by Valdo Ricca, MD; Giovanni Castellini, MD; Carolina Lo Sauro, MD; Carlo M. Rotella, MD; and Carlo Faravelli, MD
Drs. Ricca, Castellini, and Lo Sauro are from the Department of Neurology and Psychiatry, University of Florence, Florence, Italy; Dr. Rotella is from the Department of Pathophysiology, Unit of Endocrinology, University of Florence, Florence, Italy; and Dr. Faravelli is from the Department of Psychology, University of Florence, Florence, Italy.

Psychiatry (Edgemont) 2009;6(11):23–28

Funding

There was no funding for the development and writing of this article.

Financial disclosure

The authors have no conflicts of interest relevant to the content of this article.

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.

Key Words

Zonisamide, cognitive behavioral therapy, binge eating disorder, overweight

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 open[15] and one randomized, controlled trial[16] 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) criteria[1] 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).

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). 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 findings[24] 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 up[24] 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.

References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition. Washington, DC: American Psychiatric Press, Inc., 1994.
2. Pope HG Jr, Lalonde JK, Pindyck LJ, et al. Binge eating disorder: a stable syndrome. Am J Psychiatry. 2006;163:2181–2183.
3. National Task Force on the Prevention and Treatment of Obesity. Dieting and the development of eating disorders in overweight and obese adults. Arch Intern Med. 2000;160:2581–2589.
4. Ricca V, Mannucci E, Moretti S, et al. Screening for binge eating disorder in obese outpatients. Comp Psychiatry. 2000;41:111–115.
5. de Zwaan M. Binge eating disorder and obesity. Int J Obes. 2001;25(Suppl. 1):S51–S55.
6. Grucza RA, Przybeck TR, Cloninger CR. Prevalence and correlates of binge eating disorder in a community sample. Compr Psychiatry. 2007;48:124–131.
7. 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;57:301–309.
8. Striegel-Moore RH, Wilson GT, Wilfley DE, et al. Binge eating in an obese community sample. Int J Eat Disord. 1998;23:27–37.
9. Brownley KA, Berkman ND, Sedway JA, et al. Binge eating disorder treatment: a systematic review of randomized controlled trials. Int J Eat Disord. 2007;40:337–348.
10. Yager J. Binge eating disorder: the search for better treatments. Am J Psychiatry. 2008;165:4–6.
11. Gadde KM, Franciscy DM, Wagner HR, Krishnan KR. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA. 2003;289:1820–1825.
12. Wang PW, Yang YS, Chandler RA, et al. Adjunctive zonisamide for weight loss in euthymic bipolar disorder patients: a pilot study. J Psychiatr Res. 2008;42:451–457.
13. Faught E, Ayala R, Montouris GG, Leppik IE, Zonisamide 922 Trial Group. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology. 2001;57:1774–1779.
14. Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Data Syst Rev. October 14, 2005.
15. McElroy SL, Kotwal R, Hudson JI, et al. Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial. J Clin Psychiatry. 2004;65:50–56.
16. McElroy SL, Kotwal R, Guerdjikova AI, et al. Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiatry. 2006;67:1897–1906.
17. Fairburn CG, Marcus MD, Wilson GT. Cognitive-behavioural therapy for binge eating and bulimia nervosa: A comprehensive treatment manual. In: Fairburn CG, Wilson GT (eds). Binge Eating: Nature, Assessment and Treatment. New York: Guilford Press; 1993:361–369.
18. Gormally J, Black S, Daston S, Rardin D. The assessment of binge eating severity among obese persons. Addict Behav. 1982;7:47–55.
19. Fairburn CG, Beglin SA. Assessment of eating disorder pathology: interview or self-report questionnaire. Int J Eat Disord. 1994;16:363–370.
20. Beck AT, Steer R. Manual for Revised Beck Depression Inventory. New York: Psychological Corporation, 1987.
21. Spielberger CD, Gorsuch RL, Lushene RE. Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press; 1970.
22. Marcus MD. Adapting treatment for patients with binge eating disorder. In: Garner DM, Garfinkel PE (eds). Handbook of Treatment for Eating Disorders. New York: Guilford Press;1997:484–493.
23. Ricca V, Mannucci E, Mezzani B, et al. Fluoxetine and fluvoxamine combined with individual cognitive-behaviour therapy in binge eating disorder: a one-year follow-up study. Psychother Psychosom. 2001;70:298–306.
24. Wilfley DE, Welch RR, Stein RI, et al. A randomized comparison of group cognitive-behavioral therapy and group interpersonal psychotherapy for the treatment of overweight individuals with binge-eating disorder. Arch Gen Psychiatry. 2002;59:713–721.