Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.

In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.

Endocrinology-informed neuroimaging in eating disorders: GLP1, orexins, and psilocybin.

The neurobiology of eating disorders [EDs; anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED)] remains poorly understood. Here, I describe how neuroimaging, accompanied by peripheral endocrine measures, can provide insights into the neurobiological drivers of eating disorders. Orexins/hypocretins, glucagon-like peptide-1 receptor (GLP1R) agonists, and psilocybin are highlighted as avenues for investigation.

Use of glucagon-like peptide-1 receptor agonists in eating disorder populations.

Glucagon-like peptide-1 receptor agonists (GLP-1As) are being used as approved or off-label treatments for weight loss. As such, there has been increasing concern about the potential for GLP-1As to impact eating disorder (ED) symptomatology. This article seeks to (1) review the current state of knowledge regarding GLP-1As and ED symptomatology; (2) provide recommendations for future research; and (3) guide ED clinicians in how to discuss GLP-1As in clinical practice. Although evidence is limited, it is possible that GLP-1As could exacerbate, or contribute to the development of, ED pathology and negatively impact ED treatment. Preliminary research on the use of GLP-1As to treat binge eating has been conducted; however, studies have design limitations and additional research is needed. Therefore, at the current time there is not sufficient evidence to support the use of GLP-1s to treat ED symptoms. In summary, more research is required before negative or positive conclusions can be drawn about the impact of GLP-1As on EDs psychopathology. Herein, we provide specific recommendations for future research and a guide to help clinicians navigate discussions with their clients about GLP-1As. A client handout is also provided. PUBLIC SIGNIFICANCE: Despite glucagon-like peptide-1 receptor agonists (GLP-1As; e.g., semaglutide) increasingly being the topic of clinical and public discourse, little is known about their potential impact on ED symptoms. It is possible that GLP-1As could maintain, worsen, or improve ED symptoms. This article reviews the limited literature on GLP-1As and ED symptoms, recommends future research, and provides clinicians with a guide for discussing GLP-1As with ED clients.

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.

Psychedelics in the treatment of eating disorders: Rationale and potential mechanisms.

Eating disorders are serious illnesses showing high rates of mortality and comorbidity with other mental health problems. Psychedelic-assisted therapy has recently shown potential in the treatment of several common comorbidities of eating disorders, including mood disorders, post-traumatic stress disorder, and substance use disorders. The theorized therapeutic mechanisms of psychedelic-assisted therapy suggest that it could be beneficial in the treatment of eating disorders as well. In this review, we summarize preliminary data on the efficacy of psychedelic-assisted therapy in people with anorexia nervosa, bulimia nervosa, and binge eating disorder, which include studies and case reports of psychedelic-assisted therapy with ketamine, MDMA, psilocybin, and ayahuasca. We then discuss the potential therapeutic mechanisms of psychedelic-assisted therapy in these three eating disorders, including both general therapeutic mechanisms and those which are relatively specific to eating disorders. We find preliminary evidence that psychedelic-assisted therapy may be effective in the treatment of anorexia nervosa and bulimia nervosa, with very little data available on binge eating disorder. Regarding mechanisms, psychedelic-assisted therapy may be able to improve beliefs about body image, normalize reward processing, promote cognitive flexibility, and facilitate trauma processing. Just as importantly, it appears to promote general therapeutic factors relevant to both eating disorders and many of their common comorbidities. Lastly, we discuss potential safety concerns which may be associated with these treatments and present recommendations for future research.

Naltrexone plus bupropion combination medication maintenance treatment for binge-eating disorder following successful acute treatments: randomized double-blind placebo-controlled trial.

BACKGROUND: Certain treatments have demonstrated acute efficacy for binge-eating disorder (BED) but there is a dearth of controlled research examining pharmacotherapies as maintenance treatments for responders to initial interventions. This gap in the literature is particularly critical for pharmacotherapy for BED which is associated with relapse following discontinuation. The current study tested the efficacy of naltrexone/bupropion maintenance treatment amongst responders to acute treatments for BED. METHODS: Prospective randomized double-blind placebo-controlled single-site trial, conducted August 2017-December 2021, tested naltrexone/bupropion as maintenance treatment for responders to acute treatments with naltrexone/bupropion and/or behavioral weight-loss therapy for BED with comorbid obesity. Sixty-six patients (84.8% women, mean age 46.9, mean BMI 34.9 kg/m2) who responded to acute treatments were re-randomized to placebo (N = 34) or naltrexone/bupropion (N = 32) for 16 weeks; 86.3% completed posttreatment assessments. Mixed models and generalized estimating equations comparing maintenance treatments (naltrexone/bupropion v. placebo) included main and interactive effects of acute treatments. RESULTS: Intention-to-treat binge-eating remission rates following maintenance treatments were 50.0% (N = 17/34) for placebo and 68.8% (N = 22/32) for naltrexone/bupropion. Placebo following response to acute treatment with naltrexone/bupropion was associated with significantly decreased probability of binge-eating remission, increased binge-eating frequency, and no weight loss. Naltrexone/bupropion following response to acute treatment with naltrexone/bupropion was associated with good maintenance of binge-eating remission, low binge-eating frequency, and significant additional weight loss. CONCLUSIONS: Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.

The Role of the Endocannabinoid System in Binge Eating Disorder.

Eating disorders are multifactorial disorders that involve maladaptive feeding behaviors. Binge eating disorder (BED), the most prevalent of these in both men and women, is characterized by recurrent episodes of eating large amounts of food in a short period of time, with a subjective loss of control over eating behavior. BED modulates the brain reward circuit in humans and animal models, which involves the dynamic regulation of the dopamine circuitry. The endocannabinoid system plays a major role in the regulation of food intake, both centrally and in the periphery. Pharmacological approaches together with research using genetically modified animals have strongly highlighted a predominant role of the endocannabinoid system in feeding behaviors, with the specific modulation of addictive-like eating behaviors. The purpose of the present review is to summarize our current knowledge on the neurobiology of BED in humans and animal models and to highlight the specific role of the endocannabinoid system in the development and maintenance of BED. A proposed model for a better understanding of the underlying mechanisms involving the endocannabinoid system is discussed. Future research will be necessary to develop more specific treatment strategies to reduce BED symptoms.

Cognitive-behavioral therapy for binge-eating disorder for non-responders to initial acute treatments: Randomized controlled trial.

OBJECTIVE: Certain treatments have demonstrated acute efficacy for binge-eating disorder (BED) but many patients who receive "evidence-based" interventions do not derive sufficient benefit. Given the dearth of controlled research examining treatments for patients who fail to respond to initial interventions, this study tested the efficacy of cognitive-behavioral therapy (CBT) for patients with BED who do not respond to initial acute treatments. METHODS: Prospective randomized double-blind placebo-controlled single-site trial, conducted August 2017-December 2021, tested 16-weeks of therapist-led CBT for non-responders to initial treatment (naltrexone/bupropion and/or behavioral therapy) for BED with obesity. Thirty-one patients (mean age 46.3 years, 77.4% women, 80.6% White, mean BMI 38.99 kg/m2 ) who were non-responders to initial acute treatments were randomized to CBT (N = 18) or no-CBT (N = 13), in addition to continuing double-blinded pharmacotherapy. Independent assessments were performed at baseline, throughout treatment, and posttreatment; 83.9% completed posttreatment assessments. RESULTS: Intention-to-treat remission rates were significantly higher for CBT (61.1%; N = 11/18) than no-CBT (7.7%; N = 1/13). Mixed models of binge-eating frequency (assessed using complementary methods) converged revealing a significant interaction between CBT and time and a significant main effect of CBT. Binge-eating frequency decreased significantly with CBT but did not change significantly with no-CBT. Since only four patients received behavioral treatment during the acute treatments, we performed "sensitivity-type" analyses restricted to the 27 patients who received pharmacotherapy during the acute treatment and found the same pattern of findings for CBT versus no-CBT. CONCLUSIONS: Adult patients with BED who fail to respond to initial pharmacological treatments should be offered CBT. PUBLIC SIGNIFICANCE: Even with leading evidence-based treatments for binge-eating disorder, many patients do not derive sufficient benefit. Almost no controlled research has examined treatments for patients who fail to respond to initial interventions. This study found that that cognitive-behavioral therapy was effective for patients with binge-eating disorder who did not respond to initial interventions, with 61% achieving abstinence.

Systematic Review of Binge Eating Rodent Models for Developing Novel or Repurposing Existing Pharmacotherapies.

Recent advances in developing and screening candidate pharmacotherapies for psychiatric disorders have depended on rodent models. Eating disorders are a set of psychiatric disorders that have traditionally relied on behavioral therapies for effective long-term treatment. However, the clinical use of Lisdexamfatamine for binge eating disorder (BED) has furthered the notion of using pharmacotherapies for treating binge eating pathologies. While there are several binge eating rodent models, there is not a consensus on how to define pharmacological effectiveness within these models. Our purpose is to provide an overview of the potential pharmacotherapies or compounds tested in established rodent models of binge eating behavior. These findings will help provide guidance for determining pharmacological effectiveness for potential novel or repurposed pharmacotherapies.

Change in impulsivity is prospectively associated with treatment outcomes for binge-eating disorder.

BACKGROUND: Impulsivity may be a process underlying binge-eating disorder (BED) psychopathology and its treatment. This study examined change in impulsivity during cognitive-behavioral therapy (CBT) and/or pharmacological treatment for BED and associations with treatment outcomes. METHODS: In total, 108 patients with BED (NFEMALE = 84) in a randomized placebo-controlled clinical trial evaluating the efficacy of CBT and/or fluoxetine were assessed before treatment, monthly throughout treatment, at post-treatment (16 weeks), and at 12-month follow-up after completing treatment. Patients completed established measures of impulsivity, eating-disorder psychopathology, and depression, and were measured for height and weight [to calculate body mass index (BMI)] during repeated assessments by trained/monitored doctoral research-clinicians. Mixed-effects models using all available data examined changes in impulsivity and the association of rapid and overall changes in impulsivity on treatment outcomes. Exploratory analyses examined whether baseline impulsivity predicted/moderated outcomes. RESULTS: Impulsivity declined significantly throughout treatment and follow-up across treatment groups. Rapid change in impulsivity and overall change in impulsivity during treatment were significantly associated with reductions in eating-disorder psychopathology, depression scores, and BMI during treatment and at post-treatment. Overall change in impulsivity during treatment was associated with subsequent reductions in depression scores at 12-month follow-up. Baseline impulsivity did not moderate/predict eating-disorder outcomes or BMI but did predict change in depression scores. CONCLUSIONS: Rapid and overall reductions in impulsivity during treatment were associated with improvements in specific eating-disorder psychopathology and associated general outcomes. These effects were found for both CBT and pharmacological treatment for BED. Change in impulsivity may be an important process prospectively related to treatment outcome.

Machine learning v. traditional regression models predicting treatment outcomes for binge-eating disorder from a randomized controlled trial.

BACKGROUND: While effective treatments exist for binge-eating disorder (BED), prediction of treatment outcomes has proven difficult, and few reliable predictors have been identified. Machine learning is a promising method for improving the accuracy of difficult-to-predict outcomes. We compared the accuracy of traditional and machine-learning approaches for predicting BED treatment outcomes. METHODS: Participants were 191 adults with BED in a randomized controlled trial testing 6-month behavioral and stepped-care treatments. Outcomes, determined by independent assessors, were binge-eating (% reduction, abstinence), eating-disorder psychopathology, and weight loss (% loss, ⩾5% loss). Predictors included treatment condition, demographic information, and baseline clinical characteristics. Traditional models were logistic/linear regressions. Machine-learning models were elastic net regressions and random forests. Predictive accuracy was indicated by the area under receiver operator characteristic curve (AUC), root mean square error (RMSE), and R2. Confidence intervals were used to compare accuracy across models. RESULTS: Across outcomes, AUC ranged from very poor to fair (0.49-0.73) for logistic regressions, elastic nets, and random forests, with few significant differences across model types. RMSE was significantly lower for elastic nets and random forests v. linear regressions but R2 values were low (0.01-0.23). CONCLUSIONS: Different analytic approaches revealed some predictors of key treatment outcomes, but accuracy was limited. Machine-learning models with unbiased resampling methods provided a minimal advantage over traditional models in predictive accuracy for treatment outcomes.

Naltrexone-Bupropion and Behavior Therapy, Alone and Combined, for Binge-Eating Disorder: Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: Binge-eating disorder, the most prevalent eating disorder, is a serious public health problem associated with obesity, psychiatric and medical comorbidities, and functional impairments. Binge-eating disorder remains underrecognized and infrequently treated, and few evidence-based treatments exist. The authors tested the effectiveness of naltrexone-bupropion and behavioral weight loss therapy (BWL), alone and combined, for binge-eating disorder comorbid with obesity. METHODS: In a randomized double-blind placebo-controlled trial conducted from February 2017 to February 2021, using a 2×2 balanced factorial design, 136 patients with binge-eating disorder (81.6% women; mean age, 46.5 years; mean BMI, 37.1) were randomized to one of four 16-week treatments: placebo (N=34), naltrexone-bupropion (N=32), BWL+placebo (N=35), or BWL+naltrexone-bupropion (N=35). Overall, 81.7% of participants completed independent posttreatment assessments. RESULTS: Intention-to-treat binge-eating remission rates were 17.7% in the placebo group, 31.3% in the naltrexone-bupropion group, 37.1% in the BWL+placebo group, and 57.1% in the BWL+naltrexone-bupropion group. Logistic regression of binge-eating remission revealed that BWL was significantly superior to no BWL, and that naltrexone-bupropion was significantly superior to placebo, but there was no significant interaction between BWL and medication. Mixed models of complementary measures of binge-eating frequency also indicated that BWL was significantly superior to no BWL. The rates of participants attaining 5% weight loss were 11.8% in the placebo group, 18.8% in the naltrexone-bupropion group, 31.4% in the BWL+placebo group, and 38.2% in the BWL+naltrexone-bupropion group. Logistic regression of 5% weight loss and mixed models of percent weight loss both revealed that BWL was significantly superior to no BWL. Mixed models revealed significantly greater improvements for BWL than no BWL on secondary measures (eating disorder psychopathology, depression, eating behaviors, and cholesterol and HbA1c levels). CONCLUSIONS: BWL and naltrexone-bupropion were associated with significant improvements in binge-eating disorder, with a consistent pattern of BWL being superior to no BWL.

An exploratory machine learning approach to identify placebo responders in pharmacological binge eating disorder trials.

Randomized, placebo-controlled trials for binge eating disorder (BED) have revealed highly variable, and often marked, rates of short-term placebo response. Several quantitative based analyses in patients with BED have inconsistently demonstrated which patient factors attribute to an increase in placebo response. The objective of this study is to utilize machine learning (ML) algorithms to identify moderators of placebo response in patients with BED. Data were pooled from 12 randomized placebo-controlled trials evaluating different treatment options for BED. The final dataset consisted of 189 adults receiving placebo with complete information of baseline variables. Placebo responders were defined as patients experiencing ≥75% reduction in binge eating frequency (BEF) at study end point. Nine patient prerandomization variables were included as predictors. Patients were divided into training and testing subsets according to an 75%:25% distribution while preserving the proportion of placebo responders. All analysis was performed in the software Pumas 2.0. Gaussian Naïve Bayes algorithm showed the best cross-validation accuracy (~64%) and was chosen as the final algorithm. Shapley analysis suggested that patients with low baseline BEF and anxiety status were strong moderators of placebo response. Upon applying the final algorithm on the test dataset, the resulting sensitivity was 88% and prediction accuracy was 72%. This is the first application of ML to identify moderators of placebo response in BED. The results of this analysis confirm previous findings of lesser baseline disease severity and adds that patients with no anxiety are more susceptible to placebo response.

An experimental protocol for a double-blind placebo-controlled evaluation of the effectiveness of oral naltrexone in management of adolescent eating disorders.

BACKGROUND: This double-blind, placebo-controlled study evaluates the effectiveness of oral naltrexone in adolescents and young adults with eating disorders (EDs) characterized by purging with or without binge-eating behaviors. We hypothesize that participants receiving oral naltrexone will demonstrate greater improvements in body mass index in underweight participants and self-reported ED symptomatology compared to placebo. METHODS: Thirty individuals receiving treatment in a partial hospitalization program for EDs with diagnoses of anorexia nervosa binge-eating/purging type, bulimia nervosa, or purging disorder will receive six weeks of either placebo or oral naltrexone. Participants will complete a battery of self-report measures and laboratory safety monitoring every three weeks in addition to standard of medical care for treatment environment. RESULTS: Analysis will compare outcomes at weeks three and six, and follow-up at nine weeks and six-months across the oral naltrexone and placebo groups. Main effects for time will examine improvements over the course of treatment for all participants, while group × time interactions will examine differences in the rate of change over time between study arms. CONCLUSIONS: We hypothesize that participants receiving oral naltrexone will experience more rapid improvements in symptom severity and weight restoration compared to placebo across study time points. There are very few medications with high-quality data demonstrating both safety and efficacy in the treatment of eating disorders. The authors theorize this study will demonstrate a clinically significant effect of oral naltrexone on impulsive-type EDs and support its use as an effective option for treatment augmentation.

Treatment of eating disorders: A systematic meta-review of meta-analyses and network meta-analyses.

MONTELEONE, A.M., F. Pellegrino, G. Croatto, M. Carfagno, A. Hilbert, J. Treasure, T. Wade, C. Bulik, S. Zipfel, P. Hay, U. Schmidt, G. Castellini, A. Favaro, F. Fernandez-Aranda, J. Il Shin, U. Voderholzer, V. Ricca, D. Moretti, D. Busatta, G. Abbate-Daga, F. Ciullini, G. Cascino, F. Monaco, C.U. Correll and M. Solmi. Treatment of Eating Disorders: a systematic meta-review of meta-analyses and network meta-analyses. NEUROSCI BIOBEHAV REV 21(1) XXX-XXX, 2022.- Treatment efficacy for eating disorders (EDs) is modest and guidelines differ. We summarized findings/quality of (network) meta-analyses (N)MA of randomized controlled trials (RCTs) in EDs. Systematic meta-review ((N)MA of RCTs, ED, active/inactive control), using (anorexia or bulimia or eating disorder) AND (meta-analy*) in PubMed/PsycINFO/Cochrane database up to December 15th, 2020. Standardized mean difference, odds/risk ratio vs control were summarized at end of treatment and follow-up. Interventions involving family (family-based therapy, FBT) outperformed active control in adults/adolescents with anorexia nervosa (AN), and in adolescents with bulimia nervosa (BN). In adults with BN, individual cognitive behavioural therapy (CBT)-ED had the broadest efficacy versus active control; also, antidepressants outperformed active. In mixed age groups with binge-eating disorder (BED), psychotherapy, and lisdexamfetamine outperformed active control. Antidepressants, stimulants outperformed placebo, despite lower acceptability, as did CBT-ED versus waitlist/no treatment. Family-based therapy is effective in AN and BN (adolescents). CBT-ED has the largest efficacy in BN (adults), followed by antidepressants, as well as psychotherapy in BED (mixed). Medications have short-term efficacy in BED (adults).

Brain serotonin deficiency and fluoxetine lead to sex-specific effects on binge-like food consumption in mice.

RATIONALE: Although pharmacotherapies are often effective in reducing binge eating in conditions such as bulimia nervosa and binge eating disorder, subsets of patients do not benefit sufficiently from existing treatments, and the reasons for treatment failure remain unclear. OBJECTIVES: This study aimed to evaluate whether genetic reductions in brain serotonin influence binge eating and/or the ability of fluoxetine, a selective serotonin reuptake inhibitor, to reduce binge eating in mice. METHODS: This study used a validated model of binge-like consumption of high-fat diet to compare binge-like food intake in control and fluoxetine-treated wild-type and serotonin-deficient mice from the tryptophan hydroxylase 2 (R439H) knock-in line. In addition, real-time PCR was used to evaluate potential genotype and sex differences in the effects of fluoxetine on gene expression in the raphe nucleus. RESULTS: The results reveal that brain serotonin deficiency is sufficient to increase binge eating in males, but not females. However, while chronic fluoxetine reduced binge eating in both genotypes of males and in wild-type females, it failed to reduce binge eating in serotonin-deficient females. Transcriptional responses to chronic fluoxetine were also characterized by sex and genotype differences. CONCLUSIONS: Overall, this study revealed significant sex differences in the effects of fluoxetine and brain serotonin deficiency on binge-like food intake and suggests that low brain serotonin could impact eating disorders both by promoting binge eating and by limiting the efficacy of fluoxetine to reduce binge eating.