Arch Womens Ment Health (2003) 6: 147 151 DOI 10.1007/s00737-003-0172-8 Short communication A double-blind, placebo-controlled trial of fluvoxamine in binge eating disorder: a high placebo response* T. Pearlstein 1, E. Spurell 1, L. A. Hohlstein 1, V. Gurney 2, J. Read 1, C. Fuchs 3, and M. B. Keller 1 1 Department of Psychiatry and Human Behavior, Brown Medical School, Providence, RI, U.S.A. 2 Laurel Hill Inn Residential Eating Disorder Program, Medford, MA, U.S.A. 3 Boston, MA, U.S.A. Received August 7, 2002; accepted January 26, 2003 Published online April 23, 2003 Springer-Verlag 2003 Summary Twenty subjects with binge eating disorder were randomly assigned to flexible-dose fluvoxamine or placebo for 12 weeks. A significant reduction in binge frequency, Beck Depression Inventory scores and the eating concern, shape concern and weight concern subscales of the Eating Disorder Examination were noted for both fluvoxamine (n 9) and placebo (n 11) groups. There were no significant differences between fluvoxamine and placebo for any treatment outcome variables. The findings from this small trial contribute to the inconsistent results of antidepressant studies in binge eating disorder. Keywords: Binge eating disorder; fluvoxamine; placebo. Introduction Binge eating disorder (BED) is characterized by repeated episodes of eating large quantities of food while experiencing a sense of loss of control, without compensatory measures such as excessive food restriction, excessive exercise, vomiting or laxative abuse. The number of antidepressant treatment trials conducted in BED is small to date, and the results have been mixed. Three randomized, double-blind, placebo-controlled (DBPC) trials with selective serotonin reuptake inhibitors (SSRIs) have reported significantly decreased binge eating and weight with fluoxetine (Arnold et al., 2002), sertraline (McElroy * This study was presented as a poster at the 9 th International Conference on Eating Disorders, May, 2000, New York, NY. Supported in part by a grant from Solvay Pharmaceuticals. et al., 2000) and fluvoxamine (Hudson et al., 1998). Early DBPC trials reported significant reduction of binge eating with desipramine (McCann and Agras, 1990) but not imipramine (Alger et al., 1991). An open trial reported that fluvoxamine and fluoxetine did not decrease binge eating or weight (Ricca et al., 2001), while a case series suggested efficacy for venlafaxine (Malhotra et al., 2002). The efficacy of combined antidepressant medication and therapy or weight management has also yielded mixed reports. Positive reports of weight reduction have been reported in placebo-controlled trials of imipramine with diet counseling/psychological support (Laederach-Hofmann et al., 1999) and fluoxetine with behavior therapy (Marcus et al., 1990) and in open trials of fluoxetine and phentermine with cognitive behavioral therapy (CBT) (Devlin et al., 2000) and of fluvoxamine or fluoxetine with CBT (Ricca et al., 2001). However, fluvoxamine did not enhance weight loss when added to nutritional management or CBT (de Zwann et al., 1992). Treatment recommendations for BED are difficult to determine since many of the antidepressant treatment studies involve short-term treatment and high placebo response rates (Devlin, 2001). This study was expected to replicate the findings of the previous DBPC fluvoxamine trial, which showed significant reductions in binge eating and weight over 9 weeks. The current study was longer
148 T. Pearlstein et al. (12 weeks) in duration and used the Eating Disorder Examination (EDE, Cooper and Fairburn, 1987) to classify binge episodes at pre- and post-treatment instead of food logs. Another aim of the present study was to see if fluvoxamine led to a significant reduction in associated eating disorder psychopathology as measured by the eating disorder subscales of the EDE. Patients and methods Subjects were recruited by media advertisement and by referral from health professionals. Twenty-five subjects who met DSM-IV research criteria for BED signed institutionally-approved informed consent forms. Twenty subjects (17 women and 3 men) completed the protocol. The mean age of subjects was 41. Ninety percent were Caucasian, 70% were currently married, and 90% were employed. The average pretreatment Body Mass Index was 41.16 for all subjects. All subjects underwent two intake assessment sessions scheduled one week apart. During the first, the diagnosis of BED was confirmed using the EDE (Cooper and Fairburn, 1987), adapted for the BED diagnosis by including additional questions to meet DSM-IV criteria. The EDE has demonstrated ability to distinguish BED individuals from individuals with other eating disorders and from overweight individuals without an eating disorder (Wilfley et al., 2000). The EDE was administered by the second, fourth, and fifth authors. The second author had been trained by one of the developers of the interview (Fairburn), had met his standards of reliability, and had extensive experience training others to deliver the EDE. Training and administration of the other interviewers was in accordance with recommended standards of training (Cooper and Fairburn, 1987). Meetings were held regularly to discuss and review ratings, particularly those of binge episodes. Following the EDE, subjects were instructed in the filling out of food logs, and these were completed daily throughout the study. Although subjects completed food logs, the EDE binge rating was used as an outcome measure rather than self-reported binge episodes. The EDE classification of binge episodes is highly correlated with self-report binge episodes from food logs (Rosen et al., 1990), and is generally regarded to be the optimal method of assessment for eating disorders (Smith et al., 1994; Wilfley et al., 1997; Wilson, 1993). At the second intake assessment, the Structured Clinical Interview for DSM-IV (SCID, Spitzer et al., 1990), the Hamilton Depression Scale (HAM-D, Hamilton, 1960) and the Clinical Global Impression Scale (CGI, Guy, 1976) were administered, and subjects completed self-report measures including the Hopkins Symptom Checklist (SCL-90, Derogatis, 1977) and the Beck Depression Inventory (BDI, Beck, 1978). Subjects received one week of single-blind placebo, and were then randomized to flexible dose fluvoxamine (titrated up to 150mg b.i.d.) or placebo for 12 weeks. Subjects were instructed not to participate in psychotherapy or a weight reduction program during the trial. Subjects met with a research nurse and the psychiatrist weekly for the first 6 weeks of the protocol and then biweekly for the remaining 6 weeks. At each visit, food logs were collected, vital signs and adverse events were monitored, psychoeducational materials on healthy eating were distributed, and study medication was dispensed, the dose determined by response and tolerability. During the twelfth week, subjects again received the EDE interview and HAM-D by the blinded psychologist who performed the pre-treatment EDE. Subjects completed self-report questionnaires, and a blinded study nurse administered the CGI. Following completion of the 12 weeks of double-blind medication, all subjects were offered continued treatment determined by response and clinical status. Results The primary outcome variables included binge eating frequency, the four subscale scores from the EDE (restraint, eating concern, shape concern, and weight concern), weight, HAM-D, CGI, SCL-90 and BDI. At baseline the treatment groups were comparable with respect to age, sex, number of days they had a binge episode in the past month, associated eating disorder psychopathology (EDE subscale scores), weight, and level of depression from the HAM-D, SCL-90, and BDI. There were no significant differences between the two groups on any of the variables except a trend (p 0.06, independent samples t-test, two-tailed) for subjects in the placebo group to have a higher pre-treatment binge frequency. Repeated measures ANOVAs were conducted to determine if the treatment group showed a greater reduction on the outcome variables following the 12-week trial. A significant reduction in binge frequency, SCL-90 and BDI scores, and the eating concern, shape concern and weight concern subscales of the EDE were noted for both the fluvoxamine (n 9) and placebo (n 11) groups (See Table 1). Fifty percent of subjects in both groups were free of binge eating by the end of the study. There were no significant differences between fluvoxamine and placebo for any of the treatment outcome variables. Thus, while both groups showed significant improvement at post-treatment, the medication group did not show any greater improvement than the placebo group on any assessment. A blinded rating of any improvement (CGI-I 1, 2 or 3) at 12 weeks was obtained on all of the subjects who received fluvoxamine (9/9) and 7 of the 11 subjects who received placebo, while the 4 subjects who were rated as having made no improvement (CGI-I 4) were all in the placebo group; this difference approached significance (Pearson s Chi-Squre 4.09; p 0.07). The average dose achieved (administered b.i.d.) was 239mg/day in the fluvoxamine group and 264mg/ day in the placebo group. Side effects that were reported by 3 or more subjects included sedation (8 on fluvoxamine, 3 on placebo), nausea (4 on fluvoxamine, 1 on placebo), dry mouth (4 on fluvoxamine, 3 on placebo), and decreased libido (3 on
Fluvoxamine in binge eating disorder 149 Table 1. Repeated measures for treatment and placebo groups at pre- and post-treatment Variable n Mean (SD) Mean (SD) F 1 : Main F 2 : Interaction effect of pre-treat post-treat effect of time group X time Number of days with binges 41.30** 0.08 in the past 28 days Placebo group 11 20.00 (6.21) 7.31 (9.31) Treatment group 9 14.67 (55.68) 3.11 (4.20) Restraint subscale 3.78# 2.12 Placebo group 11 1.60 (1.08) 1.45 (0.98) Treatment group 9 2.04 (1.24) 0.91 (0.78) Eating concern subscale 22.60** 1.67 Placebo group 11 1.82 (1.02) 0.44 (0.55) Treatment group 9 1.10 (0.96) 0.31 (0.39) Shape concern subscale 32.18** 0.05 Placebo group 11 3.56 (0.43) 2.50 (1.15) Treatment group 9 3.38 (0.74) 2.24 (0.85) Weight concern subscale 17.32** 0.46 Placebo group 11 3.32 (0.94) 2.36 (1.07) Treatment group 9 3.73 (0.49) 2.40 (1.22) Weight 1.11 1.97 Placebo group 11 258 (96) 262 (99) Treatment group 9 243 (85) 242 (82) Beck 3 5.47* 4.02# Placebo group 9 0.68 (0.57) 0.37 (0.26) Treatment group 7 0.44 (0.22) 0.32 (0.30) Hamilton 2.10 2.71 Placebo group 8 14.27 (12.40) 7.38 (6.16) Treatment group 8 10.78 (9.22) 9.38 (9.71) SCL-90 16.63** 0.91 Placebo group 11 0.85 (0.55) 0.40 (0.29) Treatment group 9 0.62 (0.33) 0.30 (0.29) Note: F 1 indicates the main effect for the entire sample, F 2 indicates the effect when examining a difference for the two groups. # p 0.10; * p 0.01; ** p 0.001 3 : The Beck scores are presented as means instead of a total summed score to eliminate the bias of a few subjects who failed to answer items on their questionnaires fluvoxamine, 0 on placebo). The 5 subjects who did not complete the protocol withdrew consent due to lack of response (n 1), hospitalization due to an amnestic event (n 1), nausea and anxiety (n 1), knee surgery and inability to keep appointments (n 1), and moving out of state (n 1). Discussion In this study of 20 subjects with BED, both fluvoxamine and placebo were associated with decreased binge eating, eating disorder psychopathology and mood and anxiety symptoms. More than 50% of the total sample was binge free at the end of 12 weeks. The high placebo response may be accounted for by the increased awareness and control over the binge eating due to the thorough pre-treatment assessment, the keeping of daily food logs, and the regular clinical assessments during the study. None of the subjects in this study had previous treatment for an eating disorder, and the 3 5 hours of pretreatment assessment (including the SCID and EDE), may have served as a treatment intervention. The food logs were collected and reviewed briefly with the subject at each visit, and this form of self-monitoring may have served as a treatment component. Selfmonitoring alone has been demonstrated to be an effective intervention for weight loss (Foreyt and Goodrick, 1994). Even though subjects received minimal standardized psychoeducational material at each visit, subjects had weekly or biweekly visits with a nurse and a psychiatrist, and this may also have increased subject s motivation and sense of support to gain control over their eating. The results of the current study are similar to the results of a randomized, parallel series, open study
150 T. Pearlstein et al. of 108 BED subjects that reported that neither fluvoxamine 300mg/day or fluoxetine 60mg/day were effective in reducing weight, binge eating, or eating attitudes and behaviors after 24 weeks of treatment or at one year follow-up compared to baseline (Ricca et al., 2001). Similar to the current study, Ricca and colleagues used the EDE as an assessment and treatment outcome measure. The results of the current study contradict the results of the previously published DBPC studies with SSRIs. Hudson and colleagues (1998) administered flexible-dose fluvoxamine (average dose 260mg/day) or placebo to 85 BED subjects for 9 weeks. Fluvoxamine was superior to placebo in decreasing binge eating, body weight and improving outcome as measured by the CGI scale. Flexible-dose sertraline (average dose 187mg/day) in 34 subjects (McElroy et al., 2000) and flexible-dose fluoxetine (average dose 71mg/day) in 60 subjects (Arnold et al., 2002) were both superior to placebo after 6 weeks on the same outcome measures. These three studies also demonstrated substantial placebo response rates. However, the EDE, which may provide more accurate ratings for binge episodes, was not used in these three studies, and the higher placebo response rate and lack of drug-placebo difference in the current study may have been due in part to the more in-depth assessment interview with the EDE. It is of interest that the only subjects who did not improve at all during the study were all in the placebo group. The major limitations of this study were the small sample size and the inclusion of potential confounding nonspecific treatment components, i.e., rigorous assessment, self-monitoring and frequent clinical contact. 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