0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Efficacy and Safety of Lisdexamfetamine for Treatment of Adults With Moderate to Severe Binge-Eating Disorder A Randomized Clinical Trial FREE

Susan L. McElroy, MD1,2; James I. Hudson, MD, ScD3; James E. Mitchell, MD4,5; Denise Wilfley, PhD6; M. Celeste Ferreira-Cornwell, PhD7; Joseph Gao, PhD7; Jiannong Wang, PhD7,8; Timothy Whitaker, MD7; Jeffrey Jonas, MD7,9; Maria Gasior, MD, PhD7
[+] Author Affiliations
1Research Institute, Lindner Center of HOPE, Mason, Ohio
2Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio
3Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts
4Neuropsychiatric Research Institute, Fargo, North Dakota
5Department of Neuroscience, University of North Dakota School of Medicine, Fargo
6Department of Psychology, Washington University School of Medicine, St Louis, Missouri
7Shire, Wayne, Pennsylvania
8currently with CSL Behring, King of Prussia, Pennsylvania
9currently with Sage Therapeutics, Cambridge, Massachusetts
JAMA Psychiatry. 2015;72(3):235-246. doi:10.1001/jamapsychiatry.2014.2162.
Text Size: A A A
Published online

Importance  Binge-eating disorder (BED), a public health problem associated with psychopathological symptoms and obesity and possibly with metabolic syndrome, lacks approved pharmacotherapies.

Objective  To examine the efficacy and safety of lisdexamfetamine dimesylate, a dextroamphetamine prodrug, to treat moderate to severe BED.

Design, Setting, and Participants  We performed a randomized, double-blind, parallel-group, forced dose titration, placebo-controlled clinical trial at 30 sites from May 10, 2011, through January 30, 2012. Safety and intention-to-treat analyses included 259 and 255 adults with BED, respectively.

Interventions  Lisdexamfetamine dimesylate at dosages of 30, 50, or 70 mg/d or placebo were provided to study participants (1:1:1:1). Dosages were titrated across 3 weeks and maintained for 8 weeks. We followed up participants for a mean (SD) of 7 (2) days after the last dose.

Main Outcomes and Measures  We assessed the change in binge-eating (BE) behaviors measured as days per week (baseline to week 11) with a mixed-effects model using transformed log (BE days per week) + 1. Secondary measures included BE cessation for 4 weeks. Safety assessments included treatment-emergent adverse events, vital signs, and change in weight.

Results  At week 11, log-transformed BE days per week decreased with the 50-mg/d (least squares [LS] mean [SE] change, −1.49 [0.066]; P = .008) and 70-mg/d (LS mean [SE] change, −1.57 [0.067]; P < .001) treatment groups but not the 30-mg/d treatment group (LS mean [SE] change, −1.24 [0.067]; P = .88) compared with the placebo group. Nontransformed mean (SD) days per week decreased for placebo and the 30-, 50-, and 70-mg/d treatment groups by −3.3 (2.04), −3.5 (1.95), −4.1 (1.52), and −4.1 (1.57), respectively. The percentage of participants achieving 4-week BE cessation was lower with the placebo group (21.3%) compared with the 50-mg/d (42.2% [P = .01]) and 70-mg/d (50.0% [P < .001]) treatment groups. The incidence of any treatment-emergent adverse events was 58.7% for the placebo group and 84.7% for the combined treatment group. In the treatment groups, 1.5% of participants had serious treatment-emergent adverse effects. Events with a frequency of at least 5% and changes in heart rate were generally consistent with the known safety profile. The mean (SD) change in body weight was −0.1 (3.09), −3.1 (3.64), −4.9 (4.43), −4.9 (3.93), and −4.3 (4.09) kg for the placebo group, the 30-, 50-, and 70-mg/d treatment groups, and the combined treatment groups, respectively (P < .001 for each dose vs placebo group comparison in post hoc analysis).

Conclusions and Relevance  The 50- and 70-mg/d treatment groups demonstrated efficacy compared with the placebo group in decreased BE days, BE cessation, and global improvement. The safety profile was generally consistent with previous findings in adults with attention-deficit/hyperactivity disorder. Further investigation of lisdexamfetamine in BED is ongoing.

Trial Registration  clinicaltrials.gov Identifier: NCT01291173

Figures in this Article

Binge-eating disorder (BED) is gaining recognition as a serious public health problem.15 Binge-eating disorder is associated with obesity and psychiatric comorbidities, including depression, and may be predictive of metabolic syndrome.1,2,6 Many patients are undertreated despite functional impairments and personal and social difficulties leading to a poor quality of life.1,4,6,7 Binge-eating disorder is characterized by recurrent episodes of excessive food consumption accompanied by a sense of loss of control (binge eating [BE]) and psychological distress but without the inappropriate compensatory weight-loss behaviors of bulimia nervosa.6,8 In the DSM-5, BED is an official diagnosis,8 which will likely raise clinical awareness.9,10

Cognitive behavioral therapy and/or interpersonal psychotherapy reduces BE behavior, even in patients with severe symptoms and psychopathological features, but implementation has not been widespread, and not all patients respond adequately.11,12 Antidepressants, including tricyclic agents, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors, reduce the frequency of BE behavior but fail to have substantial weight-loss effects.3,13,14 Treatment with the antiobesity agent sibutramine hydrochloride demonstrated some efficacy in clinical trials; however, safety concerns led to market withdrawal.3,1416 Antiepileptics also have been studied for BED, although they are associated with high rates of discontinuation.3,17,18 The most extensively studied antiepileptic for BED, topiramate, has efficacy in BE and weight loss, but its use is limited by effects on cognition.19 At present, no pharmacologic treatments for BED are approved by the US Food and Drug Administration.3 Additional clinical trials are needed to identify effective pharmacotherapies.

Pathologic overeating may be related to dysfunction of the dopamine (DA) and norepinephrine systems, as evidenced by genetic and pharmacologic findings and animal models.2025 Food stimulation generates abnormal DA responses in obese individuals,26,27 and methylphenidate-mediated inhibition of DA transport leads to greater increases of DA levels within the caudate in obese individuals with BED compared with those without BED.27

Agents, such as dextroamphetamine, that inhibit reuptake of DA and norepinephrine and elicit release of monoamine neurotransmitters28 may alter pathologic BE and be feasible treatment options for BED. Clinical trials designed to assess psychostimulants in adults with BED are needed. Lisdexamfetamine dimesylate is a dextroamphetamine prodrug approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults.29 The aim of the present study was to examine the efficacy and safety of lisdexamfetamine vs placebo in adults with moderate to severe BED, as indicated by at least 3 BE days per week for the 2 weeks before the baseline visit.

The study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice, all local ethical and legal requirements, and the World Medical Assembly (Declaration of Helsinki). The study protocol and procedures were submitted and approved by each site’s institutional review board or independent ethics committee. Written informed consent was required for study participation.

This multicenter, randomized, double-blind, parallel-group, forced dose titration, placebo-controlled clinical trial was initiated at 31 US sites and conducted at 28 from May 10, 2011, through January 30, 2012. The median number of enrolled participants per site was 10 (range, 2-22). The overall study duration for each participant was 14 weeks; treatment was administered for 11 weeks. Study sites included clinical research centers, university-affiliated clinics, and psychiatric practices. The study was initiated at a large number of sites in anticipation of recruitment difficulties given that individuals in the population with BED often are not well recognized in clinical settings. Subsequent to study completion, 1 investigator came under investigation for reasons unrelated to this study. Lacking information on the purpose or scope of the investigation, we deemed it prudent to drop this investigator’s site from our analyses.

Adults (aged 18-55 years) who met the DSM-IV-TR diagnostic criteria30 for BED were eligible. The diagnosis was confirmed using the eating disorders module (module H) of the Structural Clinical Interview for DSM-IV-TR Axis I Disorders31 and the Eating Disorder Examination Questionnaire.32 Additional eligibility criteria included a body mass index of at least 25 and no greater than 45 (calculated as weight in kilograms divided by height in meters squared).

Exclusion criteria included current bulimia nervosa, anorexia nervosa, ADHD, or another psychiatric disorder; a lifetime history of bipolar disorder or psychosis or other conditions that may confound efficacy and safety assessments; a total Montgomery-Åsberg Depression Rating Scale (MADRS)33 score of at least 18 at screening or baseline visits; psychological or weight-loss interventions initiated within 3 months of screening; use of a psychostimulant within the prior 6 months; and a personal or family history of cardiovascular disease that could increase vulnerability to the sympathomimetic effects of psychostimulants. Any adult with a recent history of suspected substance abuse or a lifetime history of psychostimulant abuse and/or dependence was excluded. Prior (within the past 30 days) or current therapy with investigational compounds, sedatives, anxiolytics, antipsychotics, antidepressants, norepinephrine reuptake inhibitors, sedative hypnotics, benzodiazepines, antihistamines (centrally and peripherally acting), herbal preparations, over-the-counter medications, and weight-reducing agents and prior (within the past 60 days) or current therapy with psychostimulants was prohibited. Nicotine dependence was not exclusionary.

Participants were randomized (1:1:1:1) to receive placebo or 30, 50, or 70 mg/d of lisdexamfetamine dimesylate (treatment groups) using an interactive voice-response system/interactive web-response system. The study blind was maintained by overencapsulation, making placebo and active treatments appear identical in size, weight, shape, and color. The placebo capsule included components similar to those of the lisdexamfetamine capsule, with the exception of the exclusion of the active ingredient and the inclusion of croscarmellose. The 3-week forced-dose titration period was followed by an 8-week dose-maintenance period. Once-daily oral doses for participants assigned to 30-, 50-, or 70-mg/d treatment groups were initiated at the 30-mg/d dosage and titrated weekly in increments of 20 mg/d to the assigned dosage. Dosage changes and reductions were not permitted during the maintenance period; participants could discontinue treatment if they experienced intolerance.

Efficacy

The primary efficacy measure was the number of BE days per week based on clinician interview and confirmation of identified BE episodes in self-reported BE diaries. The primary efficacy end point was the change from baseline to week 11 on the log-transformed scale (BE days per week) + 1. Clinician raters needed to be credentialed and have experience and training to ensure the rigor, validity, and consistency of the ratings. Training of investigator raters was provided by an expert in the field of BED (S.L.M.) to allow for assessment standardization. Training included, but was not limited to, the DSM-IV-TR criteria for BED, description of core BED symptoms, daily BE diary content, participant diary completion instructions, completion content, and completion interpretation. At an investigators’ meeting, training included psychiatric evaluation of adults with BED based on the DSM-IV-TR, Structural Clinical Interview for DSM-IV-TR Axis I Disorders (module H), the Mini International Neuropsychiatric Interview Plus,34 and a review of the Eating Disorder Examination Questionnaire.

Secondary efficacy measures included the number of BE episodes per week, 1-week BE episode response status, and 4-week cessation from BE (free from BE episodes). The Clinical Global Impressions–Improvement Scale (CGI-I)35 rated global improvement of symptoms over time; results were dichotomized as improved (CGI-I ratings of 1 or 2 [very much/much improved]) or not improved (CGI-I ratings of 3-7). The self-reported Eating Inventory, also known as the Three-Factor Eating Questionnaire (TFEQ),36 with demonstrated sensitivity in BED trials, assessed 3 eating behavior factors (cognitive restraint of eating, emotionally based disinhibition of eating, and perceived hunger); for BED, increased scores for the cognitive restraint factor indicate improvement, whereas decreased scores for the disinhibition and perceived hunger factors indicate improvement. Another measure, the self-reported Binge Eating Scale,37 assessed behavioral, affective, and attitudinal components of BE. The Yale-Brown Obsessive Compulsive Scale modified for BE (YBOCS-BE)38 measured obsessiveness of BE thoughts and compulsiveness of BE behaviors. In addition, version 11 of the Barratt Impulsiveness Scale (BIS-11),39 a self-reported scale, measured impulsiveness. Score decreases on the Binge Eating Scale, YBOCS-BE, and BIS-11 indicate improvement. Version 2 of the 12-Item Short Form Health Survey (SF-12),40 a general measurement, assessed participant-perceived quality of life, with score increases indicating improvement. Additional secondary measures included the MADRS,33 which rated severity of depression symptoms, and the Hamilton Anxiety Rating Scale,41 which assessed anxiety.

Safety and Tolerability

Safety assessments included treatment-emergent adverse events (TEAEs), the Columbia–Suicide Severity Rating Scale,42 vital signs, electrocardiography, weight, and laboratory test results (biochemistry, hematologic analysis, and urinalysis). Urine drug testing was conducted at screening, at baseline, and at the investigators’ discretion. Weight was recorded using a calibrated scale while the participants were not wearing shoes, rounded to the nearest 0.5 pounds, and converted to kilograms (to convert, multiply by 0.45) for data reporting.

Statistical Analysis

For statistical analysis, the full-analysis set was defined as all participants who took at least 1 dose of the study drug and had at least 1 postbaseline primary efficacy assessment. The safety-analysis set was defined as all randomized participants who took at least 1 dose of the study drug and completed at least 1 follow-up safety assessment. Intergroup comparisons used a mixed-effects model for repeated measures, including fixed factors for treatment and visit, the interaction of treatment and visit, a covariate of the log-transformation ([baseline number of BE days per week] + 1), and the interaction of the baseline covariate and visit using visit as a categorical variable. Study site was not included as a factor because we had no a priori reason to suspect additional explanatory value of site owing to the use of standardized criteria and training across sites. Mixed-effects models for repeated measures estimated differences from placebo in the change from baseline of the log-transformed scale ([BE days per week] + 1) at week 11 (primary end point). Based on previous experience,18,43 log-transformation was planned to reduce skewness. A hierarchical testing procedure in descending order of lisdexamfetamine dosage was used for pairwise testing between lisdexamfetamine dosages and placebo on the primary end point because we hypothesized that higher lisdexamfetamine dosages would be more likely than lower dosages to be efficacious. We also analyzed changes from baseline in log-transformed BE episodes, TFEQ factor scores, and YBOCS-BE total score to week 11 using the mixed-effects model for repeated measures. Binge-eating episode response rates at 1 week and BE cessation at 4 weeks were analyzed by the Cochran-Mantel-Haenszel test using a modified ridit score with individual treatment arm vs placebo. Pairwise χ2 statistical tests evaluated dichotomized CGI-I ratings at week 11 or early termination for placebo vs each treatment group.

For 80% power to compare the change from baseline in BE days per week on the log-transformed scale, assuming a true effect size of 0.6 between any treatment group and the placebo group, 45 participants who completed treatment were needed in each treatment group based on a 2-sided 2-group t test at the .05 level of significance. Treatment groups of approximately 65 participants were selected, assuming that 30% would not complete the double-blind treatment phase. Double-blind randomization to treatment was assigned by an interactive voice-response system/interactive web-response system designed for this study.

At each double-blind treatment visit, the remaining pills were counted, and a treatment adherence rate was calculated based on the number of pills not returned divided by the number of days. Participants were considered adherent to treatment if the calculated rate ranged from 80% to 120% inclusive. Participants who had taken 80% to 100% of the investigational product given, as assessed by the investigator, were considered adherent for study management purposes.

Disposition and Demographics

Of 260 enrolled participants, 255 were included in the efficacy analyses and 259 in the safety analyses (Figure 1). Fifty-eight participants did not complete the study (17 in the placebo group: 15 in the 30-mg/d treatment group and 13 each in the 50-mg/d and 70-mg/d treatment groups). Seven participants withdrew because of TEAEs (all in the treatment groups) and none for lack of efficacy; no participant discontinued because of weight loss. Of the 259 participants in the safety population, 257 had an adherence rate within the 80% to 120% range. Two participants did not meet this criterion. One participant (in the 30-mg/d treatment group) had a rate less than 80%, and another (in the 70-mg/d treatment group) had a rate of 144.44%. This adherence rate beyond the specified range (>120%) was related to the a priori method for calculation of adherence but, based on medical review, was not a safety issue related to misuse of the investigational product. Demographics and baseline characteristics, including mean number of BE days per week, are shown in Table 1.

Place holder to copy figure label and caption
Figure 1.
Participant Disposition

AE indicates adverse event.

aOne participant randomized to placebo did not provide postbaseline safety assessment data and was not included in the safety population.

Graphic Jump Location
Table Graphic Jump LocationTable 1.  Demographics and Baseline Characteristics, Safety-Analysis Set
Efficacy

The change in the number of BE days per week from baseline through week 11 for all treatment groups is shown in Figure 2. The mean (SD) changes from baseline to week 11 or early termination in nontransformed BE days per week for the placebo and the 30-, 50-, and 70-mg/d treatment groups were −3.3 (2.04), −3.5 (1.95), −4.1 (1.52), and −4.1 (1.57), respectively. The primary efficacy end point (least squares [LS] mean change from baseline to week 11 on log-transformed BE days per week) was significantly decreased in the 50- and 70-mg/d treatment groups but not in the 30-mg/d treatment group compared with the placebo group (Table 2).

Place holder to copy figure label and caption
Figure 2.
Nontransformed Weekly Binge-Eating (BE) Days at Baseline and Through Week 11

Includes full-analysis set of 255 participants.

aBaseline is the number of BE days experienced in the 7 days before the baseline visit.

Graphic Jump Location

The LS mean change from baseline to week 11 of log-transformed BE episodes per week was significantly decreased for the 50- and 70-mg/d treatment groups (Table 2). At week 11 or early termination, the 1-week response status was improved in the 50- and 70-mg/d treatment groups compared with the placebo group, and the 4-week BE cessation response status was improved in the 50- and 70-mg/d treatment groups compared with the placebo group (Table 2).

Greater proportions of participants receiving lisdexamfetamine were rated improved (CGI-I rating, 1 or 2) compared with those receiving placebo at week 11 or early termination (Table 2). At baseline, mean TFEQ scores for the cognitive restraint factor were in the low to normal range (0-10). Scores were in the clinical (≥12) and high (9-11) ranges for the disinhibition and hunger factors, respectively (Table 2). At week 11, LS mean scores on all 3 TFEQ factors in the 70-mg/d treatment group and 2 of the 3 TFEQ factors (not cognitive restraint) in the 50-mg/d treatment group significantly improved compared with the placebo group (Table 2). At baseline, mean Binge Eating Scale scores were in the severe range (≥27) and demonstrated greater improvement at week 11 in all the treatment groups compared with the placebo group (Table 2). At baseline, mean YBOCS-BE total scores were in the moderate range (16-23); the LS mean total scores for this measure improved in all treatment groups compared with the placebo group at week 11 (Table 2). As additional secondary efficacy measures, significant improvement in the LS mean BIS-11 total score was found in the 70-mg/d treatment group compared with the placebo group (Table 2). The SF-12 Physical and Mental Health Component Summary aggregate scores were comparable at baseline across treatment groups. The change in the LS mean score for the aggregate Mental Health Component Summary was not significantly different between any treatment group and the placebo group. Moreover, the aggregate change in the LS mean score for the SF-12 Physical Health Component Summary was significant only for the 70-mg/d treatment group compared with the placebo group and not for the other treatment groups (Table 2). Baseline mean MADRS and Hamilton Anxiety Rating Scale symptom scores indicated that depression and anxiety symptoms were low across all groups; none of the changes in the LS mean scores for the MADRS and Hamilton Anxiety Rating Scale across the treatment groups were significantly different from those of the placebo group at week 11 (Table 2).

Safety

The frequency of TEAEs is summarized in Table 3. In the placebo group, no discontinuations owing to TEAEs, no serious TEAEs, and no deaths occurred. Among the 196 participants receiving lisdexamfetamine, 6 (3.1%) discontinued treatment owing to TEAEs and 3 (1.5%) had serious TEAEs. One participant (in the 70-mg/d treatment group) died because of toxicology findings consistent with a methamphetamine overdose. During screening, the participant denied a history of substance abuse, and results of drug tests during the study were negative. However, postmortem toxicologic analysis found methamphetamine/amphetamine levels consistent with methamphetamine overdose. The study investigator did not consider this death to be related to the study drug. Two other serious TEAEs (acute pancreatitis and appendicitis) occurred in participants in the 30-mg/d treatment group and were considered unrelated to the study drug. According to scores on the Columbia–Suicide Severity Rating Scale, no participant had suicidal ideation, thoughts, or attempts during treatment. Mean heart rate tended to increase from baseline to week 11 or early termination with lisdexamfetamine treatment (Table 3). No comparable trends were observed with systolic or diastolic blood pressure (Table 3). Also, no clinically meaningful trends were observed for clinical laboratory results or electrocardiography interval data.

Table Graphic Jump LocationTable 3.  Safety Parameters: Adverse Events and Vital Signsa

Participants’ mean weight in the treatment groups decreased with treatment; the placebo group experienced no mean weight change. The mean (SD) change in body weight was −0.1 (3.09), −3.1 (3.64), −4.9 (4.43), −4.9 (3.93), and −4.3 (4.09) kg for the placebo group; the 30-, 50-, and 70-mg/d treatment groups; and the combined treatment groups, respectively. In a post hoc analysis, the percentage of reduction in body weight was greater for all treatment groups compared with the placebo group at week 11 (all, P < .001). In addition, the LS mean (SE) differences compared with the placebo group in the percentage of reduction in body weight at week 11 for the 30-, 50-, and 70-mg treatment groups were 3.268% (0.7197%), 5.179% (0.7214%), and 5.282% (0.7229%), respectively.

In the primary analysis of this study of adults with moderate to severe BED, lisdexamfetamine dimesylate treatment with 50 and 70 mg/d, but not 30 mg/d, demonstrated a significant decrease (compared with placebo) in weekly BE days per week at week 11. Similarly, BE episodes decreased in the 50- and 70-mg/d treatment groups. The 1-week BE episode response status was improved in the 50- and 70-mg/d treatment groups, and a greater proportion of participants achieved 4-week cessation of BE episodes and global improvement of symptom severity with all lisdexamfetamine dosages. Participant-reported BE symptoms and clinician-rated BE obsessive-compulsive features were improved with all lisdexamfetamine dosages. Together, these findings provide substantial preliminary evidence that lisdexamfetamine may be effective for treatment of moderate to severe BED, which is consistent with its effect on DA and norepinephrine neurotransmitters and a potential effect on abnormal eating behaviors. Potential confounding effects due to depressive or anxiety symptoms are unlikely to have contributed to these effects given that the MADRS and Hamilton Anxiety Rating Scale scores were low at baseline and did not change during the study. Similarly, potential confounding effects due to ADHD symptoms are unlikely because comorbid ADHD was a criterion for exclusion.

Other drug classes and agents as well as psychological therapy have demonstrated efficacy in treating various aspects of BED, including BE frequency, BE response status, metabolic and medical markers, and global symptom severity.17,18,4349 However, no direct comparisons were conducted in the present study. Comparative studies of active treatments for BED are lacking and would be needed to determine the relative efficacy among treatments, including lisdexamfetamine.

Weight, in this study, was assessed as a safety variable. A post hoc analysis suggested that lisdexamfetamine treatment may result in weight decreases relative to placebo, but no participant discontinued the study owing to weight loss. Being overweight and being obese are acknowledged to be important medical issues for a significant proportion of patients with BED. As such, prospective studies are ongoing that, in addition to the effects on core features of BED (ie, BE behavior), will provide important data regarding the short- and long-term weight changes associated with lisdexamfetamine treatment in individuals with BED.

The safety profile of lisdexamfetamine was generally consistent with that seen in studies of lisdexamfetamine in adults with ADHD in the types and frequency of adverse effects.5052 In the present study, small mean increases in heart rate were noted with lisdexamfetamine treatment, consistent with other studies of psychostimulants.50,51 Discontinuation owing to lack of efficacy (none) and adverse events (7 of 259 participants) was comparable with results of selective serotonin reuptake inhibitor studies and somewhat lower than that seen in topiramate trials.13,17,49

One participant died during the study. Postmortem toxicology analysis reported that methamphetamine/amphetamine levels were consistent with a methamphetamine overdose. This was, to our knowledge, the first such report of a methamphetamine overdose during the course of a lisdexamfetamine clinical trial, because no previous publications of lisdexamfetamine clinical trials across multiple indications have reported methamphetamine overdose.50,51,5360 Although available data suggest an increased likelihood of comorbid alcohol and other substance use disorders among patients with BED,1,5 the data do not support a correlation between eating disorders and the licit or illicit use of stimulants.61 However, like other amphetamine-based medications, lisdexamfetamine is a schedule II controlled substance with a black box warning that notes the potential for abuse and dependence.62 To help physicians monitor for potential misuse, most states have prescription drug monitoring programs, which can be effective in reducing prescription drug misuse.63

This study has several limitations. Most participants were female, white, non-Hispanic/non-Latino, and overweight or obese (based on body mass index). Participants with comorbid illnesses (eg, cardiovascular or psychiatric conditions) were excluded, limiting the generalizability of these findings to all adult patients with BED.1,6,16,64 Although the lifetime prevalence of mood disorders in individuals with BED is approximately 50%1,65,66 and the prevalence of depressive symptoms in this study was very low, individuals with current Axis I disorders were excluded intentionally to limit potential confounding factors and to allow for an assessment of the effect of lisdexamfetamine specifically on BE behavior. The short study duration may have limited separation from placebo on the aggregate SF-12 physical and mental functioning measures and may limit conclusions about the long-term efficacy and safety of lisdexamfetamine. Assessment and calculation of BE days and episodes relied on diary reports by participants, which were reviewed and verified by an experienced and trained clinical investigator to ensure the accuracy of the reported BE episodes. However, because divergence between participant and physician reports were not measured formally, the level of potential discrepancies between participant and investigator reports is not known. In addition, conclusions on the large numbers of secondary end points in this study should be drawn with caution because such analyses were not subject to multiplicity adjustment. Subjective differences related to participant-reported outcomes may have occurred during data collection; therefore, the potential for variability and magnitude of the differences should be considered when evaluating the results.

This study supports further assessment of lisdexamfetamine as a treatment option for decreasing BE behavior and the BE-associated obsessive and compulsive features in adults with moderate to severe BED. Increased efficacy with increasing dosages of lisdexamfetamine suggests a dose-response relationship. In this cohort of adults, the lisdexamfetamine safety profile was generally consistent with findings in adults with ADHD.5052 Confirmation of these findings in ongoing clinical trials may result in improved pharmacologic treatment for moderate to severe BED.

Submitted for Publication: April 22, 2014; final revision received August 5, 2014; accepted August 15, 2014.

Corresponding Author: Susan L. McElroy, MD, Research Institute, Lindner Center of HOPE, 4075 Old Western Row Rd, Mason, OH 45040 (susan.mcelroy@lindnercenter.org).

Published Online: January 14, 2015. doi:10.1001/jamapsychiatry.2014.2162.

Author Contributions: Dr McElroy had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: McElroy, Hudson, Wilfley, Ferreira-Cornwell, Gao, Wang, Whitaker, Jonas, Gasior.

Acquisition, analysis, or interpretation of data: McElroy, Hudson, Mitchell, Ferreira-Cornwell, Gao, Wang, Whitaker, Jonas, Gasior.

Drafting of the manuscript: McElroy, Ferreira-Cornwell, Gao, Wang, Whitaker, Gasior.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Gao, Wang, Whitaker, Gasior.

Obtained funding: Jonas.

Administrative, technical, or material support: Ferreira-Cornwell, Gao, Jonas.

Study supervision: McElroy, Mitchell, Wilfley, Ferreira-Cornwell, Gao, Jonas.

Conflict of Interest Disclosures: Dr McElroy is a consultant to or member of the scientific advisory boards of Alkermes, Bracket, Corcept, F. Hoffmann-LaRoche, Ltd, MedAvante, Naurex, Shire, Sunovian, and Teva; has received grant support from the Agency for Healthcare Research and Quality, Alkermes, AstraZeneca, Cephalon (now Teva), Eli Lilly and Company, Forest, Marriott Foundation, National Institute of Mental Health, Naurex, Orexigen, Pfizer, Shire, Takeda, and Transcept; is listed as an inventor on US patent 6,323,236 B2 (Use of Sulfamate Derivatives for Treating Impulse Control Disorders); and, along with the patent’s assignee, University of Cincinnati, has received payments from Johnson & Johnson, which has exclusive rights under the patent. Dr Hudson has received consulting fees from Alkermes, Genentech, HealthCore, Pfizer, Roche, and Shire and has received grant support from Eli Lilly and Company, Otsuka, and Shire. Dr Mitchell is a consultant to Shire and served as an investigator on a Shire-funded protocol. Dr Wilfley has received research support from Shire and United Health. Drs Ferreira-Cornwell, Gao, Whitaker, and Gasior hold stock and/or stock options in Shire Development, LLC. No other disclosures were reported.

Funding/Support: This study was supported by Shire Development, LLC, including funding to Scientific Communications & Information and Complete Healthcare Communications, Inc, for support in writing and editing the manuscript.

Role of the Funder/Sponsor: The funding source was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. The authors exercised control over the content of the manuscript and over the decision to submit the manuscript to JAMA Psychiatry.

Additional Contributions: Under the direction of the authors, Michael Pucci, PhD, Scientific Communications & Information, Parsippany, New Jersey, provided writing assistance for the manuscript. Under the direction of Robert Axford-Gatley, MD, Complete Healthcare Communications, Inc, Chadds Fords, Pennsylvania, provided editorial assistance in formatting, proofreading, copy editing, and fact checking. These contributors are employees of the companies that were contracted by Shire Development, LCC, to provide editorial assistance.

Hudson  JI, Hiripi  E, Pope  HG  Jr, Kessler  RC.  The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007;61(3):348-358.
PubMed   |  Link to Article
Hudson  JI, Lalonde  JK, Coit  CE,  et al.  Longitudinal study of the diagnosis of components of the metabolic syndrome in individuals with binge-eating disorder. Am J Clin Nutr. 2010;91(6):1568-1573.
PubMed   |  Link to Article
McElroy  SL, Guerdjikova  AI, Mori  N, O’Melia  AM.  Pharmacological management of binge eating disorder: current and emerging treatment options. Ther Clin Risk Manag. 2012;8:219-241.
PubMed   |  Link to Article
Wilfley  DE, Wilson  GT, Agras  WS.  The clinical significance of binge eating disorder. Int J Eat Disord. 2003;34(suppl):S96-S106.
PubMed   |  Link to Article
Kessler  RC, Berglund  PA, Chiu  WT,  et al.  The prevalence and correlates of binge eating disorder in the World Health Organization World Mental Health Surveys. Biol Psychiatry. 2013;73(9):904-914.
PubMed   |  Link to Article
Mathes  WF, Brownley  KA, Mo  X, Bulik  CM.  The biology of binge eating. Appetite. 2009;52(3):545-553.
PubMed   |  Link to Article
Javaras  KN, Pope  HG, Lalonde  JK,  et al.  Co-occurrence of binge eating disorder with psychiatric and medical disorders. J Clin Psychiatry. 2008;69(2):266-273.
PubMed   |  Link to Article
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.5th ed. Washington, DC: American Psychiatric Association; 2013.
Berg  KC, Stiles-Shields  EC, Swanson  SA, Peterson  CB, Lebow  J, Le Grange  D.  Diagnostic concordance of the interview and questionnaire versions of the Eating Disorder Examination. Int J Eat Disord. 2012;45(7):850-855.
PubMed   |  Link to Article
Keel  PK, Brown  TA, Holm-Denoma  J, Bodell  LP.  Comparison of DSM-IV versus proposed DSM-5 diagnostic criteria for eating disorders: reduction of eating disorder not otherwise specified and validity. Int J Eat Disord. 2011;44(6):553-560.
PubMed   |  Link to Article
Iacovino  JM, Gredysa  DM, Altman  M, Wilfley  DE.  Psychological treatments for binge eating disorder. Curr Psychiatry Rep. 2012;14(4):432-446.
PubMed   |  Link to Article
Wilson  GT, Wilfley  DE, Agras  WS, Bryson  SW.  Psychological treatments of binge eating disorder. Arch Gen Psychiatry. 2010;67(1):94-101.
PubMed   |  Link to Article
Capasso  A, Petrella  C, Milano  W.  Pharmacological profile of SSRIs and SNRIs in the treatment of eating disorders. Curr Clin Pharmacol. 2009;4(1):78-83.
PubMed   |  Link to Article
Reas  DL, Grilo  CM.  Review and meta-analysis of pharmacotherapy for binge-eating disorder. Obesity (Silver Spring). 2008;16(9):2024-2038.
PubMed   |  Link to Article
Appolinario  JC, Bacaltchuk  J, Sichieri  R,  et al.  A randomized, double-blind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder. Arch Gen Psychiatry. 2003;60(11):1109-1116.
PubMed   |  Link to Article
Wilfley  DE, Crow  SJ, Hudson  JI,  et al; Sibutramine Binge Eating Disorder Research Group.  Efficacy of sibutramine for the treatment of binge eating disorder: a randomized multicenter placebo-controlled double-blind study. Am J Psychiatry. 2008;165(1):51-58.
PubMed   |  Link to Article
McElroy  SL, Arnold  LM, Shapira  NA,  et al.  Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(2):255-261.
PubMed   |  Link to Article
McElroy  SL, Hudson  JI, Capece  JA, Beyers  K, Fisher  AC, Rosenthal  NR; Topiramate Binge Eating Disorder Research Group.  Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
PubMed   |  Link to Article
McElroy  SL, Guerdjikova  AI, Martens  B, Keck  PE  Jr, Pope  HG, Hudson  JI.  Role of antiepileptic drugs in the management of eating disorders. CNS Drugs. 2009;23(2):139-156.
PubMed   |  Link to Article
Johnson  PM, Kenny  PJ.  Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci. 2010;13(5):635-641.
PubMed   |  Link to Article
Shinohara  M, Mizushima  H, Hirano  M,  et al.  Eating disorders with binge-eating behaviour are associated with the s allele of the 3′-UTR VNTR polymorphism of the dopamine transporter gene. J Psychiatry Neurosci. 2004;29(2):134-137.
PubMed
Latagliata  EC, Patrono  E, Puglisi-Allegra  S, Ventura  R.  Food seeking in spite of harmful consequences is under prefrontal cortical noradrenergic control. BMC Neurosci. 2010;11:15. doi:10.1186/1471-2202-11-15.
PubMed   |  Link to Article
Stice  E, Spoor  S, Bohon  C, Small  DM.  Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science. 2008;322(5900):449-452.
PubMed   |  Link to Article
Davis  CA, Levitan  RD, Reid  C,  et al.  Dopamine for “wanting” and opioids for “liking”: a comparison of obese adults with and without binge eating. Obesity (Silver Spring). 2009;17(6):1220-1225.
PubMed
Davis  C, Levitan  RD, Kaplan  AS,  et al.  Dopamine transporter gene (DAT1) associated with appetite suppression to methylphenidate in a case-control study of binge eating disorder. Neuropsychopharmacology. 2007;32(10):2199-2206.
PubMed   |  Link to Article
Rothemund  Y, Preuschhof  C, Bohner  G,  et al.  Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals. Neuroimage. 2007;37(2):410-421.
PubMed   |  Link to Article
Wang  GJ, Geliebter  A, Volkow  ND,  et al.  Enhanced striatal dopamine release during food stimulation in binge eating disorder. Obesity (Silver Spring). 2011;19(8):1601-1608.
PubMed   |  Link to Article
Heal  DJ, Cheetham  SC, Smith  SL.  The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology. 2009;57(7-8):608-618.
PubMed   |  Link to Article
Vyvanse® (Lisdexamfetamine Dimesylate) [package insert]. Wayne, PA: Shire US Inc; 2013.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.
First  M, Spitzer  RL, Gibbon  M,  et al. Structured Clinical Interview for DSM-IV-TR Axis I Disorders. New York: Biometrics Research, New York State Psychiatric Institute; 2002.
Fairburn  CG, Beglin  SJ.  Assessment of eating disorders: interview or self-report questionnaire? Int J Eat Disord. 1994;16(4):363-370.
PubMed
Montgomery  SA, Åsberg  M.  A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
PubMed   |  Link to Article
Sheehan  DV, Lecrubier  Y, Sheehan  KH,  et al.  The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33.
PubMed
Guy  W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: Psychopharmacology Research Branch, National Institute of Mental Health; 1976.
Stunkard  AJ, Messick  S.  The Three-Factor Eating Questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom Res. 1985;29(1):71-83.
PubMed   |  Link to Article
Timmerman  G.  Binge Eating Scale: further assessment of validity and reliability. J Appl Biobehav Res. 1999;4(1):1-12.
Link to Article
Goodman  WK, Price  LH, Rasmussen  SA,  et al.  The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry. 1989;46(11):1006-1011.
PubMed   |  Link to Article
Patton  JH, Stanford  MS, Barratt  ES.  Factor structure of the Barratt Impulsiveness Scale. J Clin Psychol. 1995;51(6):768-774.
PubMed   |  Link to Article
Ware  J  Jr, Kosinski  M, Keller  SD.  A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-233.
PubMed   |  Link to Article
Hamilton  M.  A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
PubMed   |  Link to Article
Posner  K, Brent  D, Lucas  C,  et al. Columbia–Suicide Severity Rating Scale.2009. http://cssrs.columbia.edu/docs/C-SSRS_1_14_09_Baseline.pdf. Accessed December 2, 2014.
McElroy  SL, Guerdjikova  A, Kotwal  R,  et al.  Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry. 2007;68(3):390-398.
PubMed   |  Link to Article
Hudson  JI, McElroy  SL, Raymond  NC,  et al.  Fluvoxamine in the treatment of binge-eating disorder: a multicenter placebo-controlled, double-blind trial. Am J Psychiatry. 1998;155(12):1756-1762.
PubMed   |  Link to Article
McElroy  SL, Casuto  LS, Nelson  EB,  et al.  Placebo-controlled trial of sertraline in the treatment of binge eating disorder. Am J Psychiatry. 2000;157(6):1004-1006.
PubMed   |  Link to Article
Grilo  CM, Masheb  RM, Wilson  GT.  Efficacy of cognitive behavioral therapy and fluoxetine for the treatment of binge eating disorder: a randomized double-blind placebo-controlled comparison. Biol Psychiatry. 2005;57(3):301-309.
PubMed   |  Link to Article
McElroy  SL, Kotwal  R, Guerdjikova  AI,  et al.  Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiatry. 2006;67(12):1897-1906.
PubMed   |  Link to Article
Guerdjikova  AI, McElroy  SL, Kotwal  R,  et al.  High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial. Hum Psychopharmacol. 2008;23(1):1-11.
PubMed   |  Link to Article
Arbaizar  B, Gómez-Acebo  I, Llorca  J.  Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review. Gen Hosp Psychiatry. 2008;30(5):471-475.
PubMed   |  Link to Article
Adler  LA, Goodman  DW, Kollins  SH,  et al; 303 Study Group.  Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364-1373.
PubMed   |  Link to Article
Weisler  R, Young  J, Mattingly  G, Gao  J, Squires  L, Adler  L; 304 Study Group.  Long-term safety and effectiveness of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. CNS Spectr. 2009;14(10):573-585.
PubMed
Wigal  T, Brams  M, Gasior  M, Gao  J, Squires  L, Giblin  J; 316 Study Group.  Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design. Behav Brain Funct. 2010;6:34. doi:10.1186/1744-9081-6-34.
PubMed   |  Link to Article
Brams  M, Weisler  R, Findling  RL,  et al.  Maintenance of efficacy of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: randomized withdrawal design. J Clin Psychiatry. 2012;73(7):977-983.
PubMed   |  Link to Article
Adler  LA, Dirks  B, Deas  PF,  et al.  Lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(7):694-702.
PubMed   |  Link to Article
Biederman  J, Krishnan  S, Zhang  Y, McGough  JJ, Findling  RL.  Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007;29(3):450-463.
PubMed   |  Link to Article
Findling  RL, Childress  AC, Cutler  AJ,  et al.  Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(4):395-405.
PubMed   |  Link to Article
Findling  RL, Ginsberg  LD, Jain  R, Gao  J.  Effectiveness, safety, and tolerability of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: an open-label, dose-optimization study. J Child Adolesc Psychopharmacol. 2009;19(6):649-662.
PubMed   |  Link to Article
Lasser  R, Dirks  B, Nasrallah  H,  et al. Adjunctive lisdexamfetamine dimesylate treatment of predominant negative symptoms of schizophrenia in clinically stable adults maintained on atypical antipsychotic agents: a 14-week trial. Paper presented at: Third Biennial Schizophrenia International Research Conference; April 16, 2012; Florence, Italy.
Madhoo  M, Keefe  RS, Roth  RM,  et al.  Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology. 2014;39(6):1388-1398.
PubMed   |  Link to Article
Trivedi  MH, Cutler  AJ, Richards  C,  et al.  A randomized controlled trial of the efficacy and safety of lisdexamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry. 2013;74(8):802-809.
PubMed   |  Link to Article
Calero-Elvira  A, Krug  I, Davis  K, López  C, Fernández-Aranda  F, Treasure  J.  Meta-analysis on drugs in people with eating disorders. Eur Eat Disord Rev. 2009;17(4):243-259.
PubMed   |  Link to Article
Panagiotou  OA, Contopoulos-Ioannidis  DG, Papanikolaou  PN, Ntzani  EE, Ioannidis  JP.  Different black box warning labeling for same-class drugs. J Gen Intern Med. 2011;26(6):603-610.
PubMed   |  Link to Article
Gugelmann  H, Perrone  J, Nelson  L.  Windmills and pill mills: can PDMPs tilt the prescription drug epidemic? J Med Toxicol. 2012;8(4):378-386.
PubMed   |  Link to Article
Grucza  RA, Przybeck  TR, Cloninger  CR.  Prevalence and correlates of binge eating disorder in a community sample. Compr Psychiatry. 2007;48(2):124-131.
PubMed   |  Link to Article
Grilo  CM, White  MA, Barnes  RD, Masheb  RM.  Psychiatric disorder co-morbidity and correlates in an ethnically diverse sample of obese patients with binge eating disorder in primary care settings. Compr Psychiatry. 2013;54(3):209-216.
PubMed   |  Link to Article
Grilo  CM, White  MA, Masheb  RM.  DSM-IV psychiatric disorder comorbidity and its correlates in binge eating disorder. Int J Eat Disord. 2009;42(3):228-234.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Participant Disposition

AE indicates adverse event.

aOne participant randomized to placebo did not provide postbaseline safety assessment data and was not included in the safety population.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Nontransformed Weekly Binge-Eating (BE) Days at Baseline and Through Week 11

Includes full-analysis set of 255 participants.

aBaseline is the number of BE days experienced in the 7 days before the baseline visit.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Demographics and Baseline Characteristics, Safety-Analysis Set
Table Graphic Jump LocationTable 3.  Safety Parameters: Adverse Events and Vital Signsa

References

Hudson  JI, Hiripi  E, Pope  HG  Jr, Kessler  RC.  The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007;61(3):348-358.
PubMed   |  Link to Article
Hudson  JI, Lalonde  JK, Coit  CE,  et al.  Longitudinal study of the diagnosis of components of the metabolic syndrome in individuals with binge-eating disorder. Am J Clin Nutr. 2010;91(6):1568-1573.
PubMed   |  Link to Article
McElroy  SL, Guerdjikova  AI, Mori  N, O’Melia  AM.  Pharmacological management of binge eating disorder: current and emerging treatment options. Ther Clin Risk Manag. 2012;8:219-241.
PubMed   |  Link to Article
Wilfley  DE, Wilson  GT, Agras  WS.  The clinical significance of binge eating disorder. Int J Eat Disord. 2003;34(suppl):S96-S106.
PubMed   |  Link to Article
Kessler  RC, Berglund  PA, Chiu  WT,  et al.  The prevalence and correlates of binge eating disorder in the World Health Organization World Mental Health Surveys. Biol Psychiatry. 2013;73(9):904-914.
PubMed   |  Link to Article
Mathes  WF, Brownley  KA, Mo  X, Bulik  CM.  The biology of binge eating. Appetite. 2009;52(3):545-553.
PubMed   |  Link to Article
Javaras  KN, Pope  HG, Lalonde  JK,  et al.  Co-occurrence of binge eating disorder with psychiatric and medical disorders. J Clin Psychiatry. 2008;69(2):266-273.
PubMed   |  Link to Article
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.5th ed. Washington, DC: American Psychiatric Association; 2013.
Berg  KC, Stiles-Shields  EC, Swanson  SA, Peterson  CB, Lebow  J, Le Grange  D.  Diagnostic concordance of the interview and questionnaire versions of the Eating Disorder Examination. Int J Eat Disord. 2012;45(7):850-855.
PubMed   |  Link to Article
Keel  PK, Brown  TA, Holm-Denoma  J, Bodell  LP.  Comparison of DSM-IV versus proposed DSM-5 diagnostic criteria for eating disorders: reduction of eating disorder not otherwise specified and validity. Int J Eat Disord. 2011;44(6):553-560.
PubMed   |  Link to Article
Iacovino  JM, Gredysa  DM, Altman  M, Wilfley  DE.  Psychological treatments for binge eating disorder. Curr Psychiatry Rep. 2012;14(4):432-446.
PubMed   |  Link to Article
Wilson  GT, Wilfley  DE, Agras  WS, Bryson  SW.  Psychological treatments of binge eating disorder. Arch Gen Psychiatry. 2010;67(1):94-101.
PubMed   |  Link to Article
Capasso  A, Petrella  C, Milano  W.  Pharmacological profile of SSRIs and SNRIs in the treatment of eating disorders. Curr Clin Pharmacol. 2009;4(1):78-83.
PubMed   |  Link to Article
Reas  DL, Grilo  CM.  Review and meta-analysis of pharmacotherapy for binge-eating disorder. Obesity (Silver Spring). 2008;16(9):2024-2038.
PubMed   |  Link to Article
Appolinario  JC, Bacaltchuk  J, Sichieri  R,  et al.  A randomized, double-blind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder. Arch Gen Psychiatry. 2003;60(11):1109-1116.
PubMed   |  Link to Article
Wilfley  DE, Crow  SJ, Hudson  JI,  et al; Sibutramine Binge Eating Disorder Research Group.  Efficacy of sibutramine for the treatment of binge eating disorder: a randomized multicenter placebo-controlled double-blind study. Am J Psychiatry. 2008;165(1):51-58.
PubMed   |  Link to Article
McElroy  SL, Arnold  LM, Shapira  NA,  et al.  Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(2):255-261.
PubMed   |  Link to Article
McElroy  SL, Hudson  JI, Capece  JA, Beyers  K, Fisher  AC, Rosenthal  NR; Topiramate Binge Eating Disorder Research Group.  Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
PubMed   |  Link to Article
McElroy  SL, Guerdjikova  AI, Martens  B, Keck  PE  Jr, Pope  HG, Hudson  JI.  Role of antiepileptic drugs in the management of eating disorders. CNS Drugs. 2009;23(2):139-156.
PubMed   |  Link to Article
Johnson  PM, Kenny  PJ.  Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci. 2010;13(5):635-641.
PubMed   |  Link to Article
Shinohara  M, Mizushima  H, Hirano  M,  et al.  Eating disorders with binge-eating behaviour are associated with the s allele of the 3′-UTR VNTR polymorphism of the dopamine transporter gene. J Psychiatry Neurosci. 2004;29(2):134-137.
PubMed
Latagliata  EC, Patrono  E, Puglisi-Allegra  S, Ventura  R.  Food seeking in spite of harmful consequences is under prefrontal cortical noradrenergic control. BMC Neurosci. 2010;11:15. doi:10.1186/1471-2202-11-15.
PubMed   |  Link to Article
Stice  E, Spoor  S, Bohon  C, Small  DM.  Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science. 2008;322(5900):449-452.
PubMed   |  Link to Article
Davis  CA, Levitan  RD, Reid  C,  et al.  Dopamine for “wanting” and opioids for “liking”: a comparison of obese adults with and without binge eating. Obesity (Silver Spring). 2009;17(6):1220-1225.
PubMed
Davis  C, Levitan  RD, Kaplan  AS,  et al.  Dopamine transporter gene (DAT1) associated with appetite suppression to methylphenidate in a case-control study of binge eating disorder. Neuropsychopharmacology. 2007;32(10):2199-2206.
PubMed   |  Link to Article
Rothemund  Y, Preuschhof  C, Bohner  G,  et al.  Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals. Neuroimage. 2007;37(2):410-421.
PubMed   |  Link to Article
Wang  GJ, Geliebter  A, Volkow  ND,  et al.  Enhanced striatal dopamine release during food stimulation in binge eating disorder. Obesity (Silver Spring). 2011;19(8):1601-1608.
PubMed   |  Link to Article
Heal  DJ, Cheetham  SC, Smith  SL.  The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology. 2009;57(7-8):608-618.
PubMed   |  Link to Article
Vyvanse® (Lisdexamfetamine Dimesylate) [package insert]. Wayne, PA: Shire US Inc; 2013.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.
First  M, Spitzer  RL, Gibbon  M,  et al. Structured Clinical Interview for DSM-IV-TR Axis I Disorders. New York: Biometrics Research, New York State Psychiatric Institute; 2002.
Fairburn  CG, Beglin  SJ.  Assessment of eating disorders: interview or self-report questionnaire? Int J Eat Disord. 1994;16(4):363-370.
PubMed
Montgomery  SA, Åsberg  M.  A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
PubMed   |  Link to Article
Sheehan  DV, Lecrubier  Y, Sheehan  KH,  et al.  The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33.
PubMed
Guy  W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: Psychopharmacology Research Branch, National Institute of Mental Health; 1976.
Stunkard  AJ, Messick  S.  The Three-Factor Eating Questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom Res. 1985;29(1):71-83.
PubMed   |  Link to Article
Timmerman  G.  Binge Eating Scale: further assessment of validity and reliability. J Appl Biobehav Res. 1999;4(1):1-12.
Link to Article
Goodman  WK, Price  LH, Rasmussen  SA,  et al.  The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry. 1989;46(11):1006-1011.
PubMed   |  Link to Article
Patton  JH, Stanford  MS, Barratt  ES.  Factor structure of the Barratt Impulsiveness Scale. J Clin Psychol. 1995;51(6):768-774.
PubMed   |  Link to Article
Ware  J  Jr, Kosinski  M, Keller  SD.  A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-233.
PubMed   |  Link to Article
Hamilton  M.  A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
PubMed   |  Link to Article
Posner  K, Brent  D, Lucas  C,  et al. Columbia–Suicide Severity Rating Scale.2009. http://cssrs.columbia.edu/docs/C-SSRS_1_14_09_Baseline.pdf. Accessed December 2, 2014.
McElroy  SL, Guerdjikova  A, Kotwal  R,  et al.  Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry. 2007;68(3):390-398.
PubMed   |  Link to Article
Hudson  JI, McElroy  SL, Raymond  NC,  et al.  Fluvoxamine in the treatment of binge-eating disorder: a multicenter placebo-controlled, double-blind trial. Am J Psychiatry. 1998;155(12):1756-1762.
PubMed   |  Link to Article
McElroy  SL, Casuto  LS, Nelson  EB,  et al.  Placebo-controlled trial of sertraline in the treatment of binge eating disorder. Am J Psychiatry. 2000;157(6):1004-1006.
PubMed   |  Link to Article
Grilo  CM, Masheb  RM, Wilson  GT.  Efficacy of cognitive behavioral therapy and fluoxetine for the treatment of binge eating disorder: a randomized double-blind placebo-controlled comparison. Biol Psychiatry. 2005;57(3):301-309.
PubMed   |  Link to Article
McElroy  SL, Kotwal  R, Guerdjikova  AI,  et al.  Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiatry. 2006;67(12):1897-1906.
PubMed   |  Link to Article
Guerdjikova  AI, McElroy  SL, Kotwal  R,  et al.  High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial. Hum Psychopharmacol. 2008;23(1):1-11.
PubMed   |  Link to Article
Arbaizar  B, Gómez-Acebo  I, Llorca  J.  Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review. Gen Hosp Psychiatry. 2008;30(5):471-475.
PubMed   |  Link to Article
Adler  LA, Goodman  DW, Kollins  SH,  et al; 303 Study Group.  Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364-1373.
PubMed   |  Link to Article
Weisler  R, Young  J, Mattingly  G, Gao  J, Squires  L, Adler  L; 304 Study Group.  Long-term safety and effectiveness of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. CNS Spectr. 2009;14(10):573-585.
PubMed
Wigal  T, Brams  M, Gasior  M, Gao  J, Squires  L, Giblin  J; 316 Study Group.  Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design. Behav Brain Funct. 2010;6:34. doi:10.1186/1744-9081-6-34.
PubMed   |  Link to Article
Brams  M, Weisler  R, Findling  RL,  et al.  Maintenance of efficacy of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: randomized withdrawal design. J Clin Psychiatry. 2012;73(7):977-983.
PubMed   |  Link to Article
Adler  LA, Dirks  B, Deas  PF,  et al.  Lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(7):694-702.
PubMed   |  Link to Article
Biederman  J, Krishnan  S, Zhang  Y, McGough  JJ, Findling  RL.  Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study. Clin Ther. 2007;29(3):450-463.
PubMed   |  Link to Article
Findling  RL, Childress  AC, Cutler  AJ,  et al.  Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(4):395-405.
PubMed   |  Link to Article
Findling  RL, Ginsberg  LD, Jain  R, Gao  J.  Effectiveness, safety, and tolerability of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: an open-label, dose-optimization study. J Child Adolesc Psychopharmacol. 2009;19(6):649-662.
PubMed   |  Link to Article
Lasser  R, Dirks  B, Nasrallah  H,  et al. Adjunctive lisdexamfetamine dimesylate treatment of predominant negative symptoms of schizophrenia in clinically stable adults maintained on atypical antipsychotic agents: a 14-week trial. Paper presented at: Third Biennial Schizophrenia International Research Conference; April 16, 2012; Florence, Italy.
Madhoo  M, Keefe  RS, Roth  RM,  et al.  Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology. 2014;39(6):1388-1398.
PubMed   |  Link to Article
Trivedi  MH, Cutler  AJ, Richards  C,  et al.  A randomized controlled trial of the efficacy and safety of lisdexamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry. 2013;74(8):802-809.
PubMed   |  Link to Article
Calero-Elvira  A, Krug  I, Davis  K, López  C, Fernández-Aranda  F, Treasure  J.  Meta-analysis on drugs in people with eating disorders. Eur Eat Disord Rev. 2009;17(4):243-259.
PubMed   |  Link to Article
Panagiotou  OA, Contopoulos-Ioannidis  DG, Papanikolaou  PN, Ntzani  EE, Ioannidis  JP.  Different black box warning labeling for same-class drugs. J Gen Intern Med. 2011;26(6):603-610.
PubMed   |  Link to Article
Gugelmann  H, Perrone  J, Nelson  L.  Windmills and pill mills: can PDMPs tilt the prescription drug epidemic? J Med Toxicol. 2012;8(4):378-386.
PubMed   |  Link to Article
Grucza  RA, Przybeck  TR, Cloninger  CR.  Prevalence and correlates of binge eating disorder in a community sample. Compr Psychiatry. 2007;48(2):124-131.
PubMed   |  Link to Article
Grilo  CM, White  MA, Barnes  RD, Masheb  RM.  Psychiatric disorder co-morbidity and correlates in an ethnically diverse sample of obese patients with binge eating disorder in primary care settings. Compr Psychiatry. 2013;54(3):209-216.
PubMed   |  Link to Article
Grilo  CM, White  MA, Masheb  RM.  DSM-IV psychiatric disorder comorbidity and its correlates in binge eating disorder. Int J Eat Disord. 2009;42(3):228-234.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment
Comment on Efficacy and Safety of Lisdexamfetamine for Treatment of Adults With Moderate to Severe Binge-Eating Disorder
Posted on March 17, 2015
Daniel J. Luchins, MD
Jesse Brown VAMC, 820 South Damen Ave Chicago, IL 60615
Conflict of Interest: Dr. Luchins is a paid consultant to Express Scripts Inc.

In their study of  binge-eating disorder (1), McElroy et al, 2015 provide an overview of the literature to underscore the clinical impact of this condition and highlight the limits of current treatment alternatives. They offer evidence from neurochemical studies to support the use of psychostimulants in treating this disorder and describe the results of their controlled trial of lisdexamfetamine.  However, what is not discussed but merits further consideration is the (literally) billion dollar question of why they chose to study  lisdexamfetamine, a dextroamphetamine prodrug currently available only in brand formulation (Vyvanse) over other dextroamaphetamine formulations. That no justification is offered in the text suggests the authors considered that they were studying a drug and not a formulation specific effect and the choice of formulations was based on practical considerations such as the  availability of funding.

I am therefore curious:  

1) whether the authors believe this effect would be seen with other formulations of dextroamphetamine, and  if not, why?  

2) With dramatic price differences amongst formulations, what compelling clinical justification would support the prescription of lisdexamfetamine?

McElroy SL,  Hudson JI, Mitchell JE, et al: Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: A randomized clinical trial. JAMA Psychiatry. 2015:72(3) 235- 246.

The Use of Lisdexamfetamine for Treatment of Binge-Eating Disorder
Posted on March 25, 2015
Mara Silver, Roisin Byrne, Elia Abi-Jaoude
University of Toronto, Department of Psychiatry
Conflict of Interest: None Declared
Dr. McElroy (1) and colleagues recently published a Shire-sponsored multicenter, randomized, placebo-controlled study to evaluate the safety and efficacy of lisdexamfetamine (LDX) for adults with Binge Eating Disorder (BED). Patients with BED, excluding all those with other co-morbid psychiatric conditions, were randomized to receive LDX at doses of 30 mg, 50 mg, or 70 mg per day or placebo for 11 weeks. The primary outcome measure was the change in the number of binge-eating days per week. All four patient groups had 4.3-4.6 binge-eating days per week at baseline, and all groups experienced substantial declines in the number of binge-eating days per week, including placebo. The authors highlight that groups treated with 50 mg or 70 mg of LDX had significantly greater drops in their reported numbers of binge-eating days per week compared to placebo (4.1 for LDX doses vs 3.2 days, respectively). In their discussion they suggest that, “these findings provide substantial preliminary evidence that LDX may be effective for treatment of moderate to severe BED…” The difference of 0.9 binge-eating days per week – or 1 binge eating episode (one of the secondary outcomes) – between placebo and high-dose LDX-treated patients is of questionable clinical significance and may simply be the result of unblinding due to adverse effects. In fact, 84.7% of subjects on LDX had treatment-emergent adverse events. These events are well-known to be associated with the stimulant use and include dry mouth, decreased appetite, nausea, constipation, diarrhea, anxiety, feeling jittery, palpitations, insomnia, and sleep disorder. Further, one patient in the study died, reportedly of an unrelated methamphetamine overdose. The authors state, “The safety profile of LDX was generally consistent with that seen in studies of LDX in adults with ADHD;” however, the sizeable effect size of for stimulant treatment in ADHD far exceeds what we see in this study. On balance, when weighed against the questionable clinical effect, the use of LDX for the treatment of BED may produce more harm than good. Further, given that approximately 4 out 5 people with BED have at least one comorbid psychiatric disorder (2), the study sample is grossly unrepresentative of the patients we treat. The authors’ findings demonstrate that short-term intervention, including placebo, for a select sample of people with BED and no co-morbid psychiatric illnesses may lead to short-term reductions in binge eating. Further implications beyond this should be subject to scrutiny. (1) McElroy SL, Hudson JI, Mitchell JE, et al. Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: A randomized clinical trial. JAMA Psychiatry. 2015; 72(3):235-246. (2) Hudson JI, Hiripi E, Pope HG, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey replication. Biological Psychiatry. 2007; 61(3): 348-358.
A possible confounder
Posted on May 14, 2015
Edward S. Weiss MD
Toronto West Medical
Conflict of Interest: None Declared
I was very interested to read McElroy et al. and their finding that lisdexamfetamine may be effective for binge-eating disorder. The authors state that they eliminated confounding due to unintended treatment of ADHD symptoms by excluding subjects with ADHD. However, it is well known that many adults with ADHD have never been diagnosed and may be unaware of the possibility of having it. Unless the authors administered screening tools to rule out ADHD at baseline, it seems very possible that administration of lisdexamfetamine may have been treating subtle underlying features of ADHD which may have been comorbid with, of causative of, the subjects' binge eating. Future studies of the use of psychostimulants in binge-eating disorder should ensure that subjects are free of ADHD symptoms not just by history, but by specific screening or psychological testing.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

8,082 Views
29 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs