Duloxetine in the Treatment of Binge Eating Disorder with Depressive Disorders: A Placebo-Controlled Trial

Transcription

1 CE ACTIVITY Duloxetine in the Treatment of Binge Eating Disorder with Depressive Disorders: A Placebo-Controlled Trial Anna I. Guerdjikova, PhD 1,2 * Susan L. McElroy, MD 1,2 Erin L. Winstanley, PhD 1,2 Eric B. Nelson, MD 2 Nicole Mori, CNP 1,2 Jessica McCoy, BA 1 Paul E. Keck Jr., MD 1,2 James I. Hudson, MD, ScD 3 ABSTRACT Objective: This study evaluated duloxetine in the treatment of binge eating disorder (BED) with comorbid current depressive disorders. Method: In this 12-week, double-blind, placebo-controlled trial, 40 pati-ents with Diagnostic and Statistical Manual of Mental Disorders-IV-TR BED and a comorbid current depressive disorder received duloxetine or placebo. The primary outcome measure was weekly binge eating day frequency. Results: In the primary analysis, duloxetine (mean 78.7 mg/day) was superior to placebo in reducing weekly frequency of binge eating days (p 5.04), binge eating episodes (p 5.02), weight (p 5.04), and Clinical Global Impression-Severity of Illness ratings for binge eating (p 5.02) and depressive disorders (p 5.01). Changes in body mass index and measures of eating pathology, depression, and anxiety did not differ between the two groups. Discussion: Duloxetine may be effective for reducing binge eating, weight, and global severity of illness in BED with a comorbid current depressive disorder, but this finding needs confirmation in larger, placebo-controlled trials. VC 2011 by Wiley Periodicals, Inc. Keywords: duloxetine; binge eating disorder; depression; obesity; longitudinal analysis (Int J Eat Disord 2012; 45: ) Introduction Binge eating disorder (BED) is characterized by recurrent, distressing episodes of binge eating without the inappropriate compensatory weight loss behaviors of bulimia nervosa. 1 Though currently listed in the Diagnostic and Statistical Manual of Mental Disorders-IV-TR (DSM-IV-TR) 1 appendix as a disorder provided for further study, it has been recommended that BED be formally included as an eating disorder in DSM-5. 2,3 It is Accepted 14 May 2011 Supported in part by a grant from Eli Lilly. Paul Keck Jr, MD, is employed by the University of Cincinnati College of Medicine, University of Cincinnati Physicians, and the Lindner Center of HOPE; Dr. Keck is presently or has been in the past year a principal or co-investigator on research studies sponsored by Alkermes, AstraZeneca, Cephalon, GlaxoSmithKline, Eli Lilly and Company, Epi-Q, Jazz Pharmaceuticals, Marriott Foundation, National Institute of Mental Health (NIMH), Orexigen, Pfizer, Shire; Dr. Keck has been reimbursed for consulting to, in the past year: 2010: Sepracor, Medco, 2009: BristolMyersSquibb, GlaxoSmithKline, Pfizer, QuantiaMD, Schering Plough, Patents: Dr. Paul E. Keck Jr. is a co-inventor on United States Patent No. 6,387,956: Shapira NA, Goldsmith TD, Keck, PE Jr. (University of Cincinnati) Methods of treating obsessive-compulsive spectrum disorder comprises the step of administering an effective amount of tramadol to an individual. Filed March 25, 1999; approved May 14, 2002; Dr. Keck has received no financial gain from this patent. Susan L. McElroy, MD, is employed by the University of Cincinnati College of Medicine, University of Cincinnati Physicians, and the Lindner Center of HOPE; Dr. McElroy is a consultant to, or member of the scientific advisory boards of Alkermes, Eli Lilly and Company, Shire; Dr. McElroy is a principal or co-investigator on research studies sponsored by Agency for Healthcare Research & Quality (AHRQ), Alkermes, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly and Company, Forest Labs, GalaxoSmith Kline, Jazz Pharmaceuticals, Marriott Foundation, National Institute of Mental Health, Orexigen Therapeutics, Pfizer Shire, Takeda Pharmaceutical Company Limited; Patents: Dr. Susan L. McElroy is also inventor on United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and, along with the patent s assignee, University of Cincinnati, Cincinnati, OH, has received payments from Johnson & Johnson Pharmaceutical Research & Development, L.L.C., which has exclusive rights under the patent. James I. Hudson, MD, has been a consultant for Eli Lilly, Pfizer, and Alkermes; and has received grant support from Eli Lilly, Otsuka, and Ortho- McNeil Janssen Scientific Affairs. Erik B. Nelson, MD, has received funding for clinical trials with Astra Zeneca, Novartis and Pamlab. Drs. Erin L. Winstanley and Anna I. Guerdjikova and Mrs. Nicole Mori and Jessica McCoy have no industry/commercial support or conflicts of interest to disclose. *Correspondence to: Anna I. Guerdjikova, PhD; Lindner Center of HOPE, Research Institute, 4075 Old Western Row Road, Mason, OH anna.guerdjikova@lindnercenter.org 1 Lindner Center of HOPE, Mason, Ohio 2 Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio 3 Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts Published online 8 July 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: /eat Ó 2011 Wiley Periodicals, Inc. International Journal of Eating Disorders 45:

2 GUERDJIKOVA ET AL. common, with a lifetime prevalence of about 2 3%, often chronic, and associated with psychopathology, obesity, reduced quality of life, and disability. 2,4 6 BED frequently co-occurs with depressive disorders, including major depressive disorder and dysthymic disorder. 2,4,6 BED patients with comorbid psychiatric disorders, including depressive disorders, may have a more severe illness than patients without comorbid psychiatric disorders, characterized by earlier age at first diet, higher lifetime body mass index (BMI), greater distress, less dietary restraint, lower self-esteem, more frequent binge eating, higher levels of negative affect, more frequent trauma and abuse histories, less successful weight loss, and overall poorer treatment outcomes. 7 9 No randomized, controlled study has specifically addressed the treatment of BED patients with a cooccurring depressive disorder. 10 Novel treatments that reduce binge eating, depressive symptoms, and body weight in this patient population that are also well tolerated are needed. Duloxetine is a selective serotonin norepinephrine reuptake inhibitor (SNRI) approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorder. 11 Several lines of evidence suggested it might be a useful treatment for BED when comorbid with depressive disorders. First, an open-label study 12 and several case reports found that duloxetine decreased binge eating in BED and the related condition bulimia nervosa. Similarly, open-label studies reported the successful treatment of BED and bulimia nervosa with the SNRIs milnacipran 17,18 and venlafaxine. 19 Second, the SNRI sibutramine, a weight loss agent withdrawn from the market in 2010 for safety concerns, 20 has been shown efficacious in three placebo-controlled studies in reducing binge eating behavior and excessive body weight in BED In one of these studies, it was also effective in reducing depressive symptoms. 21 Indeed, a range of antidepressants with various mechanism of action has been reported to reduce binge eating in BED and bulimia nervosa, including serotonin selective reuptake inhibitors (SSRIs) on the one hand and tricyclics with primarily noradrenergic reuptake inhibiting properties on the other. 10 As noted earlier, duloxetine possesses both of these mechanisms. Third, duloxetine is generally well tolerated. 11,24 In particular, it has not been associated with the adverse cardiovascular events triggering sibutramine s withdrawal from the market. 20 These observations led us to hypothesize that duloxetine would decrease binge eating, as well as excessive body weight and depressive symptoms, in BED patients with comorbid depressive disorders. To test this hypothesis we conducted a randomized, parallel-group, placebocontrolled, double-blind, flexible-dose ( mg/day) study to assess the efficacy and safety of duloxetine during a 12-week course of treatment in 40 patients with BED and a comorbid current depressive disorder. Method Participants Study participants were recruited by newspaper advertisements requesting volunteers for a study of an investigational medication for binge eating and depression. Individuals were enrolled into the study if they: (1) were between 18 and 65 years of age (inclusive); (2) met DSM- IV-TR criteria for BED; (3) met DSM-IV-TR criteria for a current depressive disorder (i.e., major depressive disorder, single episode or recurrent; dysthymic disorder; or depressive disorder not otherwise specified (NOS)] for a duration of at least 1 month, including the time preceding and during the screening period; (4) displayed 2 binge days/week (days when the participant had one or more binge eating episodes) prospectively determined by take-home binge diaries for at least 1 week before randomization; and (5) had scores of 25 on the clinicianrated version of the Inventory of Depressive Symptoms Scale (IDS-C) 25 at screening and baseline visits. Individuals were excluded from participation if they: (1) displayed a significant risk for suicide; (2) were receiving psychotherapy from a mental health professional for treatment of BED or depression within 3 months before randomization; (3) had a DSM-IV-TR diagnosis of alcohol or substance abuse or dependence, bulimia nervosa, or anorexia nervosa within 6 months before randomization; (4) had a lifetime history of a psychotic disorder, a bipolar disorder, or dementia; (5) had an Axis II disorder which might interfere with study procedures; (6) had clinically unstable medical disease; (7) had a history of seizures, including febrile seizures in childhood; (8) had a known hypersensitivity to duloxetine or any of its inactive ingredients; or (9) were receiving monoamine oxidase inhibitors, tricyclics, antipsychotics, lithium, or fluoxetine within 4 weeks before randomization. Women were excluded if they were pregnant, lactating, or if fertile, not practicing a medically accepted form of contraception. The Institutional Review Board at the University of Cincinnati Medical Center approved the study protocol, and the study was conducted in compliance with the Declaration of Helsinki. All participants signed approved 282 International Journal of Eating Disorders 45:

3 DULOXETINE IN BINGE EATING DISORDER written informed consent forms after the study procedures had been fully explained and before any study procedures were performed. Participants were enrolled from March 2007 through August Study Design This was a 12-week outpatient, randomized, placebocontrolled, double-blind, parallel-group, flexible-dose study conducted at the University of Cincinnati Medical Center and the Lindner Center of HOPE. The trial consisted of two phases: a 1- to 2-week screening period during which participants had to display 2 binge days/ week to be included in the study; and a 12-week doubleblind treatment period. Participants were evaluated at least twice during the screening period (the screening and baseline visits) and after 1, 2, 4, 6, 8, 10, and 12 weeks during the treatment period. The screening evaluation included the structured clinical interview for DSM-IV-TR (SCID) 26 to establish BED, depressive disorder, and other comorbid axis I diagnoses; the eating disorders examination-questionnaire (EDE-Q) 27 to confirm the diagnosis of BED; a physical examination; vital signs; height and weight measurements to determine BMI; an electrocardiogram (ECG); routine blood chemical and hematological tests; and urinalysis. At this evaluation and each of the following visits, participants were given takehome diaries in which to record any binge eating episodes. At the last visit of the screening period (the baseline assessment), participants continuing to meet entry criteria were enrolled in the treatment period and randomly assigned in a 1:1 ratio to therapy with duloxetine or placebo according to computer-generated coding. Randomization was balanced by use of permuted blocks. Allocation concealment was achieved by having the research pharmacy perform the randomization, package the study medication, and maintain the integrity of the blinded information throughout the trial. At each visit following the baseline visit, participants were assessed for number of binge days and binge eating episodes experienced since the last visit; medication compliance ascertained by capsule count; adverse events; use of non-study medications; vital signs; and weight. Outcome rating scales were also performed. All study medication was in identical 30 mg capsules supplied in numbered containers and dispensed to participants according to a predetermined randomization schedule. Study medication was begun at 30 mg/day for the first 7 days. At the beginning of the second week of treatment, study medication was increased, as tolerated, to 60 mg/day and this dose was kept constant for two weeks. In the absence of remission of binge eating or depressive symptoms and intolerable side effects, the dose could be further increased as following: 90 mg/day at the beginning of the forth treatment week and 120 mg/day at the beginning of the sixth treatment week. Dosing was either once per day or twice per day depending on tolerability. The intent-to-treat (ITT) population for the primary longitudinal analysis included all randomized participants, and for the secondary endpoint analysis all participants who had at least one post-baseline visit. The safety population included all participants who received at least one dose of the study medication. Outcome Measures The primary outcome measure was the weekly frequency of binge eating days (binge day frequency), defined as the mean number of binge days (days when the participant had one or more binge eating episodes) per week in the interval between visits (total number of binge days in the interval divided by number of days in the interval, then multiplied by 7). Binge eating episodes were defined using DSM-IV-TR criteria 1 and assessed via clinical interview and review of participant take-home diaries, upon which participants recorded number of binge episodes. Secondary outcome measures were weekly frequency of binge episodes, weight (kg); BMI (calculated by dividing body weight in kg by height in m 2 ); Clinical global impression-severity (CGI- S) and improvement scale (CGI-I) 28 for binge eating (CGI-S-BE and CGI-I-BE) and depressive disorder (CGI-S-DD and CGI-I-DD) symptomatology scores; Yale-brown obsessive-compulsive scale modified for binge eating scale (YBOCS-BE) 29 scores; Three factor eating questionnaire (TFEQ) 30 scores; Hamilton anxiety scale (HAM-A) 31 total scores; and the clinician-rated IDS-C 25 total scores. All scales were administered at all post-baseline visits except for the TFEQ and HAM-A, which were administered at baseline and at weeks 2, 6, 10, and 12. Other secondary outcome measures included categorical response categories for binge eating and depressive symptoms based on change from baseline to endpoint. For binge eating episodes, these were defined as follows: remission 5 cessation of binges; marked % decrease; moderate % decrease; and none 5 less than 50% decrease. For depression, response was defined as a decrease in IDS score 50% from baseline to final study visit; remission was defined as an endpoint IDS score \12. The following safety measures were assessed: adverse events, clinical laboratory data, physical examination findings, and vital signs. Statistical Methods The baseline characteristics of each group were compared by using chi-square or Fisher s exact tests for cate- International Journal of Eating Disorders 45:

4 GUERDJIKOVA ET AL. FIGURE 1. Participants who entered a 12-week placebo-controlled trail of duloxetine in binge eating disorder with comorbid depressive disorders. (a) Intent to treat (ITT) defined as all randomized participants; (b) Safety population defined as all randomized participants who received atleast one dose of study medication; (c) Inadequate protocol adherence 5 inadequate compliance with study medication (N 5 1), use of disallowed medication (hydrocodone, N 5 1), and refusal of participant follow nonstudy physician s medical recommendations (N 5 1). gorical variables and independent-sample t-tests for continuous variables. The primary efficacy analysis was a longitudinal analysis comparing the rate of change of binge day frequency during the treatment period between groups. The same analysis was applied to binge episode frequency, weight, BMI, and scores on the CGI-Severity, YBOCS-BE, and IDS scales. The difference in rate of change was estimated by random regression methods, as described in the study by Fitzmaurice et al. 32 and Gibbons et al. 33 and as used in a number of pharmacotherapy studies of BED We used a model for the mean of the outcome variable that included terms for treatment, time, and treatment-by-time interaction. Time was modeled as a continuous variable, expressed as the square root of days since randomization (baseline) unless there was evidence for a better fit with another functional form. For the analyses of binge frequency and binge day frequency, we used the logarithmic transformations log [(binges/week) 1 1] and log [(binge days/week 11)], respectively, to normalize the data and stabilize the variance. The longitudinal analyses included all participants. First-order antedependence, heterogeneous autoregressive, or autoregressive covariance structures were compared for each model and the best fitting model, with the lowest AIC value, was retained. Several secondary analyses were performed using the ITT sample. Using the last observation carried forward (LOCF), baseline to endpoint change scores were computed for each measure (on the logarithmic scale for the binging measures) and independentsamples t-tests were used to compare these changes between the treatment groups. An extension of the Wilcoxon rank-sum test ( nptrend in Stata) was used to analyze categorical response to treatment (as defined above) for the ITT group. Time to recovery (defined as the first four consecutive binge-free weeks after baseline) was analyzed with a log-rank test of survival function for the ITT population. For laboratory measures, including weight, the mean difference between endpoint and baseline measures was computed for each treatment group and then compared using the t-test. SAS software (version 9.1, Cary, N.C.) was used only for the primary analysis. Other analyses were conducted using Stata software (version 10.2, College Station, TX). All statistical tests and confidence intervals were twosided, a Results Of 64 individuals screened, 40 met entry criteria and were randomized to duloxetine or placebo (see Fig. 1). Of these 40 participants, 35 (88%) were women and 33 (83%) were 284 International Journal of Eating Disorders 45:

5 DULOXETINE IN BINGE EATING DISORDER TABLE 1. Baseline demographic and clinical characteristics of participants with binge eating disorder and depressive disorders randomly assigned to 12 weeks of double-blind treatment with duloxetine or placebo Characteristic/Variable Total Group (N 5 40) Duloxetine Placebo p Demographic characteristics Female, N (%) 35(88) 16 (80) 19 (95) 0.34 Caucasian, N (%) 33(83) 18(90.0) 15(65) 0.41 Age (years), Mean (SD) 40.1(12.0) 44.4(12.1) 35.7(10.4) 0.02 Diagnostic characteristics Eating disorders examination-questionnaire Mean (SD) 3.7(0.9) 3.7(1.0) 3.7(0.9) 0.99 Depressive disorder diagnosis, N (%): Major depressive disorder, Recurrent 25(63) 10(50) 15(75) 0.19 Major depressive disorder, Single episode 9(23) 5(25) 4(20) 1.0 Dysthymic disorder 5(13) 4(20) 1(5) 0.34 Lifetime anxiety Disorders, N (%): 12(30) 6(30) 6(30) 1.0 Lifetime substance use disorders N, (%): 5(13) 4(20) 1(5) 0.34 Primary outcome variable Binge day frequency (per week), Mean (SD) 4(1.7) 4.3(1.7) 3.8(1.7) 0.36 Secondary outcome variables Binge episode frequency (per week), Mean (SD) 4.5(2.3) 4.7(1.9) 4.2(2.6) 0.49 Weight (kg), Mean (SD) 114.7(23.6) 111.1(24.1) (23.1) 0.34 Body mass index, Mean (SD) 40.6(7.4) 38.7(6.8) 42.8(7.7) 0.09 Clinical global impression severity of illness scale for binge eating, Mean (SD) 4.8(0.7) 5.0(0.8) 4.6(0.7) 0.09 Clinical global impression Severity of Illness Scale for depressive disorders, Mean (SD) 4.2(0.7) 4.3(0.7) 4.2(0.8) 0.50 Yale-brown obsessive compulsive scale (modified for binge eating), Mean (SD) 21.9(3.1) 22.3(3.5) 21.6(2.8) 0.52 Inventory of depressive symptoms Mean (SD) 35.5(6.7) 35.6(7.9) 35.4(5.4) 0.93 Three-factor eating questionnaire mean (SD) Cognitive restraint subscale 5.2(3.8) 6(3.3) 4.4 (4.3) 0.24 Disinhibition Subscale 13.6(1.8) 13.6(2.0) 13.7(1.7) 0.97 Hunger subscale 11.5(2.4) 10.9(2.7) 12.1(2.0) 0.16 Hamilton anxiety scale, Mean (SD) 16.5(7.5) 16.9(9.1) 16.2(5.7) 0.79 Caucasian; the mean (SD) baseline weekly binge day frequency of the group was 4.0 (1.7); and the mean (SD) baseline BMI of the group was 40.6 (7.4) (Table 1). The most prevalent depressive disorder diagnosis was recurrent major depressive disorder (63%). The mean (SD) IDS score was 35.5 (6.7), indicating a moderate to severe level of depressive symptoms. 42 There were no significant differences between the treatment groups in demographic or clinical variables at baseline, except participants receiving duloxetine were older (p 5.02). Seven (35%) of the 20 participants in the duloxetine group discontinued prematurely (adverse events, N 5 3 scheduling problems, N 5 1; non-adherence with the protocol, N 5 3) and six (30%) of the 20 participants in the placebo group discontinued prematurely (lack of efficacy, N 5 1; lost to follow-up, N 5 5) (see Fig. 1). The remaining 27 (68%) participants completed the 12 weeks of treatment (N 5 13 receiving duloxetine and N 5 14 receiving placebo). The mean (SD) daily dose of duloxetine at endpoint evaluation for the 18 participants receiving drug was 78.7 (19.6) mg; for those receiving placebo it was 80.3 (25.2) mg. The mean frequency of binge eating days per week decreased over the study period in both treatment groups, but more so in the duloxetine group (see Fig. 2). The primary efficacy analysis using random regression showed that participants receiving duloxetine had a significantly greater reduction in binge day frequency than participants receiving placebo (p 5.04) (Table 2). Duloxetine was also associated with a significantly greater improvement than placebo for binge episode frequency, body weight, and scores on the CGI-S-BE and CGI-S-DD scales. The associated standardized effect sizes (Cohen s d) were 0.67, 0.78, 0.66, 0.77, and 0.82 respectively; these are all either medium ( ) or large ([0.80) range. However, there were no significant differences between the treatment groups in the change in BMI or scores on the YBOCS-BE or IDS-C scales. In the secondary analysis of baseline-to-endpoint change scores, there were no significant differences between groups in change in binge day frequency or in the secondary outcome measures (except for CGI-S-DD scale scores) (Table 2). Regarding global impression of improvement, there were no significant differences between groups on any measure. Fourteen (78%) participants in the duloxetine group and 11 (55%) participants in the placebo group had final scores of much or very much improved on both the CGI- I-BE and CGI-I-DD scales. International Journal of Eating Disorders 45:

6 GUERDJIKOVA ET AL. FIGURE 2. Mean (6 SD) weekly binge day frequency over 12 weeks of treatment in participants with binge eating disorder and depressive disorders randomly assigned to duloxetine or placebo (error bars are 95% confidence intervals). Regarding categorical response analyses, there was a numerically but not statistically significantly higher level of remission of BED for duloxetinetreated participants (56%) compared with placebotreated participants (30%) (Table 3). Numerically similar proportions of participants attained response and remission of depressive symptoms in favor of duloxetine (Table 3). Four duloxetine recipients achieved remission in both binge eating and depression compared with two placebo recipients. Duloxetine was not associated with shortened time to recovery of binge eating in the ITT group [hazard ratio (95% confidence interval) for recovery (0.67, 4.07), p 5.27]. Participants receiving duloxetine experienced a mean (SD) weight loss of 3.2 (6.4) kg from baseline to endpoint, whereas those receiving placebo experienced a mean (SD) weight loss of 0.30 (2.2) kg (p 5.07). The most common adverse events reported by duloxetine-treated participants were nausea (N 5 9), dry mouth (N 5 7), constipation (N 5 5), and hyperhydrosis (N 5 5). There were no statistically significant differences between treatment groups in the incidence of any individual event. More participants discontinued duloxetine (N 5 3; 15%) for adverse events than placebo (N 5 0) (Fisher exact p 5.19). Those events were severe gastrointestinal problems and a sinus infection (N 5 1), insomnia (N 5 1), and confusion (N 5 1). The gastrointestinal problems and sinus infection was classified as a serious adverse event as the participant required a 48-hour hospitalization; the participant recovered fully and the event was thought not to be due to duloxetine. There were no clinically significant changes in physical examination findings, vital signs, or clinical laboratory values. There was no evidence of withdrawal symptoms in the seven participants who discontinued duloxetine prematurely or in the 13 participants who discontinued duloxetine per protocol. Discussion In the primary longitudinal analysis of this 12-week randomized, placebo-controlled study of BED with a comorbid current depressive disorder, duloxetine (mean final dose 78.7 mg/day) was significantly superior to placebo in reducing binge day and binge episode frequency, body weight, and overall severity of illness for binge eating and depressive disorders, with the associated effect sizes being medium to large. The mean weight loss in the group receiving duloxetine was 3.4 kg, compared with 0.3 kg in the group receiving placebo. Taken together these findings suggest duloxetine might be efficacious in the treatment of BED when comorbid 286 International Journal of Eating Disorders 45:

7 DULOXETINE IN BINGE EATING DISORDER TABLE 2. Outcome measures before and after 12 weeks of treatment with duloxetine versus placebo and analysis of change in outcome Mean (SD) Estimated Difference Between Groups at 12 Weeks Baseline a (N 5 40) Last Observation b (N 5 38) Longitudinal Analysis c (N 5 40) Endpoint Analysis d (N 5 38) Outcome measure Placebo Duloxetine Placebo Duloxetine (N 5 18) Estimate [95% CI] p d Estimate [95% CI] p d Binge day frequency per week 3.5 (1.5) 4.0 (1.8) 1.3 (1.2) 1.0 (1.7) [21.00, 20.17] [20.29, 1.86] Binge episode frequency per week 4.0 (2.4) 4.5 (2.0) 1.3 (1.2) 1.1 (2.0) [20.89, 20.03] [20.65, 2.22] Weight (kg) (23.1) (24.1) (23.2) (23.8) [25.74, 20.09] [20.21, 5.94] Body mass index, kg/m (7.6) 38.7 (6.8) 42.9 (7.3) 37.7 (7.5) [21.84, 0.18] [20.11, 1.81] Clinical global impression-severity 4.6 (0.7) 5.0 (0.8) 2.7 (1.3) 2.3 (1.5) [24.13, 0.03] [ ] of illness scale for binge eating Clinical global impression -improvement 2.2 (1.3) 1.7 (1.0) 0.28 [20.50, 1.07] scale for binge eating Clinical global impression-severity of 4.2 (0.7) 4.3 (0.7) 2.9 (1.0) 2.3 (1.3) [22.49, 20.04] [0.07, 1.56] illness scale for depressive disorders Clinical global impression improvement 2.4 (1.4) 1.7 (1.1) 0.48 [20.43, 1.39] scale for depressive disorders Yale-brown obsessive-compulsive scale (modified for binge eating) Total 21.6 (2.8) 22.3 (3.5) 10.3 (6.3) 9.4 (7.0) [253.99, 1.77] [22.78, 5.85] Obsessions 10.7 (1.4) 11.0 (2.6) 5.5 (3.1) 5.4 (3.6) [213.64, 0.78] [22.02, 2.50] Compulsions 11.0 (2.0) 11.3 (2.1) 4.8 (3.4) 3.9 (4.0) [217.76, 0.79] [21.20, 3.80] Inventory of depressive symptoms 35.4 (5.4) 35.6 (7.9) 21.6 (12.7) 19.1 (11.5) [256.91, 18.12] [23.65, 10.95] Three-factor eating questionnaire e Cognitive restraint 4.4 (4.3) 6.0 (3.2) 7.1 (4.8) 5.6 (3.3) 1.42 [21.29, 4.13] Disinhibition 13.6 (1.7) 13.6 (2.0) 11.5 (3.3) 11.3 (4.3) 0.06 [22.46, 2.59] Hunger 12.1 (2.0) 11.0 (2.7) 9.5 (3.9) 8.7 (3.5) [23.78, 1.96] Hamilton Anxiety Scale e 16.2 (5.7) 16.9 (9.1) 7.2 (6.5) 9.6 (9.0) [25.93, 3.49] a Baseline value for the entire sample. b Last observation for the ITT sample. c Longitudinal analysis included the entire sample. d Last Observation Endpoint was defined using last observation carried forward for the ITT sample. e Measured at baseline and weeks 2, 6, 10, and 12 only. International Journal of Eating Disorders 45:

8 GUERDJIKOVA ET AL. TABLE 3. Categorical response to treatment among participants with binge eating disorder and depressive disorders randomly assigned to 12 weeks of double-blind treatment with duloxetine or placebo Placebo N (%) Duloxetine (N 5 18) N (%) p value a Response of binge eating episodes b None (\50%) 6 (30) 3 (17) Moderate (50 74%) 4 (20) 1 (6) Marked (75 99%) 4 (20) 4 (22) Remission (100%) 6 (30) 10 (56) 0.09 Response of depression c 8 (40) 11 (61) 0.19 Remission of depression d 4 (20) 5 (28) 0.71 a Chi-square, fishers exact or nptrend were used to determine a statistical difference between groups. b Percent reduction in binge eating episodes from baseline to endpoint. c 50% or greater reduction in Inventory of Depressive Symptoms Score from baseline to endpoint. d Endpoint Inventory of Depressive Symptoms Score \12. with a current depressive disorder, which may be less responsive to treatment than BED without a comorbid psychiatric disorder. 7,8 The potential mechanism of action of duloxetine in BED is unknown. As has been hypothesized for sibutramine, duloxetine might reduce binge eating by modifying internal signals controlling hunger and satiety through its combined effects on serotonergic and noradrenergic transmission Reduced binge eating, in turn, might lead to weight loss. In addition, several preliminary reports have suggested that duloxetine may have beneficial effects in substance use disorders Eating disorders, including BED, have been hypothesized to be related to addictive disorders, as they co-occur with one another and highly palatable food and drugs of abuse compete for the same brain reward circuitry. 46,47 Moreover, the dopamine-mediated reward circuits implicated in addictive disorders may also be compromised in major depressive disorder. 48 Thus duloxetine might exert its beneficial effects in BED with a comorbid depressive disorder by affecting this reward system. This study has several important limitations. First, the small sample size may have compromised the ability of the study to detect important treatment effects. It may have been under-powered to detect clinically important differences in the endpoint analysis or in secondary outcome measures, such as BMI and IDS-C scale scores. Second, the attrition rate was high, with 33% of participants withdrawing before study completion, rendering the results heavily dependent on assumptions regarding missing data. However, the primary analysis was based on data from all randomly assigned participants at all time points. Moreover, the high attrition rate found in this study is consistent with attrition rates in other placebo-controlled pharmacotherapy studies in BED A third limitation is that because the study group was primarily female and Caucasian, and the duration of treatment was short (12 weeks), the results may not generalize to males, to other racial groups, or to longer treatment periods. Fourth, because individuals with substance use disorders, severe personality disorders, and unstable medical disorders were excluded, the results may not generalize to BED and depressive disorders when also cooccurring with these conditions. In summary, in a 12-week trial in individuals with BED and comorbid depressive disorders, duloxetine was superior to placebo in reducing binge frequency, body weight, and global severity for binge eating and depressive disorders. It was associated with fairly good tolerability, but a high discontinuation rate. Controlled trials of duloxetine and other SNRIs in larger groups of participants with BED and comorbid depressive disorders appear warranted. Earn CE credit for this article! Visit: for additional information. There may be a delay in the posting of the article, so continue to check back and look for the section on Eating Disorders. Additional information about the program is available at References 1. A.P.A. Diagnostic and statistical manual of mental disorders, 4th ed. Text Revision. Washington, DC: American Psychiatric Association, 2000, pp Wonderlich SA, Gordon KH, Mitchell JE, Crosby RD, Engel SG. The validity and clinical utility of binge eating disorder. Int J Eat Disord 2009;42: A.P.A. DSM-V Development Eating Disorders, Available at: aspx?rid5372#. 4. 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: Pope HG Jr, Lalonde JK, Pindyck LJ, Walsh T, Bulik CM, Crow SJ, et al. Binge eating disorder: A stable syndrome. Am J Psychiatry 2006;163: Javaras KN, Pope HG, Lalonde JK, Roberts JL, Nillni YI, Laird NM, et al. Co-occurrence of binge eating disorder with psychiatric and medical disorders. J Clin Psychiatry 2008;69: Fichter MM, Quadflieg N, Hedlund S. Long-term course of binge eating disorder and bulimia nervosa: Relevance for nosology and diagnostic criteria. Int J Eat Disord 2008;41: Grilo CM, White MA, Masheb RM. DSM-IV psychiatric disorder comorbidity and its correlates in binge eating disorder. Int J Eat Disord 2009;42: Peterson CB, Miller KB, Crow SJ, Thuras P, Mitchell JE. Subtypes of binge eating disorder based on psychiatric history. Int J Eat Disord 2005;38: International Journal of Eating Disorders 45:

9 DULOXETINE IN BINGE EATING DISORDER 10. McElroy S, Guerdjikova A, O Melia A. The oxford handbook of eating disorders: Pharmacotherapy of the eating disorders. New York, NY: Oxford University Press, 2010, pp Gartlehner G, Thaler K, Hansen RA, Gaynes BN. The general and comparative efficacy and safety of duloxetine in major depressive disorder: A systematic review and meta-analysis. Drug Saf 2009;32: Leombruni P, Lavagnino L, Gastaldi F, Vasile A, Fassino S. Duloxetine in obese binge eater outpatients: Preliminary results from a 12-week open trial. Hum Psychopharmacol 2009;24: Bernardi S, Pallanti S. Successful duloxetine treatment of a binge eating disorder: A case report. J Psychopharmacol 2008; 24: Lai CH. Duloxetine related binge eating behaviors: A case report. Prog Neuro-Psychopharmacol Biol Psychiatry 2009;33: Christensen RC, Averbuch RN. The use of duloxetine in chronic bulimia nervosa: A case report. Psychiatry (Edgmont) 2009; 6: Hazen E, Fava M. Successful treatment with duloxetine in a case of treatment refractory bulimia nervosa: A case report. J Psychopharmacol 2006;20: Noma S, Uwatoko T, Yamamoto H, Hayashi T. Effects of milnacipran on binge eating A pilot study. Neuropsychiatr Dis Treat 2008;4: El-Giamal N, de Zwaan M, Bailer U, Strnad A, Schussler P, Kasper S. Milnacipran in the treatment of bulimia nervosa: A report of 16 cases. Eur Neuropsychopharmacol 2003;13: MalhotraS,KingKH,WelgeJA,Brusman-LovinsL,McElroySL.Venlafaxine treatment of binge-eating disorder associated with obesity: A series of 35 patients. J Clin Psychiatry 2002; 63: FDA. Meridia (sibutramine): Market Withdrawal Due to Risk of Serious Cardiovascular Events, 2010; Available from: forhumanmedicalproducts/ucm htm. Accessed 2010 February Appolinario JC, Bacaltchuk J, Sichieri R, Claudino AM, Godoy- Matos A, Morgan C, et al. A randomized, double-blind, placebocontrolled study of sibutramine in the treatment of binge-eating disorder. Arch Gen Psychiatry 2003;60: Milano W, Petrella C, Casella A, Capasso A, Carrino S, Milano L. Use of sibutramine, an inhibitor of the reuptake of serotonin and noradrenaline, in the treatment of binge eating disorder: A placebo-controlled study. Adv Ther 2005;22: Wilfley DE, Crow SJ, Hudson JI, Mitchell JE, Berkowitz RI, Blakesley V, et al. Efficacy of sibutramine for the treatment of binge eating disorder: A randomized multicenter placebo-controlled double-blind study. Am J Psychiatry 2008;165: Hudson JI, Wohlreich MM, Kajdasz DK, Mallinckrodt CH, Watkin JG, Martynov OV. Safety and tolerability of duloxetine in the treatment of major depressive disorder: Analysis of pooled data from eight placebo-controlled clinical trials. Hum Psychopharmacol 2005;20: Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C. The Inventory for Depressive Symptomatology (IDS): Preliminary findings. Psychiatry Res 1986;18: First M, Spitzer R, Gibbon M, Williams J. Structured Clinical Interview for DSM-IV-TR Axis I disorders, Research Version, Patient Edition (SCID-I/P). New York, NY: Biometrics Research Department, New York State Psychiatric Institute, Reas DL, Grilo CM, Masheb RM. Reliability of the Eating Disorder Examination-Questionnaire in patients with binge eating disorder. Behav Res Ther 2006;44: Guy W. ECDEU Assessment Manual for Psychopharmacology, U.S. Department of Health, Education, and Welfare publication (ADM). Rockville, MD: National Institute of Mental Health, Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46: Stunkard AJ, Messick S. The three-factor eating questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom Res 1985;29: Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32: Fitzmaurice G, Laird NMWare JH. Applied Longitudinal Analysis. Hoboken, NJ: John Wiley & Sons, 2004, pp Gibbons RD, Hedeker D, Elkin I, Waternaux C, Kraemer HC, Greenhouse JB, et al. Some conceptual and statistical issues in analysis of longitudinal psychiatric data. Application to the NIMH treatment of Depression Collaborative Research Program dataset. Arch Gen Psychiatry 1993;50: McElroy SL, Casuto LS, Nelson EB, Lake KA, Soutullo CA, Keck PE Jr, Hudson JI. Placebo-controlled trial of sertraline in the treatment of binge eating disorder. Am J Psychiatry 2000; 157: Arnold LM, McElroy SL, Hudson JI, Welge JA, Bennett AJ, Keck PE. A placebo-controlled, randomized trial of fluoxetine in the treatment of binge-eating disorder. J Clin Psychiatry 2002; 63: McElroy SL, Hudson JI, Malhotra S, Welge JA, Nelson EB, Keck PE Jr. Citalopram in the treatment of binge-eating disorder: A placebo-controlled trial. J Clin Psychiatry 2003;64: McElroy SL, Arnold LM, Shapira NA, Keck PE Jr, Rosenthal NR, Karim MR, et al. Topiramate in the treatment of binge eating disorder associated with obesity: A randomized, placebo-controlled trial. Am J Psychiatry 2003;160: McElroy SL, Kotwal R, Guerdjikova AI, Welge JA, Nelson EB, Lake KA, et al. Zonisamide in the treatment of binge eating disorder with obesity: A randomized controlled trial. J Clin Psychiatry 2006;67: McElroy SL, Guerdjikova A, Kotwal R, Welge JA, Nelson EB, Lake KA, et al. Atomoxetine in the treatment of binge-eating disorder: A randomized placebo-controlled trial. J Clin Psychiatry 2007;68: Guerdjikova AI, McElroy SL, Kotwal R, Welge JA, Nelson E, Lake K, et al. High-dose escitalopram in the treatment of binge-eating disorder with obesity: A placebo-controlled monotherapy trial. Hum Psychopharmacol 2008;23: Guerdjikova AI, McElroy SL, Welge JA, Nelson E, Keck PE, Hudson JI. Lamotrigine in the treatment of binge-eating disorder with obesity: A randomized, placebo-controlled monotherapy trial. Int Clin Psychopharmacol 2009;24: Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, et al. The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: A psychometric evaluation. Psychol Med 2004;34: Perroud N, Relecom C, Huguelet P. Successful treatment of nicotine withdrawal with duloxetine: A case report. J Clin Psychopharmacol 2008;28: Ji D, Gilpin NW, Richardson HN, Rivier CL, Koob GF. Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats. Behav Pharmacol 2008;19: Marcil WA, Petty F. Duloxetine associated with smoking cessation. Ann Pharmacother 2005;39: Davis C, Carter JC. Compulsive overeating as an addiction disorder. A review of theory and evidence. Appetite 2009;53: Avena NM. Examining the addictive-like properties of binge eating using an animal model of sugar dependence. Exp Clin Psychopharmacol 2007;15: Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006;59: International Journal of Eating Disorders 45: