather than sleep or mood disturbance. This suggests that behavioural weight reduction measures may be an important adjunct therapy for the majority of patients with NES seeking treatment for associated obesity. Average cumulative caloric intake curves over 24-hour periods are illustrated in figure 3 for three groups of subjects: (i) the NES study sample (n = 17) at baseline; (ii) subsequent responders to sertraline (n = 8) at week 12; and (iii) an obese control group (n = 34). The latter group was drawn from a separate outpatient characterisation study comparing the pattern of food intake, as recorded in food diaries over a 1-week period, in obese controls versus obese patients with NES.[6] The NES group’s cumulative caloric curve prior to treatment differs from that of the obese control group in two principal respects: (i) cumulative caloric intake in patients with NES is lower throughout the day and lacks the distinct midday and evening inflections found in the control group (figure 3). These upward inflections are reflective of the more regular meal pattern in the control subjects; and (ii) the control group manifests an evening plateau in food intake seen after 8pm,  2005 Adis Data Information BV. All rights reserved.

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whereas patients with NES continue food intake into the evening and night and eventually marginally exceed the total caloric intake of the control group (figure 3). The cumulative caloric intake curve of the responder subgroup is more like that of the control group, with the emergence of a plateau from 8pm onwards as evening and nocturnal hyperphagia diminish (figure 3). 4.4.3 Possible Therapeutic Mechanism of SSRIs in Night Eating Syndrome

Both the clinical trial of sertraline[9] (section 4.4.2) and the case series from Japan[34] (section 4.4.1) suggest a benefit from SSRIs in the treatment of NES. At this juncture, in the absence of controlled studies, the possibility that the response to SSRIs observed might simply be a placebo effect cannot be ruled out. However, a purely placebo-type response as an explanation for the results observed appears unlikely. First, there appears to be a low rate of spontaneous remission of the syndrome. Only one patient in the clinical trial (2% of the screened sample) went into remission between the time of the initial telephone screen and entry into the study,[9] suggesting a low susceptibility to placebo effects. In addition, many of the patients with NES had previously tried medications in the community without observed benefit. There is also reason to believe that the therapeutic benefits of sertraline are not due to an antidepressant effect on the concomitant depressed mood frequently found in patients with NES. Patients were excluded from this study if they were severely depressed at the initial assessment, and the overall level of depression in the sample was fairly mild, with a baseline score of 12 points (± 4.6) on the 17-item Hamilton Depression Rating Scale. In all, only 3 of 17 patients (18%) met criteria for current major depressive episodes, which were mild in severity.[9] Furthermore, only a small and non-significant correlation was found between the change in the global measure of improvement of NES (CGI-I score) and the change in depressive symptoms (r = 0.3, p = 0.4).[9] Therefore, it appears that something other than an antidepressant mechanism must be related to the effects of sertraline. The observation of a fast therapeutic effect with paroxetine and fluvoxamine in the case series described in section 4.4.1[34] is also sugCNS Drugs 2005; 19 (12)


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gestive, with all of the patients achieving full remission of NES symptoms within 3 weeks. Rapid therapeutic effects of this magnitude are usually not expected with SSRI medication, but, interestingly, are reported in the treatment of premenstrual dysphoric disorder (PMDD).[36] In PMDD, starting the administration of fluoxetine or sertraline from the midpoint of the menstrual cycle (so called intermittent dosing) has been shown to be effective in curbing the premenstrual symptoms that emerge within a few days of entry into the luteal phase of the cycle. Somewhat similar to NES, food cravings may also be present in PMDD, but, unlike NES, they are luteal-phase bound, and there does not appear to be a shift in the timing of the food intake rhythm into the evening or night. In NES, we suspect that sertraline is having some direct effect on the control of the circadian rhythm of food intake. The key clinical feature of NES appears to be a phase delay in the timing of food intake. Ordinarily, the circadian rhythms of eating and sleep are synchronised with each other in humans, so that food intake does not occur nocturnally. The synchronisation of these rhythms is performed by a central pacemaker in the suprachiasmatic nucleus of the hypothalamus.[37] The suprachiasmatic nucleus is known to receive serotonergic input from the cell bodies of the dorsal raphe nuclei of the brain stem, the main source of

serotonin neurons in the CNS.[37] Serotonergic effects at the serotonin 5-HT1A receptor appear to have a role in the entrainment of circadian rhythms in animals.[37] It is possible that sertraline, and other SSRIs, may be of benefit in the treatment of NES by promoting the entrainment of a more normal circadian rhythm of food intake through effects on the suprachiasmatic nucleus. 4.5 Topiramate

A potentially distinct pharmacological approach to treating NES is the use of the anticonvulsant topiramate. This agent is a monosaccharide compound that inhibits the activity of certain carbonic anhydrase isoenzymes, blocks voltage-dependent sodium channels and has a stimulatory effect at the GABAA receptor. The rationale for the use of topiramate as a putative agent to treat NES symptoms is derived from observations concerning its adverse event profile in trials conducted in patients with seizure disorders. For instance, there appears to be high somnolence rate (28%) at dosages of 200–400mg daily, which in the setting of NES might serve to promote sleep.[38] Also, topiramate has already demonstrated efficacy in two placebo-controlled trials in binge eating disorder where it robustly reduced the frequency of binges.[39,40] It may, therefore, also have the potential to suppress the food cravings that occur in NES. Control subjects NES patients at baseline NES responders to sertraline at week 12

Mean cumulative caloric intake (kcal)

3000 2500 2000 1500 1000 500 0 6am

8am 10am 12pm 2pm

4pm

6pm

8pm 10pm 12am 2am 4am

Time Fig. 3. Mean cumulative caloric intake over 24 hours in patients with night eating syndrome (NES) in a 12-week clinical study of sertraline therapy.[9] Results are shown for all patients (n = 17) at baseline, patients whose symptoms had responded to sertraline by week 12 (n = 8) and obese control subjects (n = 34) [baseline results from another study[6]] (reproduced from O’Reardon et al.,[9] with permission).


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In this regard, topiramate was reported to be useful in NES in a small case series (n = 4, two subjects with NES, two subjects with SRED).[41] Treatment with topiramate was very effective for the two patients with NES at fairly low dosages of 100–125mg daily. One of the patients with SRED also responded, and, overall, a substantial weight loss in the four patients occurred (mean weight loss of 11.1kg; range 6.8–15.0kg) with a decrease in BMI from 30.0 at baseline to 26.1 over a period of 6–12 months. 4.6 Psychological Interventions

Psychological approaches may be of benefit in NES and may be appropriate as a first-line option for some patients before proceeding to medication options. A recent study reported short-term benefits from a 20-minute progressive muscle relaxation intervention when compared with a control condition (sitting quietly for the same amount of time).[42] The experimental group received a single session of training in progressive muscular relaxation and then applied the technique daily for 1 week. At follow up 1 week later, the treatment group, but not the control group, had significant improvements in anxiety and stress levels as well as higher levels of hunger in the morning and lower levels of hunger in the evening (p < 0.05). A trend in favour of less nocturnal ingestions and increased food intake in the morning was noted. However, this study extended over only 1 week and further studies are needed to see if these reported benefits are sustained beyond the very short term. The benefit observed with an anxiety reduction technique is supportive of the concept that NES appears to be a stress disorder and thus susceptible to interventions that might reduce the impact of stress psychologically. Similarly, sertraline has a strong empirical database supporting efficacy in several anxiety disorders, including obsessive-compulsive disorder, panic disorder, social anxiety disorder and post-traumatic stress disorder. Thus, it could be argued that the effect of sertraline observed in the clinical trial[9] discussed in section 4.4.2 might at least be partially related to an anxiety-reducing mechanism. In the future, it is likely that psychological approaches, such as cognitive behavioural therapy,  2005 Adis Data Information BV. All rights reserved.

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which are effective in other eating disorders, will be adapted to NES. In the interim, either self-help or formal methods directed at stress management and reduction may be of some benefit in some patients. 5. Medication Selection and Administration At this early stage of research, no definite conclusions can be drawn regarding the efficacy of any of the medications reviewed above. Based on findings from a single open label trial[9] (section 4.4.2) and a single case series[34] (section 4.4.1), there is some evidence in favour of SSRI medications, specifically sertraline and paroxetine. This benefit appears to be independent of any effects on concomitant depressed mood. The effective dosage of these SSRIs appears to be in the typical range (paroxetine 10–30 mg/day; sertraline 50–200 mg/day). Some patients with NES appear to experience a fast therapeutic result in response to an SSRI, but this does not appear to be always the case.[34] Some patients with NES will need a full 8–12 weeks’ trial of an SSRI before the outcome can be judged accurately. For those who experience remission of NES symptoms in response to sertraline (and possibly other SSRIs), there may be positive effects in terms of controlling weight,[9] but it is unknown at this time whether this is sustained over the longer term (section 4.4.2). SSRIs may be a more acceptable first-line medication choice than topiramate, given their generally more favourable adverse effect profile. However, topiramate is also promising and may well have a more potent weight-reducing effect than SSRIs. In our experience, concerns over obesity usually cause most individuals with NES to actively seek help. On the other hand, topiramate is associated with a significant rate of unpleasant adverse effects, such as interference with cognition (20%).[38] It seems to be better tolerated if titrated at a slow rate of 25mg per week for the first month. Patients should be encouraged to maintain good hydration, particularly at warm times of the year, because of the risk of kidney stones. Those with a prior history of renal calculi should generally avoid topiramate. It is recommended that bicarbonate levels be periodically monitored in individuals taking topiramate, as inhibition of the carbonic anhydrase enzyme may result in reduced serum levels of bicarbonate and a risk of metabolic CNS Drugs 2005; 19 (12)


acidosis. There is also a very low risk (