Zonisamide Combined with Cognitive Behavioral Therapy in Binge Eating Disorder

Abstract

Objective. Binge eating disorder is a serious, prevalent eating disorder that is associated with overweight. Zonisamide is an antiepileptic drug that can promote weight loss. We evaluated the efficacy and safety of zonisamide as augmentation to individual cognitive behavioral therapy in the treatment of binge eating disorder patients.

Design: controlled open study.

Participants: Twenty four threshold and subthreshold binge eating disorder patients were enrolled in the cognitive behavioral therapy treatment group, and 28 patients in the cognitive behavioral therapy plus zonisamide group.

Measurements: At the beginning (T0), at the end (T1) of treatment, and one year after the end of treatment (T2), body mass index was measured and Eating Disorder Examination-Questionnaire, Binge Eating Scale, Beck Depression Inventory, and State-Trait Anxiety Inventory were administered.

Results. At T1 the cognitive behavioral therapy plus zonisamide group showed a higher mean reduction of body mass index, Eating Disorder Examination-Questionnaire, Beck Depression Inventory, and Binge Eating Scale scores. At T2, the cognitive behavior therapy group regained weight, while the cognitive behavioral therapy plus zonisamide group reduced their body mass and showed a higher reduction in binge eating frequency and Binge Eating Scale, Eating Disorder Examination-Questionnaire Restraint, and State and Trait Anxiety Inventory scores.

Conclusion. The zonisamide augmentation to individual cognitive behavior therapy can improve the treatment of binge eating disorder patients, reducing body weight and the number of binge eating episodes. These results are maintained one year after the end of treatment.

Introduction

Binge eating disorder (BED) is a stable syndrome characterized by recurrent binge eating with a significant sense of loss of control, without compensatory behaviors.^1,2 It represents a clinically significant public health problem,³ with high prevalence of obesity^4–6 and psychiatric and medical comorbidities.^7,8 Cognitive behavioral therapy (CBT) has been shown to reduce the binge frequency and to improve the main psychopathological features of BED; however, CBT initial results do not seem to be maintained in the long-term.^9,10

Several studies showed that zonisamide, a new generation anticonvulsant drug, can promote weight loss in obese,¹¹ bipolar,¹² and epileptic patients.^13,14 One open¹⁵ and one randomized, controlled trial¹⁶ suggested that zonisamide might be a useful treatment for BED, reducing the binge frequency and the body weight in the short term.

Considering the difficulties in maintaining weight loss and binge eating reduction of CBT, since January 2007 our research group used zonisamide augmentation with encouraging results. As no study has explored the effectiveness of the combination of CBT plus zonisamide in BED, we evaluated the efficacy and safety of zonisamide as augmentation to individual CBT at the end of treatment and one year later.

Materials and Methods

All patients (aged 18–60 years) attending Outpatient Clinic for Eating Disorders of the University of Florence between April 1 to June 30, 2006, and between April 1 to June 30, 2007, were enrolled in the study, with the following inclusion criteria: diagnosis of BED according to the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) criteria¹ or subthreshold BED (sBED, with a binges minimum average frequency of once a week over the six-month period preceding the interview),⁸ assessed by a face-to-face interview.

The exclusion criteria were as follows: any organic disease interfering with eating behavior; illiteracy and mental retardation; lifetime history of psychotic, bipolar, or substance abuse disorders; history of seizures, contraindication to treatment with zonisamide; and pregnancy or lactation.

The study protocol was approved by the internal review board of the Department of Neuroscience of the University of Florence, and participants provided their written informed consent.

Among the 38 patients enrolled between April 1 and June 30, 2006 (assigned to the CBT group), five patients refused to participate in the study and nine did not meet the inclusion criteria. Among those enrolled between April 1 and June 30, 2007 (42 patients assigned to CBT-ZNS group), eight patients refused to participate in the study, and six did not meet the inclusion criteria.

The two final groups (CBT: 24 patients; CBT-ZNS: 28 patients) did not differ significantly for demographic and clinical variables (Table 1).

Table 1.

Characteristics of patients at baseline

DEMOGRAPHICS	CBT	CBT + ZONISAMIDE
Number	24	28
Diagnosis	BED: 10; sBED: 14	BED: 12; sBED: 16
Gender	4 M; 20 F	5 M; 23 F
Age (years), mean ± SD	34.8 ± 11.09	36.07 ± 11.56
Age of onset (years), mean ± SD	27.17 ± 4.85	28.14 ± 6.07
Duration of illness, (years) mean ± SD	7.67 ± 3.07	6.06 ± 3.96
BMI (Kg/m2), mean ± SD	39.22 ± 7.84	38.43 ± 5.70
Psychiatric comorbidities
Unipolar depression	5 (20.8%)	6 (21.4%)
Panic disorder	3 (12.5%)	4 (14.2%)
Generalized anxiety disorder	5 (20.8%)	4 (14.2%)
Obsessive compulsive disorder	1 (4.1%)	2 (7.1%)

KEY

CBT

cognitive behavioral therapy

BED

binge eating disorder

sBED

subthreshold binge eating disorder

BMI

body mass index

M

male

F

female

Treatments. Individual CBT. The CBT program consists of 22 individual sessions of 50 minutes each for 24 weeks.¹⁷ Patients were randomly assigned to two trained and qualified cognitive behavior psychotherapists (V.R. and G.C.).

CBT+ zonisamide (ZNS). The initial dose of zonisamide was 25mg/day for the first seven days. The dosage was then increased, as tolerated, by 50mg/day every seven days to a maximum of 100mg/day for those subjects with a body mass index (BMI) <35kg/m² and to a maximum of 150mg/day for those subjects with a BMI >;35kg/m². The pharmacological treatment was interrupted in the case of adverse events or ineffectiveness.

After the 24th week, psychotherapy ended (T1). Zonisamide was progressively decreased up to total discontinuation over a period of five weeks. No further treatment was applied, and no follow-up visits were done for one year. One year after the end of treatment (T2), patients were contacted and re-evaluated.

At baseline (T0), at T1, and at T2, BMI was calculated, and the following psychometric instruments were administered: Binge Eating Scale (BES),¹⁸ Eating Disorder Examination Questionnaire (EDE-Q),¹⁹ Beck Depression Inventory (BDI),²⁰ and State-Trait Anxiety Inventory (STAI).²¹

Statistical analysis. Mann-Whitney U test was adopted for between-group comparison, and Paired-Samples Wilcoxon Test was used to compare clinical variables for each group at different time (between T0 and T1, between T1 and T2, and between T0 and T2). Clinical variables were studied by intention-to-treat analysis (with last observation carried forward for subjects lost to follow up) and only for completers. All analyses were performed using SPSS for Windows 14.0 (Chicago Inc., USA).

Results

Twenty-four patients started the CBT (10 patients with BED and 14 with sBED). Eight subjects (33%, 3 BED and 5 sBED) dropped out from the CBT. Twenty-eight patients started the treatment with CBT plus zonisamide (12 patients with BED and 16 with sBED). Fourteen subjects (50%, 2 with BED, 12 with sBED) failed to complete the study due to the following reasons: side effects [headache (2 cases), nausea (2 cases), dizziness (2 cases)], lack of efficacy (1 case), and difficulties with protocol adherence (7 cases). Three patients were lost to follow up in CBT and four in CBT-ZNS.

No significant difference was found in terms of clinical variables between patients who discontinued zonisamide treatment or interrupted CBT and those who completed the trial and between drop out patients of CBT and CBT-ZNS groups (data not shown).

The mean (± standard deviation [SD]) daily dose of zonisamide at endpoint evaluation was 112±32mg. CBT and CBT-ZNS did not differ significantly for gender, age, BMI, duration of disease, and BED/sBED rate. No significant difference was found between patients assigned to each psychotherapist in terms of BMI and psychopathology at baseline and after treatment (data not shown).

Both treatment resulted in effectiveness on primary outcome measures (Figure 1), with a significant reduction of BMI and binge eating frequency (Table 2); at T2, CBT group regained weight, and BMI was not significantly lower compared to baseline, while the CBT-ZNS reduced their BMI, though not significantly when compared to T1. At T2, binge-eating frequency was significantly higher in the CBT compared to T1 (p<0.05). These results were confirmed for completers analysis (data not shown).

Figure 1.

Body mass index and binge eating frequency at baseline, end of treatment (6 months), and one year after the end of treatment (18 months)

Key

BMI

body mass index

CBT

cognitive behavioral therapy

ZNS

zonisamide

Table 2.

Clinical characteristic at baseline (T0:), at the end of treatment (T1: 6 months), and at follow up (T2: one year after the end of treatment)

MEASURES	CBT			CBT + ZONISAMIDE
	T0	T1	T2	T0	T1	T2
BMI mean Kg/m2 (SD)	39.21 (7.82)	38.41 (7.67)*	38.99 (7.02)	38.43 (5.70)	36.77 (5.84)**	36.49 (5.96)
Binge eating frequency/month	5 (4.0 18.7)	2.0 (1.03.0)**	3.0 (2.03.0)*	5.0 (4.015.0)	2.0 (0.05.0)**	2.0 (0.05.0)
BES	15 (9.5 21.5)	10 (5.0 11.7)**	9.0 (5.512.7)	15 (11.0 18.0)	7 (3.0 16.0)**	7 (2.0 16.0)
EDE-Q: total score	2.8 (2.03.6)	2.6 (1.83.1)**	2.7 (1.9 3.0)	2.8 (2.0 3.6)	2.1 (1.73.2)**	2.2 (1.63.1)
EDE-Q: restraint	2.2 (0.92.6)	2.2 (1.42.6)**	2.2 (1.93.0)*	2.0 (0.9 3.4)	1.8 (0.62.8)**	1.6 (0.62.5)
EDE-Q: eating concern	2.5 (1.23.5)	2.0 (1.2 3.2)	1.9 (1.2 3.3)	2.5 (1.6 2.7)	1.8 (1.62.6)**	1.8 (1.4 3.6)
EDE-Q: weight concern	3.0 (2.14.1)	2.9 (1.8 3.8)	2.9 (1.9 3.3)	3.2 (2.3 3.8)	2.8 (1.83.2)**	2.6 (1.93.4)
EDE-Q: shape concern	3.8 (2.54.5)	3.1 (2.14.1)**	3.1 (2.2 4.2)	4.0 (2.7 4.9)	3.2 (2.14.7)**	3.2 (2.14.7)
BDI	19.5 (16.2 26.0)	14.5 (11.021.7)**	17.5 (13.0 22.0)*	20 (14.0 27.0)	16 (11.0 20.0)**	16.0 (14.020.0)
STAI	46 (39.0 52.7)	40 (38.5 44.0)*	42 (38.5 45.5)	43 (38.0 52.0)	40 (32.0 45.0)**	38 (30.044.0)

Statistics—Results are expressed as median with 25th/75th percentiles in parenthesis; Wilcoxon test: comparison versus precedent value

^*p<0.05

^**p<0.01

Abbreviations

CBT

cognitive behavioral therapy

BMI

body mass index

BES

Binge Eating Scale

EDE-Q

Eating Disorder Examination Questionnaire

BDI

Beck Depression Inventory

STAI

State-Trait Anxiety Scale

Considering the comparison between groups of change rate at T1, CBT-ZNS showed a higher reduction of BMI (p<0.01), BES (p<0.05), EDE-Q total (p<0.01), EDE-Q weight concern (p<0.01), shape concern (p<0.05), and BDI (p<0.05) scores. At T2, CBT-ZNS showed a higher reduction of binge-eating frequency (p<0.01) and BES (p<0.01), EDE-Q Restraint (p<0.01), and STAI (p<0.05) scores.

Discussion

This study demonstrated that the zonisamide augmentation to CBT can improve the treatment of BED in reducing body weight and binge eating episodes, according to the assumption of the CBT program that once the eating behavior is normalized, weight loss should subsequently follow.^22,23

According to previous findings²⁴ in our study at one-year follow up, the CBT patients showed a weight gain trend, demonstrating that CBT was effective in weight reduction in the short time, but capable of inducing a permanent normalization of body weight.^9,10 Also the CBT-ZNS group obtained a significant weight reduction at the end of the treatment, confirming previous studies in subjects with obesity,¹¹ and subjects with obesity and BED;^15,16 however, unlike CBT group, CBT-ZNS patients did not regain weight, maintaining their BMI significantly lower than baseline. Moreover, it is of note that the magnitude of BMI reduction at the end of the treatment was significantly higher in CBT-ZNS compared to CBT group.

A similar trend was observed for the binge eating frequency, with a significant reduction at the end of both treatments and a significant increase in the CBT group at follow up²⁴ that was not observed in CBT-ZNS. According to previous studies,^7–24 CBT was found to be effective in modifying the eating attitudes and behavior of BED patients, as demonstrated by a significant reduction in the EDE-Q total and subscale score in both groups. Moreover, the treatments also determined significant improvements in mood and anxiety symptoms.

The interpretation of these results is difficult, but it can be hypothesized that zonisamide is able to act on the central hunger and satiety mechanisms, reducing the urge to binge, and therefore promoting improvement in the typical concerns that characterize the psychopathological nucleus of BED syndrome. It can be hypothesized that these effects could in turn contribute to the amelioration of the anxious and depressive syndromes in the BED patients.

Study limitations. This study is an open study, and the absence of a placebo pill in the CBT group reduces the power of the results. Larger, controlled trials are warranted.

Conclusion

Our results seem to support that the addition of zonisamide to CBT can represent a useful tool in the treatment of BED patients.