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Volume 43, Issue 1,
, Pages 112-122.e1
Author links open overlay panelCarlos M.GriloPhD12PersonEnvelopeJanet A.LydeckerPhD1Peter T.MorganMD, PhD13RalitzaGueorguievaPhD14
Binge-eating disorder (BED), the most prevalent eating disorder, is associated strongly with obesity and functional impairments. Few evidence-based treatments for BED exist; a pharmacotherapy effective in reducing both binge eating and weight needs to be identified. This placebo-controlled double-blind pilot RCT evaluated the acute effects of naltrexone+bupropion (NB) on BED with obesity and examined the longer-term effects through 6-month follow-up after the discontinuation of medication.
Twenty-two adult patients with BED were randomized to receive 12 weeks of double-blind treatment with fixed-dose NB (naltrexone+bupropion XL 50/300mg) or placebo. Independent (blinded) researcher–clinicians evaluated patients at major outcome time points (baseline, posttreatment, and 6-month follow-up after the treatment period); patients were also evaluated for the tracking of course/tolerability throughout treatments and at 3-month follow-up. Primary outcomes were changes from baseline in binge-eating frequency and percentage weight. Secondary outcomes were changes in eating-disorder psychopathology and depression.
A total of 22 patients were enrolled (86.4% women; mean age, 50.4 years), with 77.3% of patients completing treatments; completion rates (NB, 83.3%; placebo, 70.0%) and adverse events did not differ significantly between NB and placebo. Analyses revealed significant reductions from baseline in binge-eating, eating-disorder psychopathology, depression, and weight during treatment, but these changes with NB did not differ significantly from those with placebo. The percentage of patients who attained 3% weight loss was significantly greater with NB than with placebo (45.5% vs 0%); weight-loss and binge-eating reductions were significantly correlated in the group that received NB. At 6-month follow-up, outcomes remained improved relative to baseline, with no significant differences between NB and placebo.
The findings from this pilot RCT suggest that NB was well-tolerated in these patients with BED and comorbid obesity. Most outcomes were not statistically different between NB and placebo. A larger-scale, adequately powered RCT is needed for determining the efficacy of NB in the treatment of BED. ClinicalTrials.gov identifier: NCT02317744.
Binge-eating disorder (BED) is characterized by recurrent binge eating (ie, eating unusually large quantities of food, accompanied by a feeling of loss of control), marked distress, and the absence of inappropriate weight-compensatory behaviors.1 BED, the most prevalent formal eating-disorder diagnosis,2 has been significantly associated with medical and psychiatric comorbidities,3 and functional impairments.2 BED has been associated strongly with obesity2 and with a heightened risk for obesity-related metabolic problems.4
Although controlled treatment research has provided empiric support for certain pharmacologic approaches,5 many patients do not cease binge eating or lose weight.6 Producing weight loss in patients with BED comorbid with obesity has been particularly challenging. The majority of treatment studies have reported little weight loss,7 and the weight losses reported in studies of treatments for BED are less than those in obesity without BED.8 Of the medications for BED tested to date and available on the market, only 2 have been found to significantly reduce both binge eating and weight. The use of topiramate, an antiseizure agent, has been associated with significantly reduced binge eating and weight relative to placebo9 and with significantly enhanced outcomes compared to placebo, when added to cognitive–behavioral therapy.10 The use of topiramate, however, has been associated with concerning adverse events and limited tolerability, leading to very high discontinuation rates.11
Lisdexamfetamine dimesylate, a prodrug stimulant and the sole medication that the US Food and Drug Administration (FDA) has approved for use in the treatment of BED, in addition to being associated with a significant reduction in binge eating relative to placebo, has been reported to reduce weight.12 Importantly, weight loss was examined as a safety measure rather than as a clinical outcome, and the FDA approval of lisdexamfetamine dimesylate includes a Limitation of Use specifying that it is not indicated or recommended for weight loss and noting that its safety and efficacy in the treatment of obesity have not been demonstrated. Thus, effective pharmacologic approaches to reducing both binge eating and weight in BED remains a pressing need. Such research should include follow-up assessments of longer-term outcomes after discontinuation of medications, which are sorely needed for informing clinicians about the durability of the outcomes and the risk for relapse.13 To date, follow-up assessments in randomized, controlled trials (RCTs) of pharmacotherapy-only for BED have been reported in only 2 studies, and both suggested high and rapid relapse rates.14,15
Although several FDA-approved weight-loss medications are currently available, to date none has been tested as a monotherapy for BED.13 The use of 1 specific agent, the combination of naltrexone + bupropion (NB), seems logical given the putative mechanisms of action relevant for reducing both binge eating and weight, per hypothesized effects on the brain regions involved in the regulation of food intake and weight, based, in turn, on the findings from research on the mechanisms of action of leptin.16 The anorectic effects of leptin result from its excitatory effects on pro-opiomelanocorin (POMC) neurons in the melanocortin system of the hypothalamus.17 Stimulated POMC signaling decreases food intake and increases energy expenditure, but is then inhibited by endogenous feedback.17 The combination of naltrexone + bupropion is thought to stimulate POMC neurons (bupropion) plus block endogenous feedback that inhibits POMC activity (naltrexone).16,18 Several double-blind RCTs have reported that NB was effective in promoting weight loss in patients with obesity.18, 19, 20, 21, 22 Naltrexone and bupropion have been marketed for many years and are now available as generic products. Fixed-dose combination extended-release tablets became available in 2014 as a branded product with FDA approval for use as an adjunct to a reduced-calorie diet and increased physical activity in long-term weight management in adults with obesity (or with a body mass index [BMI] of 27 or greater in the presence of weight-related comorbidity). The present double-blind pilot RCT evaluated the acute effects of NB delivered for 12 weeks and examined the longer-term effects through 6-month follow-up after the discontinuation of medication in patients with BED with obesity.
Participants were 22 consecutively assessed patients who met the criteria for BED and obesity. Respondents to media advertisements for the treatment study at a medical school program and who passed initial screening were assessed for eligibility during in-person evaluations. Eligibility criteria included an age of 18–65 years, full Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)1–defined criteria for BED, and a BMI of 30–50kg/m2. Exclusion criteria in this pilot
Randomization, Patients' Characteristics, and Completion/Follow-up Rates
Figure1 summarizes the flow of patients throughout the study. Of the 268 screened individuals, 40 were evaluated in person, and 22 met eligibility and were randomized to treatment. The mean (SD) age of the participants was 50.4 (8.8) years; BMI, 37.1 (5.9); 86.4% (n=19) were women; 72.7% (n=16) self-identified as white; and 86.4% (n=19) attended or finished college. The 2 treatment groups did not differ significantly with regard to demographic variables (age, sex, race/ethnicity,
This study was the first to evaluate the potential effectiveness of NB, a generic formulation of an FDA-approved weight-loss medication, in the treatment of BED in persons with obesity. The findings from this small-sample double-blind pilot RCT suggest that NB was well tolerated in these patients with BED and comorbid obesity. The NB and placebo groups did not statistically differ with regard to most outcomes. Patients receiving NB were significantly more likely than were those receiving
The findings from this pilot RCT suggest that NB was well tolerated in these patients with BED and comorbid obesity. NB and placebo did not statistically differ with regard to most outcomes. A larger, adequately powered RCT is needed for determining the efficacy of NB in the treatment of BED.
C.M. Grilo provided conceptualization, methodology; validation; investigation; writing, editing, and final review of the manuscript; and visualization. J.A. Lydecker provided methodology; project administration; validation; formal analysis; investigation; writing, review, editing, and final review of the manuscript; and visualization. P.T. Morgan provided methodology; investigation; and writing, review, editing, and final review of the manuscript. R. Gueorguieva provided formal analysis and
This research was supported, in part, by National Institutes of Health grants R01 DK49587 and K24 DK070052 to CMG. The authors' research was also supported, in part, by National Institutes of Health grants K23 DK115893 to JAL, UL1 TR001863 to JAL, R01 DK114075, and R01 DK112771 to CMG. The funder played no role in the content of this article.
C.M. Grilo has received consultant's fees from Sunovion and Weight Watchers; honoraria for lectures, Continuing Medical Education activities, and presentations at scientific conferences; and royalties from Guilford Press and Taylor & Francis. R. Gueorguieva has received royalties from CRC Press, and consultant's fees from Cohen Veterans Bioscience. The authors have indicated that they have no conflicts of interest with regard to the content of this article.
- J.A. Coffino et al.Rates of help-seeking in U.S. adults with lifetime DSM-5 eating disorders: prevalence across diagnoses and sex and ethnic/racial differences
Mayo Clinic Proc
- A.T. Beck et al.Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation
Clin Psychol Rev
- D.L. Reas et al.Reliability of the Eating Disorder Examination-Questionnaire in patients with binge eating disorder
Behav Res Ther
- F.L. Greenway et al.Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
- C.M. Grilo et al.Treatment of binge eating disorder in racially and ethnically diverse obese patients in primary care: randomized placebo-controlled clinical trial of self-help and medication
Behav Res Ther
(2014)(Video) Let's Talk "Binge-Eating Disorder in Adults" with Dr. Garber
- T. Udo et al.Prevalence and correlates of DSM-5-defined eating disorders in a nationally representative sample of US adults
Diagnostic and Statistical Manual of Mental Disorders
- T. Udo et al.
Psychiatric and medical correlates of DSM-5 eating disorders in a nationally representative sample of adults in the United States
Int J Eat Disord
- J.I. Hudson et al.
Longitudinal study of the diagnosis of components of the metabolic syndrome in individuals with binge-eating disorder
Am J Clin Nutr
- S.L. McElroy
Pharmacologic treatments for binge-eating disorder
Meta-analysis of the efficacy of psychological and medical treatments for binge-eating disorder
JConsult Clin Psychol
Meta-analysis on the long-term effectiveness of psychological and medical treatments for binge-eating disorder
Int J Eat Disord
Responses to weight loss treatment among obese individuals with and without BED: a matched-study meta-analysis
Eat Weight Disord
Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial
Am J Psychiatr
Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive-behavior therapy in binge-eating disorder
Topiramate in the long-term treatment of binge-eating disorder associated with obesity
Lisdexamfetamine dimesylate for adults with moderate to severe binge eating disorder: results of two pivotal phase 3 randomized controlled trials
Combining pharmacological and psychological treatments for binge eating disorder: current status, limitations, and future directions
Curr Psychiatr Rep
- Neurobiological and neuropharmacological aspects of food addiction
2022, Neuroscience and Biobehavioral Reviews
This review aims to draw attention to current studies on syndromes related to food eating behavior, including food addiction, and to highlight the neurobiological and neuropharmacological aspects of food addiction toward the development of new therapies. Food addiction and eating disorders are influenced by several neurobiological factors. Changes in feeding behavior, food addiction, and its pharmacological therapy are related to complex neurobiological processes in the brain. Thus, it is not surprising that there is inconsistency among various individual studies. In this review, we assessed literature including both experimental and clinical studies regarding food addiction as a feeding disorder. We selected articles from animal studies, randomized clinical trials, meta-analyses, narrative, and systemic reviews given that, crucial quantitative data with a measure of neurobiological, neuropharmacological aspects and current therapies of food addiction as an outcome. Thus, the main goal to outline here is to investigate and discuss the association between the brain reward system and feeding behavior in the frame of food addiction in the light of current literature.
- Eating Disorders Update 2021: What We Know, What We Don't Know, and Next Steps
2021, Clinical Therapeutics(Video) Clinical Update: Anorexia Nervosa
- The Neurobiology of Binge-eating Disorder Compared with Obesity: Implications for Differential Therapeutics
2021, Clinical Therapeutics
Emerging work indicates divergence in the neurobiologies of binge-eating disorder (BED) and obesity despite their frequent co-occurrence. This review highlights specific distinguishing aspects of BED, including elevated impulsivity and compulsivity possibly involving the mesocorticolimbic dopamine system, and discusses implications for differential therapeutics for BED.
This narrative review describes epidemiologic, clinical, genetic, and preclinical differences between BED and obesity. Subsequently, this review discusses human neuroimaging work reporting differences in executive functioning, reward processing, and emotion reactivity in BED compared with obesity. Finally, on the basis of the neurobiology of BED, this review identifies existing and new therapeutic agents that may be most promising given their specific targets based on putative mechanisms of action relevant specifically to BED.
BED is characterized by elevated impulsivity and compulsivity compared with obesity, which is reflected in divergent neurobiological characteristics and effective pharmacotherapies. Therapeutic agents that influence both reward and executive function systems may be especially effective for BED.
Greater attention to impulsivity/compulsivity-related, reward-related, and emotion reactivity–related processes may enhance conceptualization and treatment approaches for patients with BED. Consideration of these distinguishing characteristics and processes could have implications for more targeted pharmacologic treatment research and interventions.
Development, validation and clinical use of the Eating Behaviors Assessment for Obesity (EBA-O)
2022, Eating and Weight Disorders
Research articleShort-term Effects of Alfacalcidol on Hospital Length of Stay in Patients Undergoing Valve Replacement Surgery: A Randomized Clinical Trial
Clinical Therapeutics, Volume 43, Issue 1, 2021, pp. e1-e18
Vitamin D deficiency is highly prevalent in critically ill patients, and has been associated with more prolonged length of hospital stay and poor prognosis. Patients undergoing open-heart surgery are at higher risk due to the associated life-threatening postoperative complications. This study investigated the effect of alfacalcidol treatment on the length of hospital stay in patients undergoing valve-replacement surgery.
This single-center, randomized, open-label, controlled trial was conducted at El-Demerdash Cardiac Academy Hospital (Cairo, Egypt), from April 2017 to January 2018. This study included adult patients undergoing valve-replacement surgery who were randomized to the intervention group (n=47; alfacalcidol 2μg/d started 48h before surgery and continued throughout the hospital stay) or to the control group (n=42). The primary end points were lengths of stay (LOS) in the intensive care unit (ICU) and in the hospital. Secondary end points were the prevalence of postoperative hospital-acquired infections, cardiac complications, and in-hospital mortality.
A total of 86 patients were included in the final analysis, with 51 (59.3%) being vitamin D deficient on hospital admission. Treatment with alfacalcidol was associated with a statistically significant decrease in ICU LOS (hazard ratio=1.61; 95% CI, 1.77–2.81; P=0.041) and hospital LOS (hazard ratio=1.63; 95% CI, 1.04–2.55; P=0.034). Treated patients had a significantly lower postoperative infection rate than did the control group (35.5% vs 56.1%; P=0.017). The median epinephrinedose was lower in the intervention group compared to that in the control group (5.9 vs 8.2mg; P=0.019). The rate of in-hospital mortality was not significantly different between the 2 groups.
Early treatment with 2μg of alfacalcidol in patients undergoing valve-replacement surgery is promising and well tolerated. This effect may be attributed to its immunomodulatory and cardioprotective mechanisms. ClinicalTrials.gov identifier: NCT04085770.
Research articleDifferentiating the Effect of an Opioid Agonist on Cardiac Repolarization From µ-Receptor–mediated, Indirect Effects on the QT Interval: A Randomized, 3-way Crossover Study in Healthy Subjects
Clinical Therapeutics, Volume 38, Issue 2, 2016, pp. 315-326
A thorough QT study was conducted in healthy subjects to evaluate the effect of buprenorphine hydrochloride administered through a buccal soluble film under coverage of naltrexone to block confounding, secondary QT effects.
Healthy subjects were enrolled in a randomized, partially blinded, 4-way crossover designed study. Subjects received buprenorphine 3 mg with naltrexone, naltrexone alone (with placebo films), placebo (placebo films and placebo naltrexone), and open-label moxifloxacin 400 mg with placebo naltrexone in separate in-house treatment periods. Naltrexone treatment (50 mg) was initiated 12 hours before buprenorphine and was given every 12 hours for a total of 4 doses. ECG data were extracted from a continuous recording predose and serially after dosing on the treatment day. ECG intervals were measured at a central ECG laboratory by using the high-precision QT technique. The QT interval was corrected for heart rate with Fridericia’s formula (QTcF), and change-from-predose baseline QTcF (∆QTcF) was analyzed by using a mixed effect model.
Fifty-eight subjects (35 males) with a mean age of 32 were enrolled into the study. Treatment with buprenorphine 3 mg resulted in a small QT effect with the largest mean naltrexone-corrected ∆QTcF reaching 5.8 msec at 8 hours’ postdosing (upper bound of the 90% CI below 10 msec). Exposure response analysis with a linear model demonstrated a significant linear relationship between plasma levels and naltrexone-corrected ∆QTcF, with an estimated mean slope of 0.65 msec per nanogram/milliliter (90% CI, 0.22 to 1.08). Using the exposure response model, an effect on ∆QTcF of 4.5 msec (2.80 to 6.12) can be predicted at the observed geometric peak plasma level after administration of the 3-mg buprenorphine dose in this study (3.6 ng/mL [3.33 to 3.98]). Naltrexone alone did not have a relevant effect on the QTcF interval.
The present study showed that buprenorphine plasma levels up to 5 ng/mL had no effect on the QTc above the level of clinical concern.(Video) Robert Kushner, USA
Research articleDose Optimization of Vancomycin Using a Mechanism-based Exposure–Response Model in Pediatric Infectious Disease Patients
Clinical Therapeutics, Volume 43, Issue 1, 2021, pp. 185-194.e16
This study aimed to determine the appropriate vancomycin dosage, considering patient size and organ maturation, by simulating the bacterial count and biomarker level for drug administration in pediatric patients with gram-positive bacterial (GPB) infections.
Natural language processing for n-gram analysis was used to detect appropriate pharmacodynamic (PD) markers in infectious disease patients. In addition, a mechanism-based model was established to describe the systemic exposure and evaluate the PD marker simultaneously in pediatric patients. A simulation study was then conducted by using a mechanism-based model to evaluate the optimal dose of vancomycin in pediatric patients.
: C-reactive protein (CRP) was selected as a PD marker from an analysis of ~270,000 abstracts in PubMed. In addition, clinical results, including the vancomycin plasma concentrations and CRP levels of pediatric patients (n=93), were collected from electronic medical records. The vancomycin pharmacokinetic model with allometric scaling and a maturation function was built as a one-compartment model, with an additional compartment for bacteria. Both the effects of vancomycin plasma concentrations on the destruction of bacteria and those of bacteria on CRP production rates were represented by using a maximum achievable effect model (Emax model). Simulation for dose optimization was conducted not only by using the final model but also by exploring the possibility of therapeutic failure based on the MICs of vancomycin for GPB. Clinical cure was defined as when the CRP level fell below the upper limit of the normal range. Our dose optimization simulations suggested a vancomycin dosage of 10mg/kg every 8h as the optimal maintenance dose for pediatric patients with a postconceptual age <30 weeks and 10mg/kg every 6h for older children, aged up to 12 years. In addition, the MIC of 3μg/mL was assessed as the upper concentration limit associated with successful vancomycin treatment of GPB infections.
This study confirmed that the changes in bacterial counts and CRP levels were well described with mechanistic exposure–response modeling of vancomycin. This model can be used to determine optimal empiric doses of vancomycin and to improve therapeutic outcomes in pediatric patients with GPB.
Research articleEffects of Postoperative Percutaneous Coronary Intervention, Pharmacologic Treatment, and Predisposing Factors on Clinical Outcomes in Patients With and Without Type 2 Diabetes Along With Critical Limb Ischemia
Clinical Therapeutics, Volume 43, Issue 1, 2021, pp. 195-210.e2
Critical limb ischemia (CLI) has been identified as being connected to rates of cardiovascular mortality and lower extremity amputation (LEA). This prospective study investigated the effects of percutaneous coronary intervention (PCI), pharmacologic treatment, and predisposing factors on clinical outcomes in patients with and without type 2 diabetes mellitus (DM) along with CLI after endovascular intervention.
249 consecutive patients with CLI (Fontaine stages III–IV) received pharmacologic treatment after successful endovascular intervention. Their primary patency rates of infrapopliteal lesions and cardiovascular and amputation events during a 36-month follow-up period were assessed.
Patients with DM were more likely to be younger (P=0.026); 50% (n=63), 42.9% (n=54), 52.4% (n=66), and 77% (n=97) of DM patients had arterial calcification, end-stage renal disease, diabetic neuropathy, and Fontaine stage IV (P<0.001, P<0.001, P<0.001, and P=0.019, respectively). The primary patency rates were 61%, 48.8%, and 42.3% at 12, 24, and 36 months, in the patients without DM (P=0.034, P=0.013, and P=0.005). Patients with DM had higher risks of 36-month coronary artery disease, cerebrovascular accident, mortality, and LEA (P=0.005, P=0.042, P=0.042, and P<0.001). Patients with CLI receiving long-term cilostazol treatment had a better primary patency and amputation-free survival, and a lower risk of mortality at 36 months (P<0.001, P<0.001, and P=0.001). Statin use was associated with 36-month amputation-free survival but not with primary patency (P=0.032 and P=0.088). Subgroup multivariate Cox analyses showed that primary patency was independently associated with long-term cilostazol treatment, PCI in the first postoperative year, and direct revascularization in the DM group, whereas in the control group, long-term cilostazol treatment was the main independent factor. The risk of amputation was independently associated with a high high-sensitivity chronic reactive protein level, diabetic neuropathy, sole use of an oral hypoglycemic agent, and lack of supervised exercise.
Long-term cilostazol treatment, aggressive management of dyslipidemia, and meticulous assessment and prevention of postoperative unstable coronary artery disease should be considered in CLI patients with and without DM to maximize clinical outcomes. PCI in the first postoperative year may be a predisposing factor for patency failure in patients with CLI, especially those with DM. A large-scale prospective randomized trial should be conducted to confirm these findings (TVGH IRB No. 2013-08-020B).
Research articleReduced Mortality After Oral Polio Vaccination and Increased Mortality After Diphtheria-tetanus-pertussis Vaccination in Children in a Low-income Setting
Clinical Therapeutics, Volume 43, Issue 1, 2021, pp. 172-184.e7
The diphtheria-tetanus-pertussis vaccine (DTP) and oral polio vaccine (OPV) were introduced in children 3 of 5 months of age in 1981–1983 in Bandim, in the capital of Guinea-Bissau. Because DTP has been linked to deleterious nonspecific effects (NSEs) and OPV to beneficial NSEs, we followed up this cohort to 3 years of age and examined the effects of DTP with OPV on all-cause mortality and the interactions of DTP and OPV with the measles vaccine (MV).
DTP and OPV were offered at 3 monthly community weighing sessions. Vaccination groups were defined by the last vaccine received. We compared overall mortality for different groups in Cox proportional hazards regression models, reporting hazards ratios (HRs) with 95% CIs.
The study cohort included 1491 children born in Bandim from December 1980 to December 1983. From 3 to 35 months of age, with censoring for MV, children vaccinated with DTP and/or OPV had higher mortality than both unvaccinated children (HR=l.66; 95% CI, 1.03–2.69) and OPV-only vaccinated children (HR=2.81; 95% CI, 1.02–7.69); DTP-only vaccinated children had higher mortality than OPV-only vaccinated children (HR=3.38; 95% CI, 1.15-–9.93). In the age group of 3–8 months, before MV is administered, DTP-only vaccination was associated with a higher mortality than DTP with OPV (HR=3.38; 95% CI, 1.59–7.20). Between 9 and 35 months of age, when MV is given, DTP-vaccinated and MV-unvaccinated children had higher mortality (HR=2.76; 95% CI, 1.36–5.59) than children who had received MV after DTP, and among children who received DTP with MV or after MV, DTP-only vaccination was associated with a higher mortality than DTP with OPV (HR=6.25; 95% CI, 2.55–15.37).
Because the 2 vaccines had differential effects and the healthiest children were vaccinated first, selection biases are unlikely to explain the estimated impact on child survival. OPV had beneficial NSEs, and administration of OPV with DTP may have reduced the negative effects of DTP.
Research articleOrlistat on plasma lipids and body weight reduction: A really effective drug?
Pharmacological Research, Volume 123, 2017, p. 26(Video) "Weight Loss Management" by Katherine Lyons, MD
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