A randomized, double-blind trial comparing sertraline and fluoxetine 6-month treatment in obese patients with Binge Eating Disorder

Progress in Neuro-sychopharmacology & Biological Psychiatry 32 (2008) 1599–1605

Contents lists available at ScienceDirect

Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p b p

A randomized, double-blind trial comparing sertraline and fluoxetine 6-month treatment in obese patients with Binge Eating Disorder Paolo Leombruni ⁎, Andrea Pierò, Luca Lavagnino, Annalisa Brustolin, Stefania Campisi, Secondo Fassino Department of Neurosciences, Psychiatry Section, University of Torino, Centre for Eating Disorders and Obesity, Ospedale San Giovanni Battista “le Molinette” of Torino, Via Cherasco 11, Torino, Italy

A R T I C L E

I N F O

Article history: Received 19 September 2007 Received in revised form 5 June 2008 Accepted 6 June 2008 Available online 14 June 2008 Keywords: Binge Eating Disorder Fluoxetine Medication Obesity Sertraline

A B S T R A C T Previous studies support the use of selective serotonin reuptake inhibitors (SSRIs), in overweight patients with Binge Eating Disorder (BED), but results are far from conclusive. Sertraline has been studied less extensively, and there have been a few studies concerning SSRIs that report follow-up data at more than 12 weeks of follow-up. The present study assesses the effectiveness of sertraline and fluoxetine over a period of 24 weeks in obese patients with BED (DSM-IV-TR). Forty-two obese outpatients were randomized and assigned to one of two different drug treatments: 22 were treated with sertraline (dose range: 100–200 mg/ day) and 20 with fluoxetine (dose range: 40–80 mg/day). Subjects were assessed at baseline and at 8, 12, and 24 weeks of treatment for binge frequency, weight loss, and severity of psychopathology. No significant differences were found between the two treatments. After 8 weeks of treatment a significant improvement in the Binge Eating Scale score and a significant weight loss emerged. These results were maintained by responders (weigh loss of at least 5% of baseline weight) over 24 weeks. The results suggest that a 6-month treatment with SSRI may be an effective option to treat patients with BED. © 2008 Elsevier Inc. All rights reserved.

1. Introduction Obesity is a complex disorder that is currently diagnosed according to a single clinical criterion: a body mass index (BMI = weight/height2, kg/m2) greater than 30. Obesity is not per se an eating disorder, but obesity can include eating problems (De Zwaan et al., 1994), such as Binge Eating Disorder (BED), an eating disorder characterized by binge eating episodes without inappropriate compensatory behaviors (Casper, 1995; APA Guideline, 2006). BED is associated with obesity in near 65% of patients (Striegel-Moore et al., 2001), and it represents a severe and often chronic syndrome (Pope et al., 2006). In recent years, the opinion has emerged that two distinct and specific subgroups of obese patients exist: obese with and without binge eating. Many authors argue that patients with BED have a higher genetic vulnerability (Hudson et al., 2006), a higher risk for comorbid psychiatric disorders (Bulik et al., 2002; White and Grilo, 2006) and personality disorders (Fassino et al., 2002, 2003; van Hanswijck de Jonge et al., 2003), a lower quality of life (Rieger et al., 2000), and a higher risk for medical comorbidity (Bulik et al., 2002), compared to the non-BED obese individuals. For these reasons an effective

Abbreviations: BED, Binge Eating Disorders; BMI, Body Mass Index; BES, Binge Eating Score; BDI, Beck Depression Inventory; EDI, Eating Disorder Inventory; CGI, Clinical Global Impression; EDs, Eating Disorders; AN, Anorexia Nervosa; BN, Bulimia Nervosa; NES, Night Eating Syndrome; SSRIs, selective serotonin reuptake inhibitors. ⁎ Corresponding author. Tel.: +39 011 6335425; fax: +39 011 673473. E-mail address: [email protected] (P. Leombruni). 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.06.005

medication should be particularly beneficial in obese subjects with BED (Casper, 1995; Steffen et al., 2006). To date, no established psychopharmacologic treatment for BED has been devised (Bulik et al., 2007), although the literature offers support for the use of agents from three major categories of medication (Appolinario and McElroy, 2004; Carter et al., 2003; Steffen et al., 2006; Brownley et al., 2007): antidepressants (particularly the selective serotonin reuptake inhibitors — SSRIs), appetite suppressants, and anticonvulsants (e.g. topiramate). Among SSRIs fluoxetine and fluvoxamine are the drugs that have been studied most extensively (Bulik et al., 2007; Brownley et al., 2007), but at this moment the evidence about their effectiveness is controversial; after 12 weeks of treatment fluoxetine (average dose 71.3 mg/day) was associated with improvement in binge frequency and depressed mood (Arnold et al., 2002); nevertheless a study did not support its efficacy in patients with BED in comparison to placebo and cognitive behavioral therapy (Grilo et al., 2005), and other studies confirmed these findings (Devlin et al., 2005) also after a two-year follow-up (Devlin et al., 2007). About the effectiveness of fluvoxamine one RCT study showed a significant reduction of binge frequency and depressed mood (Pearlstein et al., 2003) and another a reduction in binge frequency and body weight (Hudson et al., 1998), whereas an open trial reported that fluvoxamine and fluoxetine did not decrease binge eating nor weight (Ricca et al., 2001). Sertraline (mean dose 187 mg/day) was associated with a significantly greater reduction in the frequency of binges, clinical

1600

P. Leombruni et al. / Progress in Neuro-sychopharmacology & Biological Psychiatry 32 (2008) 1599–1605

global severity, and a greater rate of clinical improvement compared with placebo in a 6-week trial (McElroy et al., 2000). A recent open trial seems to confirm the effectiveness of sertraline at a longer followup (Leombruni et al., 2006a). Finally also citalopram (McElroy et al., 2003) and escitalopram (Guerdjikova et al., 2008) seem to be effective in reducing weight and global severity of illness in obese subjects with BED. As indicated by this short review the literature on SSRIs is still controversial and medication recommendations for BED are difficult to determine because many of the studies in this field have several limitations (APA Guidelines, 2006) related to short duration of the studies, small sample sizes (Brownley et al., 2007) and high dropout and placebo response rates (Bulik et al., 2007). Moreover recent evidence shows a high response to placebo in BED subjects (Jacobs-Pilipski et al., 2007) and in some cases a greater effectiveness of CBT treatment in comparison with medication (Grilo et al., 2005; Bulik et al., 2007). The placebo response seems to be transitory or incomplete and to be related to the variable stability of the diagnosis of BED in subjects with less severe symptoms at intake (Jacobs-Pilipski et al., 2007), whereas CBT seems not effective in reaching a sustainable weight loss (Bulik et al., 2007). The high response to placebo in the first weeks of treatment and the relative instability of BED diagnosis suggest the need of further study on the effectiveness of medication with a longer follow-up. Therefore most of the results obtained in the first weeks of treatment could to be lost in the next few months. For the same reasons predictors of response to medication are still inconsistent in the literature (Bulik et al., 2007). The present randomized-controlled study compares the effectiveness of sertraline and fluoxetine over a period of 2, 3, and 6 months in obese women with BED. We focused our attention not only on markers of primary outcome (weight loss, binge frequency, and score on the Binge Eating Scale [BES]) but also on markers of secondary outcomes, considering aspects of depressive and specific eating-related psychopathology. The major aims of this study were: (1) to evaluate if treatment with SSRIs can improve binge eating symptomatology, general associated psychopathology and lead to a significant weight loss in a sample of obese women with BED during 6 months of treatment; (2) to preliminarily assess if sertraline treatment is equally effective than fluoxetine treatment in these subjects; and (3) to gather preliminary data about the response rate and duration of treatment.

3 days to a maximum of 200 mg/day, as tolerated (range 100–200; mean dosage 165.9 mg SD = 32.3). Fluoxetine treatment was commenced with a dose of 10 mg for 3 days, after which the dose was increased with 10-mg increments every 3 days to a maximum of 80 mg/day (range 40–80 mg; mean dosage 64.5 mg SD = 9.9). The study used a flexible dose to allow targeting treatment to individual responses. Written informed consent was obtained from all patients prior to enrolment. 2.2. Patient population

2. Materials and methods

Forty-two obese patients with BED were recruited from 176 overweight patients who applied to the Eating Disorders Pilot Centre of the Psychiatric Clinic of the University of Turin from January 2003 to January 2005. The inclusion criteria were: (1) primary obesity with a BMI equal or higher than 30, (2) a diagnosis of BED according to research criteria of appendix of DSM-IV-TR (APA, 2000), (3) female gender, (4) age between 18 and 65 years, (5) absence of medically unstable conditions, (6) absence of full-syndrome Axis I disorders, and (7) signing an informed consent to participate to the study. None of the patients involved in the study had a history of vomiting. Diagnostic assessment for Axis I disorders was carried out at intake by trained psychiatrist with the support of the Structured Clinical Interview for DSM-IV (SCID-OP; First et al., 1996). A total of 134 patients applied to the Centre but were excluded for the following reasons: (1) age out of the established range (N = 11); (2) BMI ranging from 27.3 to 30 (N = 9); (3) overweight caused by pharmacologic treatments or secondary to already diagnosed or suspected metabolic or endocrine disorders (N = 17); (4) the presence of any unstable medical condition influencing eating or weight (N = 12); (5) comorbidity of an acute full-syndrome Axis I disorder (N = 45), including Mood (N = 16), Anxiety (N = 14), and other (N = 9) disorders; (6) comorbidity with Bulimia Nervosa (N = 6); (7) male gender (N = 4); and (8) binge eaters who did not meet the DSM-IV criteria for BED (N = 19); and (9) patients who met the inclusion criteria but refused to participate in the study (N = 7). Subjects were assessed at the first visit with the SCID-I and -II, the Eating Disorder Inventory 2 (EDI-2), the Binge Eating Scale (BES), the Beck Depression Inventory (BDI), and the Clinical Global Impression (CGI). The patients were assessed every 2 weeks for 8 weeks and then every 4 weeks until week 24. AtT0, T8, T12 and T24, we assessed the number of binges per week, medication dose, body weight, and scores on the CGI, EDI-2, BES, and BDI.

2.1. Study design

2.3. Assessment instruments

This was a prospective, randomized, double-blind study in outpatients with obesity and BED, conducted in accordance with the Declaration of Helsinki. Drug administration and assessment of side effects were carried out by two researchers before the psychiatric management sessions at T0 (intake), T8 (two months later), T12 (three months later) and T24 (six months later). All the subjects received a session of nutritional training and two sessions of individual dietary counselling during the period of the study according to APA Guidelines (2006). Moreover all the subjects received a psycho-educational short book about BED and obesity. Subjects were randomized with a classic randomization method to be treated with either sertraline or fluoxetine. There was no placebo control group because both the drugs have demonstrated in previous studies to be moderately more effective than placebo for primary and secondary outcomes in obese subjects with BED (APA Guideline, 2006). Moreover placebo response is greater in short-term studies, and probably less important in a longer period such as our 6-month trial. Sertraline was administered in a dose of 25 mg/day after lunch for 3 days, after which the dose was increased in 25-mg increments, every

2.3.1. BMI BMI, an index of body mass (kg/m2), is related to the nutritional state of the subject. In female subjects a BMI between 18.7 and 24.9 is considered normal. A BMI between 25 and 29.9 defines “overweight,” and a BMI higher than 30 defines obesity (Pi-Sunyer, 1998). 2.3.2. EDI-2 The EDI-2 (Garner, 1991) is a self-report questionnaire that measures disordered eating attitudes and behaviors and personality traits common to individuals with EDs. The EDI-2 is a 91-item inventory and is composed of eight subscales and three provisional subscales. 2.3.3. BES The BES is a self-administered questionnaire comprised of 18 items specifically designed for the assessment of eating behavior and psychological features related to binge eating in obese patients (Gormally et al., 1983) The questionnaire has been validated in a number of studies and can be used for recording repeated measures to

P. Leombruni et al. / Progress in Neuro-sychopharmacology & Biological Psychiatry 32 (2008) 1599–1605

investigate response to treatment. A cut-off of 17 can be used for screening for BED in patients with obesity (Gormally et al., 1983; Ricca et al., 2000). 2.3.4. BDI The BDI (Beck and Steer, 1987) is a self-report questionnaire with 13 items that is largely used to assess the severity of symptoms of depression. The version used in this study showed reliability and internal consistency similar to the original 21-item version (GrothMarnat, 1990). 2.3.5. CGI This is a well-known assessment tool, which is administered by the clinician to evaluate the illness severity (item 1), attributing a score between 0 (non-assessed) and 7 (extreme severity). In this study it has been used to assess the severity of the alteration of eating attitudes and habit (including valuable information about previous clinical history and treatments delivered). Item 2 assesses the degree of improvement the patient experiences and item 3 assesses the balance between effectiveness of the treatment provided and burden of side effects.

1601

amount of schooling was 9.5 years (SD ± 3.7 years). Their mean BMI was 39.3 (SD ± 3.5; range 33.3–49.5). At the time of inclusion in the study, none of the patients was following a structured diet program or taking psychotropic medications or other drugs to decrease hunger. All the patients had previously (lifetime) been administered at least one diet treatment. 3.2. Response rate in the whole sample (at 3 months) Twenty patients (47.6%) experienced a significant body weight response (loss of at least 5% of body weight), whereas 22 (52.4%) did not (Table 1). Nineteen women (45.3%) achieved a significant reduction in BES (score b 17), but 23 (54.7%) did not (Table 1). No difference emerged for group treatment in both cases (Table 1). There was an association between these two kinds of response: 70% of the subjects in whom BES was significantly reduced also achieved a significant weight loss. Also rate of abstinence in the two groups did not differ with the Chi-Square analysis (Table 1). 3.3. Side effects

2.4. Data analyses All data analyses were performed using the Statistical Package for Social Sciences (SPSS, 2000). The researcher who analyzed the data was not informed about the kind of treatment the patients were receiving. First, we described the sample and two treatment groups with descriptive statistics. The association among categorical descriptive variables was tested with χ2 to investigate the possibility of an association between body weight and reduction in BES scores, between response and treatment modality, between the same variables and dropout rates, and between treatment modality and side effects. We considered as responders with concerning weight those patients who showed a weight loss of at least 5% of their own body weight, in accordance with other authors (Malhotra et al., 2002); we considered as responders for BES those patients who reached a score on the BES lower than 17, defined as a cut-off for pathology (Mannucci et al., 2001). A t test for independent samples was used to test the validity of randomization. We performed the inferential analysis. Using the General Linear Model (GLM) and ANOVA for repeated measures, the scores obtained from the 42 patients at T0, T8, T12, and T24 (CGI, weight, binge per week), and the psychometric tests (BDI, BES, EDI-2) were compared for the four times of observation (time factor). We also included in the GLM a group (treatment) factor to evaluate the differences between the sertraline and the fluoxetine groups at the four times of observation (time× treatment interaction). The post-hoc comparisons were made with the Bonferroni test (corrected for number of comparisons). A second GLM with ANOVA for repeated measures (GLM) has been used to study variations in weight and BES scores over time, dividing the population into groups based on response to treatment (concerning body weight) at 3 months from initiation of treatment instead of on the basis of the type of treatment received. Effect sizes (partial eta squared) were analyzed for significant variables. A final t test was used to compare responders with non-responders. Since missing data were very few (0.1%) no additional procedure was necessary for minimising their effect on the analysis.

Six patients had mild or severe side effects in the first 2 weeks of treatment (nausea, N = 5; headache, N = 3; anxiety, N = 3; insomnia, N = 1, diarrhea, N = 2) but none of these discontinued the pharmacologic treatment before T8 because of these side effects. This might be due to the thoroughness of the information provided by the therapists about the possible side effects of SSRI treatment. No differences emerged in comparison of the two treatments (Table 1).

Table 1 Association among categorical variables: response, side effects and dropout rates Sertraline group 9 (45.0%) Responders (weight loss) T12b 11 (55%) Non-responders (weight loss) T12b 10 (50%) Responders (BES) T12b 10 (50%) Non-responders (BES) T12b Side effects T8–T12c Yes 3 (15%) No 17 (85%) Dropout T12b 2 (9%) Completers T12b 20 (91%) b Dropout T24 6 (27.3%) Completers T24b 16 (72.7%) Abstinent yes T12 9 (45%) Abstinent not 11 (55%) Abstinent yes T24 12 (60%) Abstinent not 8 (40%) Responder T12 (weight loss)b Responders (BES) T12b Non-responders (BES) T12b Dropout T24b Completers T24b

3. Results 3.1. Sample description The sample at T0 included 42 women with obesity (BMI N 30), with a mean age of 39.6 years (SD ± 8.5; range: 21–57 years); their mean duration of illness was 144 months (SD ± 46.5 months), and their mean

Dropout T24b Completers T24b a b c

Fluoxetine group 8 (47%)

χ2a

P

0.091

.768

0.516

.551

.449

.665

.028

.867

.129

.787

.863

.353

.187

.664

9 (53%) 7 (41.2%) 10 (58.8%)

2 (11.8%) 15 (98.2%) 3 (15%) 17 (85%) 5 (25%) 15 (75%) 8 (47.1%) 9 (52.9%) 9 (52.9%) 8 (47.1%) Non-responder T12 (weight loss)b

13 (72.3%)

5 (25%)

5 (27.7%)

15 (75%)

χ2

P

6.019

0.014

.757

.384

4 (20%) 16 (80%)

7 (31.8%) 15 (68.2%)

Side effectsc T12 yes

Side effectsc T12 no

χ2

P

8 (21.6%) 29 (78.4%)

.152

.314

3 (60%) 2 (40%)

df = 3; the percentages are indicated in the column. For non-responder and dropout definitions, see the text. Presence of side effects with clinical relevance (see the text).

1602

P. Leombruni et al. / Progress in Neuro-sychopharmacology & Biological Psychiatry 32 (2008) 1599–1605

Table 2 Effectiveness of sertraline and fluoxetine: differences among the four times of observation, T0 (baseline), T8 (2 months), T12 (3 months), and T24 (6 months) on clinical features T0

T8

T12

⁎GLM

T24

F

Fluoxetine (F)

N = 20

N = 20

N = 18

N = 15

Sertraline (S)

N = 22

N = 22

N = 20

N = 16

Weight — F Weight — S BMI — F BMI — S Binge/week — F Binge/week — S CGI — F CGI — S BES — F BES — S BDI — F BDI — S

101.9 ± 12.5 99.6 ± 14.5 40.2 ± 3.9 38.6 ± 3.8 4.6 ± 3.2 6.2 ± 7.3 4.0 ± 0.7 3.8 ± 0.6 32.1 ± 3.5 26.1 ± 8.5 11.1 ± 4.5 13.3 ± 7.0

98.3 ± 12.6 96.1 ± 16.3 38.8 ± 3.9 37.2 ± 3.9 1.3 ± 1.9 0.8 ± 1.1 3.4 ± 0.8 3.1 ± 0.8 18.0 ± 8.7 16.7 ± 6.3 8.7 ± 4.1 8.6 ± 5.2

97.4 ± 13.6 95.5 ± 17.5 38.4 ± 4.2 36.9 ± 4.1 1.3 ± 2.0 0.6 ± 0.6 2.9 ± 1.0 3.0 ± 1.0 19.2 ± 7.8 15.6 ± 8.5 7.1 ± 4.1 9.5 ± 5.9

98.6 ± 14.8 94.7 ± 17.8 38.5 ± 5.0 36.6 ± 4.3 0.9 ± 1.1 1.1 ± 3.3 3.1 ± 0.9 2.8 ± 0.9 19.2 ± 11.5 15.9 ± 8.2 8.4 ± 6.2 9.9 ± 5.9

⁎GLM P

F

P

Time

Group

Time effect

Time × group effect

11.26 13.48 13.19 20.47 29.32 5.88

.002° § = .589 .001° § = .608 .000° § = .517 .001° § = .339 .001° § = .631 .001° § = .318

0.665 0.569 0.857 1.006 0.805 0.565

.576 § = .099 .569 § = .101 .467 § = .091 .393 § = .025 .495 § = .093 .640 § = .144

Rush scores and standard deviation of clinical characteristics (weight and binge/week) and of BDI, BES, and CGI scores at four times of observation. ⁎A GLM and ANOVA for repeated measures were performed to compare data among four times of observation controlling also for group effect. Post-hoc test used was Bonferroni (corrected for multiple comparisons) for time factor: ° = T0 N T8, T12, T24. § = partial eta squared (measure of effect size).

3.4. Dropout Eleven patients dropped out of treatment before the conclusion of the study (T24), six in the sertraline group and five in the fluoxetine group (Table 1). Additionally four dropped out within T12 (two in each group) and seven within T12 and T24 (4 and 3 respectively). No patient dropped out before the 8th week. Patients who dropped out of the study did not differ significantly from the those who completed the study in terms of age, duration of illness, and age of onset (data will be available for interested readers on request). Dropout was not associated with clinical response nor with emerging side effects (Table 1). The frequency of side effects was assessed by means of item 3 of the CGI and by using clinical records from control visit.

All the dropout subjects had no additional contact with our institution, so we were unable to determine if they were still taking the drug. For this reason, these subjects were excluded from statistical analyses since their last follow-up visit before dropout. 3.5. Comparison between the two groups at T0 Baseline comparison between the two randomized groups of treatment (fluoxetine and sertraline) did not show any difference with respect to age, education, duration of illness (BED), weight, BMI, binges per week, or BES, BDI, EDI-2 and CGI scores at T0. Some of these data are shown in Tables 2 and 3 (T0), other data will be available to interested readers upon request.

Table 3 Effectiveness of sertraline and fluoxetine: differences among the four times of observation, T0 (baseline), T8 (2 months), T12 (3 months), and T24 (6 months), on eating attitudes T0

T8

T12

T24

⁎GLM

Fluoxetine (F)

N = 20

N = 20

N = 18

N = 15

Sertraline (S)

N = 22

N = 22

N = 20

N = 16

DT — F DT — S BU — F BU — S BD — F BD — S IN — F IN — S P—F P—S ID — F ID — S IA — F IA — S MF — F MF — S ASC — F ASC — S IR — F IR — S SI — F SI — S

11.9 ± 3.8 13.6 ± 4.4 11.6 ± 3.9 10.8 ± 4.6 22.1 ± 4.9 21.4 ± 3.9 8.1 ± 3.9 9.1 ± 5.2 3.5 ± 1.9 4.9 ± 2.0 4.7 ± 3.9 6.8 ± 3.8 10.2 ± 4.9 9.1 ± 4.0 5.8 ± 2.5 5.8 ± 3.2 5.2 ± 2.5 8.2 ± 3.1 5.2 ± 3.1 5.8 ± 4.0 5.8 ± 2.0 6.3 ± 2.5

11.5 ± 4.6 13.5 ± 4.6 5.3 ± 3.3 5.4 ± 4.3 17.5 ± 4.4 17.1 ± 4.7 6.8 ± 4.1 7.5 ± 2.8 3.5 ± 2.5 5.1 ± 2.4 4.1 ± 2.1 5.1 ± 2.5 6.1 ± 4.5 6.2 ± 5.3 5.2 ± 3.4 4.6 ± 3.5 5.0 ± 2.0 6.8 ± 2.3 4.7 ± 3.9 4.4 ± 3.2 5.4 ± 2.4 5.8 ± 2.3

11.3 ± 4.9 12.1 ± 4.6 4.5 ± 2.6 5.2 ± 3.4 16.8 ± 5.1 16.0 ± 6.6 6.7 ± 3.5 7.5 ± 3.7 3.3 ± 2.0 4.1 ± 2.5 3.8 ± 1.7 5.4 ± 2.2 3.9 ± 2.5 4.6 ± 3.8 6.6 ± 3.7 5.3 ± 3.7 4.7 ± 2.4 6.5 ± 3.0 5.2 ± 2.9 4.1 ± 4.0 5.8 ± 2.9 5.6 ± 3.4

11.7 ± 4.2 12.9 ± 4.8 4.7 ± 2.3 4.0 ± 3.2 14.7 ± 6.1 15.4 ± 7.3 7.2 ± 3.7 9.0 ± 3.7 3.0 ± 2.0 5.6 ± 4.3 2.9 ± 2.4 6.0 ± 3.7 3.5 ± 1.6 5.5 ± 5.5 6.2 ± 4.7 5.6 ± 3.5 4.3 ± 2.2 7.8 ± 3.7 4.9 ± 2.5 4.0 ± 2.9 4.7 ± 2.5 5.5 ± 3.3

⁎GLM Pb

F Time effect

1.13 39.5 17.83 2.27 .969

Pb

F

Time × group effect

.340 #

.000 § = .698 .000° § = .644 .085

.387

.763

.495

.687 § = .161 .861 § = .062 .854

.250 .260

.411

1.60

.194

.132

1.09

.356

1.59

2.40

.000⁎⁎ § = .676 .080

.196 § = .141 .578

1.40

.247

1.38

.252

1.84

.145

1.13

.342

1.17

.324

1.92 21.8

.661

.426

.735

EDI-2 indicates Eating Disorder Inventory 2; DT, drive for thinness; BU, bulimia; BD, body dissatisfaction; IN, ineffectiveness; P, perfectionism; ID, interpersonal distrust; IA, interoceptive awareness; MF, maturity fears; ASC, asceticism; IR, impulse regulation; SI, social insecurity. ⁎A GLM and ANOVA for repeated measures were performed to compare data among four times of observation controlling also for group effect. Post-hoc test used was Bonferroni (corrected for multiple comparisons) for time factor: #,° = T0 N T8, T12, T24; ⁎⁎ = T0 N T8 N T12, T24. § = partial eta squared (measure of effect size).

P. Leombruni et al. / Progress in Neuro-sychopharmacology & Biological Psychiatry 32 (2008) 1599–1605

1603

Table 4 Comparison between responder and non-responder groups: differences among the four times of observation, T0 (baseline), T8 (2 months), T12 (3 months) and T24 (6 months) T0

T8

T12

T24

⁎GLM

⁎⁎GLM Pb

F Time Weight — R Weight — NR BES — R BES — NR BDI — R BDI — NR

99.9 ± 7.3 101.5 ± 18.1 29.2 ± 6.4 27.8 ± 7.9 12.2 ± 5.2 12.5 ± 7.1

94.1 ± 7.3 100.4 ± 19.2 13.4 ± 6.5 21.1 ± 6.5 9.3 ± 5.2 7.8 ± 3.9

92.2 ± 7.9 100.9 ± 20.1 13.8 ± 7.5 20.8 ± 7.7 8.3 ± 5.6 8.5 ± 4.9

90.9 ± 9.4 102.7 ± 19.5 12.8 ± 8.9 21.7 ± 8.5 8.3 ± 6.3 10.3 ± 5.6

24.21 36.41 6.18

Pb

F Time × group

.000 § = .455 .000 § = .537 .009 § = .333

29.96 6.428 .917

.000 § = .508 .001 § = .194 .437 § = .147

Rush scores and standard deviation of clinical characteristics (weight) and of BDI and BES scores. ⁎A GLM and ANOVA for repeated measures were performed to compare data among four times of observation, and ⁎⁎comparing the effect due to the group inclusion (responders [R] or non-responders about weight loss). § = partial eta squared (measure of effect size).

3.6. Outcome measures Table 2 reports the features of the two groups of patients at T0, T8, T12 and T24: global clinical severity (CGI), body weight, binges per week, BES, and depression (BDI). Table 3 shows the EDI-2 scores obtained from the subjects in the two groups at the four times of observation. For weight loss, we considered responders to be those subjects who lost at least 5% of their baseline weight. For the BES score we considered responders to be those patients who reached a score of 17 or lower (considered in the literature as a cut-off point to screen for binge eating behavior). 3.7. Comparisons between responder and non-responder groups We compared body weight, BES, and BDI measures of the whole sample at the four times of observation between responder and nonresponder subjects on the basis of percentage weight loss (Table 4). The comparison between responders and non-responders at T0 did not show any significant difference between the groups, whereas responders had a significantly higher reduction in the BES score after SSRIs administration (at T8, T12 and T24). Figs. 1 and 2 show the course of changes in BES score and body weight in these two groups. 4. Discussion With regard to the first aim of the study, the results showed a significant reduction in body weight, a reduction in the frequency of binges, and an improvement in binge behavior as measured by the BES in both the fluoxetine- and sertraline-treated groups. The clinical improvement that can be seen at T8 in different variables assessing body weight, eating behavior and psychopathology tends to continue at T12 and T24, but without any additional significant improvement.

Fig. 1. Comparison of BES total score between responder and non-responder groups based on weight loss.

The primary outcome measures showed a significant reduction in weight (BMI), binge eating (BES), and depression (BDI). These data seem to confirm results reported by other authors (Leombruni et al., 2006a; McElroy et al., 2000) on the efficacy of sertraline on measures of primary outcome in short-term treatment, as well as in the maintenance of weight loss in a longer treatment period (Leombruni et al., 2006a). Obviously the absence of a control group with placebo limits the generalizability of these results. The improvement in depression scores confirms the effects on mood of SSRI drugs (Leombruni et al., 2006b; Vaswani et al., 2003). In fact, after excluding from the study the subjects with major comorbidity for Axis I disorders, in this sample sertraline and fluoxetine appeared to be effective in relieving depressive symptoms, as shown by the decrease in BDI score. Obviously we cannot rule out a temporary improvement deriving from the instability of the BED diagnosis (Jacobs-Pilipski et al., 2007), or the influence of a placebo effect derived from the accuracy of continued care (Jacobs-Pilipski et al., 2007; Grilo et al., 2005). The rate of responders at T12 regarding body weight reduction (subjects who lost at least 5% of their initial weight) and BES (reduction below the threshold of 17) was near 50% in both treatment groups. This rate, which is not very high, is lower than the rate of response after SSRI treatment in patients with BN (Bacaltchuk and Hay, 2001); however, it is in keeping with the literature on pharmacologic treatment of binge eaters with obesity (Grilo et al., 2005; McElroy et al., 2000). Also the rate of remission of binge eating is equivalent to previous studies (Brownley et al., 2007). Responses regarding weight loss and binge eating were found to be associated, thus suggesting a specific effect of SSRIs on the binge eating and compulsivity related to food (Kaye et al., 2005). In comparing responders to non-responders, we were not able to identify factors that could reliably predict response to treatment at T0, which is in keeping with the difficulty other authors have encountered in identifying

Fig. 2. Comparison of weight loss progression between responder and non-responder groups based on weight loss.

1604

P. Leombruni et al. / Progress in Neuro-sychopharmacology & Biological Psychiatry 32 (2008) 1599–1605

predictive factors associated with efficacy of treatment in patients with BED (Brownley et al., 2007; Bulik et al., 2007). In literature only preliminary evidence about the prognostic significance of rapid response in patients with BED can be found (Grilo and Masheb, 2007). Regarding eating psychopathology measured by the EDI-2, a significant improvement in bulimia, interoceptive awareness, and body dissatisfaction (BD) emerged. The first two scales represent some key features of attitudes on binge eating (Garner, 1991), probably suggesting that sertraline and fluoxetine act specifically on the psychopathology of binge eating. The efficacy of SSRIs on these features is an important issue in the pharmacologic treatment of EDs, because recent studies have suggested that they are associated with the pathogenesis and outcome of these disorders (Fassino et al., 2004). Particularly high interoceptive awareness creates a greater difficulty in the ability to discriminate between sensations and feelings, and between the sensations of hunger and satiety (Garner, 1991). These confusion and uncertainty in recognizing emotional states, and in relation to the ability to discriminate hunger and satiety sensations, are often core psychopathologic factors important in the relationship to feeding habits, particularly to binge eating (Waters et al., 2001; Bean et al., 2000). Previous results have suggested that patients with a more unstable eating behavior (BN and BED) are also those scoring higher on interoceptive awareness (Fassino et al., 2004) and that the difficulties with emotional awareness might have a core pathogenic role for bulimic behaviors. Moreover, interoceptive awareness is a trait strongly related to alexithymia (Taylor et al., 1996), which is described as a diminished capacity to verbally describe and identify emotional states, and a common finding in obesity (Morosin and Riva, 1997). This ED-related psychological dimension could be an important target of the pharmacologic treatment of BED. The improvement of the third scale, BD, also represents a goal of treatment because it strongly affects the quality of life of patients with obesity (Fassino et al., 2003). These subjects manifest a reduction in BD mostly between T0 and T8, the same period in which most of the weight reduction occurs; afterwards, BD remains lower than at T0 but it does not show further improvement. These findings might explain why some patients, even if they obtain a positive response from treatment, tend to drop out or to question the efficacy of treatment after some time, as has been described by many clinicians (Molinari et al., 2005). In fact, no significant difference emerged in dropout rate between responders and non-responders at 6 months of treatment (T12). No significant differences were found between the two drugs in the treatment of binge eaters with obesity. The profile of side effects, their frequency, and their influence on dropout do not show any substantial difference. Of course, the limits of this study make these results only preliminary; they need to be confirmed by larger studies. Regarding the course of the improvement, the statistical analysis demonstrates that the best improvements in body weight, eating symptomatology, and binge attitudes are generally within the first 8 weeks (independent of treatment group). If we consider only responders, the trend of improvement (especially regarding body weight) seemed to be constant during the whole of the study period (Fig. 1 and 2). This finding confirms previous evidence (Grilo and Masheb, 2007) and seems to suggest that the lack of response to sertraline or fluoxetine at 8 weeks with regard to binge eating should lead to modification of the pharmacologic treatment in these patients (Leombruni et al., 2006a). In non-responders a different pharmacologic treatment (McElroy, 2003) or a cognitive behavioral treatment — CBT (Grilo et al., 2005; Devlin et al., 2007), also in combination with the SSRIs (Ricca et al., 2001) should be considered. Particularly CBT seems to be associated with a greater reduction of binge episodes in comparison to fluoxetine treatment: 62% vs 33% (Devlin et al., 2005). In this study a rate of 53–60% of abstinent subjects was detected at T24 (Table 1). The study methodology has some weaknesses that limit the confidence of the results obtained: (1) the lack of a control group with placebo, (2) a small sample size in both treatment groups, (3) use of

only one rating scale (CGI) and (4) the exclusion of subjects with Axis I comorbidity. These limitations could in part decrease the generalizability of the results. Particularly the lack of a placebo group seems at this moment the major limitation because of the high rate of placebo responders in BED subjects (Jacobs-Pilipski et al., 2007). However, the follow-up of 24 weeks reduces the extent of the placebo effect, since it is usually transitory (Jacobs-Pilipski et al., 2007). 4.1. Conclusion and clinical implications In conclusion, the present study suggests that: (1) treatment with SSRIs (with no difference between sertraline and fluoxetine) seems to be able to yield a statistically significant reduction in body weight and bulimic symptoms in patients with obesity and BED; (2) this effect seems to be linked to a specific action in relation to binge eating core symptoms and psychopathology; (3) not all subjects responded in the same way, because a subgroup of responders could be identified (near 50% of the sample) who obtained benefits sooner, and tended to continue to improve up to 6 months of treatment; (4) no factors predictive of response could be identified, apart from an initial response regarding binge eating and BES scores; and (5) continuing treatment in patients who failed to respond at 2 months did not seem advisable. Further studies should confirm these results in larger samples and compare these treatments with psychotherapy (e.g. cognitive behavioral therapy), which seems effective both in reducing symptoms and improving quality of life (Grilo et al., 2005). Acknowledgments We acknowledge the help of S. Marozio, MD, V. Mondelli, and M. Levi, MD in data collection. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, see: http://www.textcheck.com/cgi-bin/cerificate.cgi?id=raWWma. References American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Press; 2000. Text Revision. American Psychiatric Association. Practice guideline for the treatment of patients with eating disorders, third edition. Am J Psychiatry 2006;163:4–54. Appolinario JC, McElroy SL. Pharmacological approaches in the treatment of binge eating disorder. Curr Drug Targets 2004;5(3):301–7. Arnold LM, McElroy SL, Hudson JI, Welge JA, Bennet AJ, Keck PE. A placebo-controlled, randomized trial of fluoxetine in the treatment of binge-eating disorder. J Clin Psychiatry 2002;63(11):1028–33. Bacaltchuk J, Hay P. Antidepressants versus placebo for people with bulimia nervosa. Cochrane Database Syst Rev 2001;4:CD003391. Bean P, Shiltz T, Hallinan P, Holbrook T. Self-functioning traits affecting meal compliance in eating disorders patients. Eat Weight Dis 2000;5:198–205. Beck AT, Steer RA. Beck depression manual. New York: Psychological Corporation; 1987. Brownley KA, Berkman ND, Sedway JA, Lohr KN, Bulik CM. Binge eating disorder treatment: a systematic review of randomized controlled trials. Int J Eat Dis 2007;40:337–48. Bulik CM, Sullivan PF, Kendler KS. Medical and psychiatric morbidity in obese women with and without binge eating. Int J Eat Disord 2002;32(1):72–8. Bulik CM, Brownley KA, Shapiro JR. Diagnosis and management of binge eating disorder. World Psychiat 2007;6:142–8. Carter WP, Hudson JI, Lalonde JK, Pindyck L, McElroy SL, Pope Jr HG. Pharmacologic treatment of binge eating disorder. Int J Eat Dis 2003;34:S74–88. Casper RC. Binge eating: nature, assessment and treatment. J Clin Psychopharmacol 1995;15(2):149–50. Devlin MJ, Goldfein JA, Petkova E, Jiang H, Raizman PS, Wolk S, et al. Cognitive behavioral therapy and fluoxetine as adjuncts to group behavioral therapy for binge eating disorder. Obes Res 2005;13(6):1077–88. Devlin MJ, Goldfein JA, Petkova E, Liu L, Walsh BT. Cognitive behavioral therapy and fluoxetine for binge eating disorder: two-year follow-up. Obesity 2007;15(7):1702–9. De Zwaan M, Mitchell JE, Seim HC, Specker SM, Pyle RL, Raymond NC. Eating related and general psychopathology in obese females with binge eating disorder. Int J Eat Disord 1994;15:45–52. Fassino S, Leombruni P, Pierò A, Abbate-Daga G, Amianto F, Rovera G, et al. Temperament and character in obese women with and without binge eating disorder. Compr Psychiatry 2002;43(6):431–7. Fassino S, Leombruni P, Pierò A, Abbate-Daga G, Rovera GG. Mood, eating attitudes, and anger in obese women with and without binge eating disorder. J Psychosom Res 2003;54(6):559–66.

P. Leombruni et al. / Progress in Neuro-sychopharmacology & Biological Psychiatry 32 (2008) 1599–1605 Fassino S, Abbate-Daga G, Boggio S, Garzaro L, Pierò A. Use of reboxetine in bulimia nervosa: a pilot study. J Psychopharmacol 2004;18(3):423–8. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders—Outpatient Edition (SCID-O/P, version 2.0). New York: Biometric Research, New York State Psychiatric Institute; 1996. Garner DM. EDI-2. Eating disorder inventory 2. Professional manual; 1991. Odessa FL. Gormally J, Black S, Daston S, Rardin D. The assessment of binge eating severity among obese patients. Addict Behav 1983;7(1):47–59. Grilo CM, Masheb RM. Rapid response predicts binge eating and weight loss in binge eating disorder: findings from a controlled trial of orlistat with guided self-help cognitive behavioral therapy. Behav Res Ther 2007;45(11):2537–50. 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):301–9. Groth-Marnat G. The handbook of psychological assessment. 2nd ed. New York: John Wiley & Sons; 1990. Guerdjikova AI, McElroy SL, Kotwal R, Welge JA, Nelson F, Lake K, et al. High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebocontrolled monotherapy trial. Hum Psychopharmacol 2008;23(1):1–11. Hudson JI, McElroy SL, Raymond NC, Crow S, Keck Jr PE, Carter WP, et al. Fluvoxamine in the treatment of binge-eating disorder: a multicenter placebo-controlled, doubleblind trial. Am J Psychiatry 1998;155(12):1756–62. Hudson JI, Lalonde JK, Berry JM, Pindyck LJ, Bulik CM, Crow SJ, et al. Binge-eating disorder as a distinct familial phenotype in obese individuals. Arch Gen Psychiatry 2006;63(3):313–9. Jacobs-Pilipski MJ, Wilfley DE, Crow SJ, Walsh BT, Lilenfeld LR, West DS, et al. Placebo response in binge eating disorder. Int J Eat Disord 2007;40(3):204–11. Kaye WH, Frank GK, Bailer UF, Henry SE, Meltzer CC, Price JC, et al. Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies. Physiol Behav 2005;85(1):73–81. Leombruni P, Pierò A, Brustolin A, Mondelli V, Levi M, Campisi S, et al. A 12 to 24 weeks pilot study of sertraline treatment in obese women binge eaters. Hum Psychopharmacol 2006a;21(3):181–8. Leombruni P, Amianto F, Delsedime N, Gramaglia C, Abbate-Daga G, Fassino S. Citalopram versus fluoxetine for the treatment of patients with bulimia nervosa: a single-blind randomized controlled trial. Adv Ther 2006b;23(3):481–94. Malhotra S, King KH, Welge JA, Brusman-Lovins L, McElroy SL. Venlafaxine treatment of binge-eating disorder associated with obesity: a series of 35 patients. J Clin Psychiatry 2002;63(9):802–6. Mannucci E, Ricca V, Rotella CM. Il Comportamento Alimentare nell'Obesità. Milano: EDRA; 2001. McElroy SL, Casuto LS, Nelson EB, Lake KA, Soutullo CA, Keck Jr PE, et al. Placebocontrolled trial of sertraline in the treatment of binge eating disorder. Am J Psychiatry 2000;157(6):1004–6.

1605

McElroy SL, Hudson JI, Malhorta S, Welge JA, Nelson EB, Keck Jr PE. Citalopram in the treatment of binge-eating disorder: a placebo-controlled trial. J Clin Psychiat 2003;64:807–13. Molinari E, Baruffi M, Croci M, Marchi S, Petroni ML. Binge eating disorder in obesity: comparison of different therapeutic strategies. Eat Weight Disord 2005;10(3):154–61. Morosin A, Riva G. Alexithymia in a clinical sample of obese women. Psychol Rep 1997;80:387–94. Pearlstein T, Spurell E, Hohlstein LA, Gurney V, Read J, Fuchs C, et al. A double-blind, placebo-controlled trial of fluvoxamine in binge eating disorder: a high placebo response. Arch Women Ment Health 2003;6(2):147–51. Pi-Sunyer FX. NHLBI Obesity Education Initiative Expert Panel on the identification, evaluation, and treatment of overweight and obesity in adults — the evidence report. Obes Res 1998;6:51S–209S. Pope Jr HG, Lalonde JK, Pindyck LJ, Walsh T, Bulik CM, Crow SJ, et al. Binge eating disorder: a stable syndrome. Am J Psychiatry 2006;163(12):2181–3. Ricca V, Mannucci E, Moretti S, Di Bernardo M, Zucchi T, Cabra PL, et al. Screening for binge eating disorder in obese outpatients. Compr Psychiatry 2000;41(2):111–5. Ricca V, Mannucci E, Mezzani B, Moretti S, Di Bernardo M, Bertelli M, et al. Fluoxetine and fluvoxamine combined with individual cognitive-behaviour therapy in binge eating disorder: a one-year follow-up study. Psychother Psychosom 2001;70(6):298–306. Rieger E, Wilfley DE, Stein RI, Marino V, Crow SJ. A comparison of quality of life in obese individuals with and without binge eating disorder. Int J Eat Disord 2000;37(3):234–40. SPSS Base 11.0. Application guide. Chicago: SPSS; 2000. Steffen KJ, Roerig JL, Mitchell JE, Uppala S. Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs 2006;11(2):315–36. Striegel-Moore RH, Cachelin FM, Dohm FA, Pike KM, Wilfley DE, Fairburn CG. Comparison of binge eating disorder and bulimia nervosa in a community sample. Int J Eat Dis 2001;29:157–65. Taylor GJ, Parker JD, Bagby RM, Bourke MP. Relationship between alexithymia and psychological characteristics associated with eating disorders. J Psychosom Res 1996;41:561–8. van Hanswijck de Jonge P, Van Furth EF, Lacey JH, Waller G. The prevalence of DSM-IV personality pathology among individuals with bulimia nervosa, binge eating disorder and obesity. Psychol Med 2003;33(7):1311–7. Vaswani M, Linda FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuro-psychopharmacol Biol Psychiatry 2003;27(1):85–102. Waters A, Hill A, Waller G. Internal and external antecedents of binge eating episodes in a group of women with bulimia nervosa. Int J Eat Dis 2001;29:17–22. White MA, Grilo CM. Psychiatric comorbidity in binge-eating disorder as a function of smoking history. J Clin Psychiatry 2006;67(4):594–9.