Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 .

Liraglutide in Obese or Overweight Individuals With Stable Bipolar Disorder.

BACKGROUND: Obesity is common among persons with bipolar disorder (BD). Liraglutide 3.0 mg/d subcutaneous injection is indicated for chronic weight management and associated with minimal adverse neuropsychiatric effects. This study evaluated whether liraglutide 3 mg/d reduced body weight, improved metabolic factors and eating psychopathology, and was safe and well tolerated in persons with stable BD who were obese (body mass index [BMI] >30 kg/m 2 ) or overweight (BMI ≥27 kg/m 2 ) with at least one weight-related comorbidity. METHODS: This was a 40-week, randomized (1:1 ratio), placebo-controlled, double-blind, parallel-group, 2-arm clinical trial of liraglutide targeted to 3.0 mg/d (in combination with a reduced-calorie diet and increased physical activity) in 60 participants with stable BD who were obese or overweight. Primary outcome was percent change in body weight from baseline to study end. Secondary outcomes included percentage of patients who lost ≥5% of baseline body weight, and changes in metabolic variables and measures of eating psychopathology. RESULTS: There were no significant baseline differences between the 29 liraglutide recipients and the 31 placebo recipients, except that liraglutide recipients had higher levels of binge eating and lower levels of high-density lipoprotein cholesterol. Compared with placebo, liraglutide was associated with significantly greater reductions in percent change in body weight, percentage of participants who lost at least 5% of body weight, and reductions in weight, BMI, hemoglobin A 1c levels, binge eating, and hunger. Liraglutide was well tolerated. CONCLUSIONS: Liraglutide 3 mg/d may be efficacious and safe for weight loss in individuals with stable BD and obesity or overweight. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03158805).

Efficacy, safety, and tolerability of nivasorexant in adults with binge-eating disorder: A randomized, Phase II proof of concept trial.

OBJECTIVE: This Phase II, placebo-controlled, double-blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge-eating disorder (BED). METHODS: Adults meeting the DSM-5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale-Brown Obsessive-Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD-17). Key safety outcomes included treatment-emergent adverse events (TEAEs) and adverse events of special interest (i.e., somnolence and fatigue). RESULTS: Sixty-eight participants were randomized to each treatment arm. The change from baseline to Week 12 in the number of BE days/week was the same for placebo (least squares mean [LSM]: -2.93) and nivasorexant (LSM: -2.93), with no difference between the treatment groups (LSM difference = .000 [95% confidence interval (CI): -.69, .69], p = .9992). Furthermore, no differences between treatment groups were observed in the exploratory efficacy endpoints. Nivasorexant was well tolerated; the overall incidence of TEAEs was balanced between treatment groups, and the frequency of somnolence and fatigue in the nivasorexant group were similar to placebo. DISCUSSION: In this proof-of-concept study, 100 mg b.i.d. nivasorexant did not improve BE in adults with moderate to severe BED. PUBLIC SIGNIFICANCE: The results of this Phase II study indicate that nivasorexant was well tolerated in adults with BED, but did not improve binge eating behavior over placebo. Further research is needed to improve our understanding of the role of the orexin-1 receptor in BED.

Placebo response and cessation in binge eating disorder: A pooled analysis of two randomized parallel-group clinical trials.

OBJECTIVE: This study aims to explore predictors and clinical correlates of placebo response and cessation in binge eating disorder (BED). METHOD: Data from two identically designed, randomized, placebo-controlled, parallel-group, and multicenter pharmacotherapy studies for adults with moderate to severe BED were pooled. RESULTS: Of 360 placebo recipients, 134 (37%) were responders and 53 (15%) achieved 4-week binge eating cessation. Placebo response and cessation were each associated with higher baseline disability scores but not with measures of BED symptomatology severity. Compared with placebo noncessation, placebo cessation was further associated with increased blood pressure at baseline and greater improvement in pulse and triglyceride levels at endpoint. DISCUSSION: Future clinical trial design for BED pharmacotherapy trials might consider disability level among participants to enhance signal detection. Cessation of binge eating with placebo might be associated with improvement in cardiovascular and metabolic variables, at least over the short term.

Medical comorbidity of binge eating disorder.

PURPOSE: To gain further understanding of the general medical comorbidity of binge eating disorder (BED) beyond its association with obesity. METHOD: We reviewed studies of general medical comorbidity in people with BED or clinically significant binge eating behavior beyond obesity. We also reviewed studies of BED in specific medical conditions. RESULTS: Three broad study categories of medical comorbidity in BED were found: cross-sectional studies of medical conditions in BED; prospective studies of medical conditions in BED; and studies of BED in specific medical conditions. Cross-sectional epidemiologic data suggest that BED is associated with medical conditions related to obesity, including diabetes, hypertension, dyslipidemias, sleep problems/disorders, and pain conditions, and that BED may be related to these conditions independent of obesity and co-occurring psychiatric disorders. Prospective data suggest that BED may be associated with type 2 diabetes and metabolic syndrome. BED or binge eating behavior is also associated with asthma and gastrointestinal symptoms and disorders, and among women, menstrual dysfunction, pregnancy complications, intracranial hypertension, and polycystic ovary syndrome. CONCLUSIONS: BED is associated with substantial medical comorbidity beyond obesity. Further study of the general medical comorbidity of BED and its relationship to obesity and co-occurring psychiatric disorders is greatly needed.

Lisdexamfetamine dimesylate in binge eating disorder: a placebo controlled trial.

OBJECTIVE: To evaluate lisdexamfetamine dimesylate (LDX) in the treatment of binge eating disorder (BED). METHOD: Fifty participants with BED received LDX (20-70 mg/day) (n = 25) or placebo (n = 25) for up to 12 weeks in a single-center, randomized, double-blind, and flexible-dose trial. The primary outcome measure was binge eating (BE) days/week. RESULTS: In the primary longitudinal analysis, compared with placebo, LDX was not associated with a significantly greater rate of reduction in BE days/week, as well as BE episodes/week, and scores on the Clinical Global Impression-Severity or Yale-Brown Obsessive-Compulsive Scale modified for binge eating scales. It was, however, associated with significantly decreased weight, body mass index, and fasting triglyceride level. In the secondary last observation carried forward analyses, LDX was associated with statistically significant reductions in BE days/week, BE episodes/week, weight, and BMI, as well as a statistically significant greater level of categorical response and global improvement. The mean (standard deviation) LDX daily dose at endpoint evaluation was 59.6 (14.9) mg. One participant discontinued LDX for a serious adverse cardiovascular event, which resolved fully. CONCLUSION: Lisdexamfetamine dimesylate may have clinical utility for BED but further studies of its efficacy, tolerability, and safety in this population are needed. Copyright © 2016 John Wiley & Sons, Ltd.

Psychopharmacologic treatment of eating disorders: emerging findings.

Psychopharmacologic treatment is playing a greater role in the management of patients with eating disorders. In this paper, we review randomized, placebo-controlled trials (RCTs) conducted in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and other eating disorders over the past 3 years. Fluoxetine remains the only medication approved for an eating disorder, that being BN. RCTs of antipsychotics in AN have had mixed results; the only agent with some evidence of efficacy is olanzapine. One study suggests dronabinol may induce weight gain in AN. Preliminary studies suggest lack of efficacy of alprazolam, dehydroepiandrosterone, or physiologic estrogen replacement in AN; erythromycin in BN; and the opioid antagonist ALKS-33 in BED. In BED with obesity or overweight, bupropion may cause mild weight loss without seizures, and chromium may improve glucose regulation. Also in BED, three RCTs suggest the stimulant prodrug lisdexamfetamine may reduce binge eating episodes, and another RCT suggests intranasal naloxone may decrease time spent binge eating. There remains a disconnection between the size of eating disorders as a public health problem and the lack of pharmacotherapy research of these conditions.

Overview of the treatment of binge eating disorder.

We performed a qualitative review of treatment studies of binge eating disorder (BED), focusing on randomized clinical trials (RCTs). Limited effectiveness has been demonstrated for self-help strategies, and substantial effectiveness has been shown for cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). CBT and IPT may each be more effective than behavior weight loss therapy (BWLT) for reducing binge eating over the long term. The stimulant pro-drug lisdexamfetamine dimesylate (LDX) is the only drug approved by the FDA for the treatment of BED in adults based on 2 pivotal RCTs. Topiramate also decreases binge eating behavior, but its use is limited by its adverse event profile. Antidepressants may be modestly effective over the short term for reducing binge eating behavior and comorbid depressive symptoms, but are not associated with clinically significant weight loss. A RCT presented in abstract form suggests that intranasal naloxone may decrease time spent binge eating. There is no RCT of obesity surgery in BED, but many patients with BED seek and receive such surgery. While some studies suggest patients with BED and obesity do just as well as patients with obesity alone, other studies suggest that patients with BED have more post-operative complications, less weight loss, and more weight regain. This evidence suggests that patients with BED would benefit from receiving highly individualized treatment.

Placebo cessation in binge eating disorder: effect on anthropometric, cardiovascular, and metabolic variables.

OBJECTIVE: The aim of this study was to evaluate the effects of cessation of binge eating in response to placebo treatment in binge eating disorder (BED) on anthropometric, cardiovascular, and metabolic variables. METHOD: We pooled participant-level data from 10 randomized, double-blind, placebo-controlled trials of medication for BED. We then compared patients who stopped binge eating with those who did not on changes in weight, body mass index (BMI), systolic and diastolic blood pressure, pulse, and fasting lipids and glucose. RESULT: Of 234 participants receiving placebo, 60 (26%) attained cessation from binge eating. Patients attaining cessation showed modestly decreased diastolic blood pressure compared with patients who continued to binge eat. Weight and BMI remained stable in patients who stopped binge eating, but increased somewhat in those who continued to binge eat. DISCUSSION: Patients who stopped binge eating with placebo had greater reductions in diastolic blood pressure and gained less weight than patients who continued to binge eat. Self-report of eating pathology in BED may predict physiologic variables. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.

Placebo response in binge eating disorder: a pooled analysis of 10 clinical trials from one research group.

OBJECTIVE: The aim of this study was to gain further understanding of placebo response in binge eating disorder. METHOD: We pooled participant-level data from 10 double-blind, placebo-controlled, randomized trials of medications for binge eating disorder. The primary outcomes were response (75% reduction in binge eating episodes), cessation of binge eating episodes, change in mean weekly binge eating episodes and binge eating episodes per week. RESULTS: Of 234 participants receiving placebo, 89 (38%) were responders and 59 (26%) attained cessation. Placebo-treated participants significantly reduced their binge eating. The mean (SD) binge eating episodes per week at baseline was 5.2 (3.2) and at endpoint was 2.2 (2.6). Lower baseline binge eating episode frequency and longer study participation were significantly associated with response and cessation. DISCUSSION: Less severe eating pathology at baseline was associated with higher placebo response and cessation rates. Future clinical trials may want to stipulate that participants exceed a threshold of illness severity, which may lead to better placebo and drug separation.

Zonisamide in the treatment of bulimia nervosa: an open-label, pilot, prospective study.

OBJECTIVE: To assess preliminarily the effectiveness of zonisamide in bulimia nervosa. METHOD: This was an open-label, prospective, 12-week, flexible dose study of zonisamide in bulimia nervosa. The primary outcome was binge-purge episode frequency. RESULTS: Twelve individuals received zonisamide, 10 completed at least one post-baseline evaluation, and six completed the study. Mean dose at endpoint was 420 (SD = 215) mg/day. Zonisamide was associated with significant reductions in frequency of binge-purge episodes and binge-purge days as well as measures of binge eating behavior, purging behavior, clinical severity, obsessive-compulsive features, and depressive symptoms. Weight was unchanged. DISCUSSION: In this open-label trial, zonisamide was effective in bulimia nervosa, but associated with a high discontinuation rate.

A placebo-controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder.

OBJECTIVE: To assess preliminarily the effectiveness of a novel opioid antagonist, ALKS-33, in binge eating disorder (BED). METHOD: In this randomized, placebo-controlled, flexible dose, proof-of-concept trial, 62 outpatients with BED and obesity received ALKS-33 (N = 26) or placebo (N = 36) for 6 weeks. Outcome measures of binge eating, body weight, and eating pathology were assessed. RESULTS: A large decrease in binge eating episode frequency was observed following both ALKS-33 and placebo treatment. There was no significant difference between treatment groups in binge eating episode frequency or any other measure of binge eating, body weight, or eating pathology. DISCUSSION: In this preliminary proof-of-concept study in BED, ALKS-33 did not separate from placebo. Although a failed trial cannot be excluded, the finding is consistent with earlier observations in bulimia nervosa with other opioid antagonists and suggests ALKS-33, at least when administered daily for 6 weeks, may not be efficacious for BED.

A randomized, placebo-controlled study of zonisamide to prevent olanzapine-associated weight gain.

Weight gain is commonly observed with olanzapine treatment. Zonisamide is an antiepileptic drug associated with weight loss. This study examined the effectiveness of zonisamide in preventing weight gain in 42 patients beginning olanzapine for bipolar disorder or schizophrenia. Each patient had a body mass index of 22 mg/kg or greater and was randomized to taking olanzapine with either zonisamide (n = 20) or placebo (n = 22) for 16 weeks. The primary outcome measure was change in body weight in kilograms from baseline. In the primary analysis using longitudinal regression, patients who received zonisamide had a significantly slower rate of weight gain and increase in body mass index than those who received placebo. The patients treated with zonisamide gained a mean (SD) of 0.9 (3.3) kg, whereas those treated with placebo gained a mean (SD) of 5.0 (5.5) kg; P = 0.01. None of the patients in the zonisamide group, compared with 7 patients (33%) in the placebo group, gained 7% of body weight or greater from baseline (Fisher exact test, P = 0.009). The zonisamide group, however, reported significantly more cognitive impairment as an adverse event than the placebo group (25% vs 0, respectively; P = 0.02). Zonisamide was effective for mitigating weight gain in patients with bipolar disorder or schizophrenia initiating treatment with olanzapine but was associated with cognitive impairment as an adverse event.

Bulimia nervosa presenting as rectal purging and rectal prolapse: case report and literature review.

Rectal prolapse, but not rectal purging (excessive finger evacuation to induce defecation), has been formally associated with eating disorders in the medical literature. We describe a young woman with bulimia nervosa and irritable bowel syndrome who used rectal purging as a method of counteracting the effects of her binge eating and who underwent two corrective surgeries for rectal prolapse in a 15-month interval. Further research into the relationship between eating disorders, rectal purging, and gastrointestinal dysfunction is called for.

Binge eating disorder in elderly individuals.

OBJECTIVE: To preliminarily describe the clinical features of elderly individuals with binge eating disorder (BED). METHOD: The psychological and general medical characteristics of 20 elderly individuals (65 years of age and older) who met DSM-IV-TR for BED were systematically evaluated. RESULTS: Elderly individuals with BED reported an average (SD) of 4.5 (2.9) binge eating episodes per week. Weight and shape concerns were of significant importance for participants' schema for self-evaluation. Mood disorders were the most frequent co-occurring psychiatric disorders. Despite having a mean (SD) body mass index of 36.4 (10.6), most participants presented in good general medical health. DISCUSSION: Regarding eating pathology, psychiatric comorbidity, and associated obesity, BED in this group of elderly individuals was similar to BED in younger adults. However, other than presenting with obesity, the participants reported good general medical health. BED might be a problem for a subset of physically healthy elderly individuals. Studies further examining psychiatric and medical presentation, including metabolic profile, of elderly individuals with BED may be warranted.

Duloxetine in the treatment of binge eating disorder with depressive disorders: a placebo-controlled trial.

OBJECTIVE: This study evaluated duloxetine in the treatment of binge eating disorder (BED) with comorbid current depressive disorders. METHOD: In this 12-week, double-blind, placebo-controlled trial, 40 patients with Diagnostic and Statistical Manual of Mental Disorders-IV-TR BED and a comorbid current depressive disorder received duloxetine (N = 20) or placebo (N = 20). The primary outcome measure was weekly binge eating day frequency. RESULTS: In the primary analysis, duloxetine (mean 78.7 mg/day) was superior to placebo in reducing weekly frequency of binge eating days (p = .04), binge eating episodes (p = .02), weight (p = .04), and Clinical Global Impression-Severity of Illness ratings for binge eating (p = .02) and depressive disorders (p = .01). Changes in body mass index and measures of eating pathology, depression, and anxiety did not differ between the two groups. DISCUSSION: Duloxetine may be effective for reducing binge eating, weight, and global severity of illness in BED with a comorbid current depressive disorder, but this finding needs confirmation in larger, placebo-controlled trials.

A matter of time: A systematic scoping review on a potential role of the circadian system in binge eating behavior.

Background: Emerging research suggests that food intake timing, eating behavior and food preference are associated with aspects of the circadian system function but the role that the circadian system may play in binge eating (BE) behavior in humans remains unclear. Objective: To systematically evaluate the evidence for circadian system involvement in BE behavior. Methods: Systematic searches of PubMed, EMBASE, and Scopus were performed for reports published from inception until May 2020 (PROSPERO Registration CRD42020186325). Searches were conducted by combining Medical Subject Headings related to the circadian system, BE behavior, and/or interventions. Observational and interventional studies in humans with BE behavior published in peer-review journals in the English language were included. Studies were assessed using quality and risk of bias tools (AXIS, ROB 2.0, or ROBINS). Results: The search produced 660 articles, 51 of which were included in this review. Of these articles, 46 were observational studies and 5 were interventional trials. Evidence from these studies suggests that individuals with BE behavior tend to have more food intake, more binge cravings, and more BE episodes later in the day. Hormonal and day/night locomotor activity rhythm disturbances may be associated with BE behavior. Furthermore, late diurnal preference ("eveningness") was associated with BE behavior and chronobiological interventions that shift the circadian clock earlier (e.g., morning bright light therapy) were found to possibly decrease BE behavior. Substantive clinical overlap exists between BE and night eating behavior. However, there is a significant knowledge gap regarding their potential relationship with the circadian system. Limitations include the lack of studies that use best-established techniques to assess the chronobiology of BE behavior, heterogeneity of participants, diagnostic criteria, and study design, which preclude a meta-analytic approach. Conclusion: Current evidence, although limited, suggests that the circadian system may play a role in the etiology of BE behavior. Further mechanistic studies are needed to fully characterize a potential role of the circadian system in BE behavior. A chronobiological approach to studying BE behavior may lead to identification of its neurobiological components and development of novel therapeutic interventions. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020186325], identifier [CRD42020186325].

Sodium oxybate in the treatment of binge eating disorder: an open-label, prospective study.

OBJECTIVE: To assess preliminarily the effectiveness of sodium oxybate in binge eating disorder. METHOD: This was an open-label, prospective, 16-week, flexible dose study of sodium oxybate in binge eating disorder. The primary outcome was binge eating episode frequency. RESULTS: Twelve individuals received sodium oxybate, 10 completed at least one postbaseline evaluation, and five completed the study. Mean dose at endpoint was 7.1 (2.0) g/day. Sodium oxybate was associated with significant reductions in frequency of binge days and binge episodes, as well as measures of clinical severity, eating pathology, obsessive-compulsive symptoms, food cravings, body mass index, and body weight. Nine participants had remission of binge eating and five lost ≥5% of their baseline weight; all five of the latter participants had remission of binge eating. DISCUSSION: In this open-label trial, sodium oxybate was effective in binge eating disorder, but associated with high a discontinuation rate.