- Email: [email protected]
Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review
Available online at www.sciencedirect.com
General Hospital Psychiatry 30 (2008) 471 – 475
Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review Beatriz Arbaizar, M.D. a , Inés Gómez-Acebo, B.Sc.b,c , Javier Llorca, M.D., Ph.D.b,c,⁎ a
Unit of Mental Health, Hospital de Laredo, 39770-Laredo (Cantabria), Spain b CIBER Epidemiología y Salud Pública (CIBERESP), Spain c Group of Epidemiology and Computational Biology, University of Cantabria, 39011 Santander, Spain Received 19 January 2008; accepted 12 February 2008
Abstract Objective: The objective of this review was to establish the efficacy of topiramate as treatment for eating disorders associated with obesity. Methods: We reviewed all five published controlled clinical trials that tested the efficacy of topiramate in treating bulimia nervosa (BN) or binge-eating disorder (BED). Two trials involving 128 patients studied topiramate efficacy in BN, and three trials (528 patients) studied patients with BED. Data on the number of participants, weeks of follow-up, dropouts, binge frequency and weight were extracted. Results: Short-term treatment with topiramate is more effective than treatment with placebo in decreasing binge episodes per week (overall result: topiramate group: −5.0±0.6; placebo group: −3.3±1.2), binge days per week (topiramate group: −3.5±0.6; placebo group: −2.3±0.7) and corporal weight (topiramate group: −4.6±2.3; placebo group: −0.5±0.6) in both BN and BED. The high number of withdrawals and the small sample sizes in four of the five controlled clinical trials limit the generalizability of this result. Conclusion: Topiramate is effective in the short-term treatment of eating disorders associated with obesity. Additional studies are needed to prove its efficacy in the long term and to determine the optimal effective dose. © 2008 Elsevier Inc. All rights reserved. Keywords: Binge-eating disorder; Bulimia nervosa; Controlled clinical trial; Topiramate
1. Introduction Topiramate is an anticonvulsant that is currently indicated for therapy in tonic–clonic seizures, as well as for migraine prophylaxis [1]; recently, it has been used to treat some addictive behaviors, mainly alcohol dependence [2,3]. Its proposed mechanisms of action include inhibition of voltagegated sodium and calcium channels, activation of γ-aminobutyric acid A receptors, inhibition of enzyme carbonic anhydrase and blockade of kainite/amino-3-hydroxy5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors [4].It has been found to be effective in migraine prophylaxis, essential tremor, neuropathic pain and other neurological or psychiatric disorders [5,6]. Mechanisms of action for the treatment of nonepileptic conditions have been described by Rogawski and Löscher [5]. A number of ⁎ Corresponding author. Medicina Preventiva y Salud Pública, Faculdad de Medicina, Avda. Herrera Oria s/n, 39011 Santander, Spain. Tel.: +34 942201993; fax: +34 942201903. E-mail address: [email protected] (J. Llorca). 0163-8343/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2008.02.002
randomized clinical trials support its efficacy in decreasing appetite and weight [7,8]. Its effect on the kainite/AMPA glutamate receptors is the rationale for suggesting that it may be effective in eating disorders associated with obesity, such as bulimia nervosa (BN) and binge-eating disorder (BED) [9]. Until now, the possible treatments tested for BN had been nonpharmacological (such as cognitive–behavioral therapy and interpersonal therapy) and pharmacological (such as tricyclic antidepressants and selective serotonin reuptake inhibitors) strategies; although these approaches have beneficial effects, they are not good enough for most patients to obtain total remission [10]. The same strategies are available for BED; however, it appears that treatments that are useful for weight loss are not effective for reducing binge frequency and vice versa [11,12]. Lately, a group of new drugs, such as topiramate [13], sibutramine [14–16], orlistat plus cognitive–behavioral therapy [12], zonisamide [17] and atomoxetine [18], has demonstrated efficacy in reducing both binge frequency and weight in controlled clinical trials. Nowadays, there is no consensus on the first-line treatment of eating disorders associated with obesity. In
472
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
this report, we review the published randomized controlled clinical trials on the efficacy of topiramate in BN or BED. 2. Methods 2.1. Data sources We searched the MEDLINE database for articles reporting controlled clinical trials on the efficacy of topiramate in BN or BED. The search keywords used were “topiramate” AND “binge-eating disorder” and “topiramate” AND “bulimia nervosa”; the last search was performed on January 2, 2008. Abstracts were revised to identify original articles on controlled clinical trials; these articles were obtained in full. 2.2. Extracting information Data on the number of patients in both intervention and control (i.e., placebo) groups, weeks of follow-up, withdrawals, topiramate doses, number of binge episodes per week, days with binge episodes per week, weight, body mass index and several psychological scores (as Clinical Global Impression—Severity Scale, Hamilton—Anxiety and Hamilton—Depression) were extracted. We also recorded changes in clinical and ponderal characteristics after the intervention. 2.3. Summary measures The main measures for efficacy were changes in the number of binge episodes per week, days with binge episodes per week and weight. 3. Results We found five randomized clinical trials on the use of topiramate in eating disorders associated with obesity; three trials had been performed on BED [13,19,20], and the remaining two had been performed on BN [10,21]. All five trials were placebo controlled. A description of the main clinical and demographic base data appears in Table 1. 3.1. Topiramate in BN Two clinical trials involving 129 patients have been published; the period of follow-up in both trials was 10 weeks. Hoopes et al. [21] randomly assigned 34 BN patients to topiramate (dose: 25–400 mg/day) and 34 patients to placebo. Nine patients from the topiramate group and 15 patients from the placebo group dropped out of the study; the reasons for withdrawal were as follows: lost to follow-up (8 topiramate/4 placebo), adverse events (1 topiramate/ 2 placebo), patient choice (1 topiramate/7 placebo), lack of efficacy (0 topiramate/2 placebo) or others (2 topiramate/ 1 placebo). Adverse events included the following: fatigue (11 topiramate/8 placebo), influenza-like symptoms (10 topiramate/6 placebo), paresthesia (8 topiramate/2 placebo), hypoesthesia (7 topiramate/1 placebo), nausea (6 topiramate/3 placebo), constipation (5 topiramate/2 placebo), difficulty with concentration (5 topiramate/2 placebo), head-
ache (4 topiramate/5 placebo) and nervousness (4 topiramate/ 2 placebo). The mean age at recruitment was about 30 years (Table 1). Before the intervention, patients reported about 11 binge episodes/week, on average, and 4.8 binge days/ week. After 10 weeks of follow-up, binge episodes per week decreased more in the topiramate group (−5.3) than in the placebo group (−3.2); the decrease in binge days per week and the decrease in corporal weight were also greater in the topiramate group (Table 2). The other clinical trial on BN [10] assigned 30 patients to both groups (topiramate and placebo); only 5 patients in the topiramate group and 6 patients in the placebo group withdrew from the study (no reasons were reported). Adverse events were not more frequent in the topiramate group; they included sedation (2 topiramate/3 placebo), dizziness (1 topiramate/2 placebo), headache (3 topiramate/2 placebo) and paresthesia (2 topiramate/2 placebo). Patients were younger than in the Hoopes et al. study (21 years, on average) and suffered fewer binge episodes per week (8.0) (Table 1). Binge frequency dropped by −3.4 binge episodes/week in the topiramate group, while it remained constant in the placebo group. Corporal weight fell by −4.0 kg in the intervention group and −0.3 kg in the control group (Table 2). 3.2. Topiramate in BED A total of 528 patients have participated in three trials on topiramate efficacy in BED treatment; nevertheless, this figure is strongly influenced by the largest study performed: about four of five patients participated in the study published by McElroy et al. [19]. The first trial on BED and topiramate was published in 2003 [13]. It involved 61 patients [31 received topiramate (50–600 mg/day) and 30 took placebo]; withdrawals were frequent, although without any relevant difference between the groups (14 with topiramate and 12 with placebo). Reasons for withdrawing from the study were as follows: adverse events [6 topiramate (3 headache, 2 paresthesia, 1 amenorrhea)/ 3 placebo (1 leg cramps, 1 sedation, 1 testicular soreness)]; lack of efficacy (1 topiramate/2 placebo); nonadherence to protocol (6 topiramate/7 placebo); and exacerbation of previous medical condition (1 topiramate/0 placebo). The more frequent adverse events included the following: paresthesia (21 topiramate/3 placebo), dry mouth (13 topiramate/9 placebo), headache (12 topiramate/7 placebo), dyspepsia (9 topiramate/7 placebo), somnolence (8 topiramate/8 placebo), nervousness (7 topiramate/3 placebo), language problems (6 topiramate/1 placebo) and taste perversion (6 topiramate/0 placebo). The mean age was about 41 years, and patients reported about 6 binge episodes/week and 4.5 binge days/week, on average (Table 1). After 14 weeks of follow-up, greater declines in binge episodes per week (−4.2 in the topiramate group vs. −2.9 in the placebo group), binge days per week (−3.4 in the topiramate group vs. −2.0 in the placebo group) and weight (−5.9 kg in the topiramate group vs. −1.2 kg in the placebo group) were observed in the topiramate group (Table 2).
Reference
Hoopes et al. [21] Nickel et al. [10] McElroy et al. [13] McElroy et al. [19] Claudino et al. [20]
Diagnosis
n (topiramate/ placebo)
Weeks of follow-up
Withdrawals (topiramate/ placebo) [n (%)]
Age range (years)
Mean age in years (topiramate/ placebo)
16–50
29.0/29.6
33/1
N18
21.5/21.1
30/0
Binge episodes/week (topiramate/ placebo)
Binge days/week (topiramate/ placebo)
Clinical Global Impression— Severity Scale score (topiramate/placebo)
Range of topiramate dose (mg/24 h) a
34/0
10.8/11.3
4.8/4.7
4.9/4.6
30/0
8.0/8.0
NA/NA
NA/NA
25–400 (median: 100) 250
–
5.3/6.3
4.3/4.8
4.7/4.9
300–600
Women/men (n) Topiramate
Placebo
BN
34/34
10
13 (37)/16 (47)
BN
30/30
10
5 (17)/6 (20)
BED
30/31
14
14 (47)/12 (39)
18–60
40.9/40.7
52/8 b
BED
195/199
16
57 (29)/61 (31)
18–65
44.0/45.0
170/32
170/32
6.6/6.6
4.6/4.6
4.8/4.8
400
BED
37/36
21
7 (19)/10 (28)
NA
41.1/35.4
36/1
34/2
4.7/3.8
4.2/3.4
NA/NA
200–300
NA: not available. a All studies began with a dose of 25 mg/24 h, which progressively increased until the objective dose had been reached. b No detailed data for topiramate and placebo groups.
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
Table 1 Description of studies included in this revision
473
474
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
Table 2 Changes in clinical variables Reference
Hoopes et al. [21] Nickel et al. [10] McElroy et al. [13] McElroy et al. [19] Claudino et al. [20] Mean of two studies on BN b Mean of three studies on BED b Mean of five studies b
Conclusion a
Binge episodes/week
Binge days/week
Weight
Topiramate
Placebo
Topiramate
Placebo
Topiramate
Placebo
−5.3 −3.4 −4.2 −5.3 −4.7 −4.4±1.3 −5.2±0.3 −5.0±0.6
−3.2 −0.1 −2.9 −3.8 −3.5 −1.7±2.2 −3.7±0.4 −3.3±1.2
−2.3 NA −3.4 −3.5 −4.2 – −3.7±0.4 −3.5±0.6
−1.8 NA −2.0 −2.5 −3.3 – −2.5±0.3 −2.3±0.7
−1.8 −4.0 −5.9 NA −6.8 −2.8±1.6 −6.4±0.6 −4.6±2.3
+0.2 −0.3 −1.2 NA −0.9 −0.03±0.35 −1.0±0.2 −0.5±0.6
+/+ ++/++ +/++ +/? +/++ ++/++ +/++ +/++
NA: not available. a The first sign represents effect on binges; the second sign represents effect on weight. b Weighting by the number of participants; standard deviations represent interstudy variability rather than interpatient variability.
Three hundred ninety-four patients participated in the largest controlled clinical trial performed on BED and topiramate [19]. One hundred ninety-five patients were randomly assigned to the topiramate group, and 199 patients were randomly assigned to the placebo group; 118 patients withdrew from the study [57 topiramate (12, subject choice; 29, adverse event; 1, lack of efficacy; 13, lost to follow-up; 2, other reasons) vs. 61 placebo (21, subject choice; 16, adverse events; 3, lack of efficacy; 17, lost to follow-up; 4, other reasons)]. Some adverse events were more frequent in the topiramate group: paresthesia (113 in the topiramate group vs. 25 in the placebo group), upper respiratory tract infection (37 in the topiramate group vs. 20 in the placebo group), taste perversion (28 in the topiramate group vs. 2 in the placebo group), difficulty with concentration/attention (26 in the topiramate group vs. 5 in the placebo group) and difficulty with memory (25 in the topiramate group vs. 12 in the placebo group). Patient age was 45 years, on average, and the patients reported 6.6 binge episodes/week and 4.6 binge days/week (Table 1). After a 16-week follow-up, a larger reduction was found in binge episodes per week (−5.3 vs. −3.8) and in binge days per week (−3.5 vs. −2.5) in the topiramate group (Table 2). The last published controlled clinical trial on topiramate in BED enrolled 73 patients (37 were allocated to topiramate plus cognitive–behavioral therapy and 36 were allocated to placebo) [20]; there were 17 dropouts (7 topiramate, 10 placebo). Topiramate patients were older (41.1 vs. 35.4 years, on average), had a higher number of binge episodes per week (4.7 vs. 3.8) and had a higher number of binge days per week (4.2 vs. 3.4) (Table 1). Patients were followed for 21 weeks. A dramatic decrease in weight was observed in the topiramate group (−6.8 kg); less improvements were found in binge episodes per week and binge days per week (Table 2). 4. Discussion Topiramate enhances the main clinical variables in eating disorders associated with obesity. This improvement consistently occurs in binge episodes per week, binge days per week and, especially, corporal weight. This result is steady when treating BED or BN.
Topiramate has several mechanisms of action: increase in GABAergic activity, blockade of glutamatergic neurotransmission and inhibition of voltage-gated calcium and sodium channels. Its efficacy in the treatment of eating disorders was suggested because of its inhibitor effect on kainate/AMPA glutamate receptors [9]. Kainate/AMPA agonists produced an intense dose-dependent increase in food intake in animal models [22]; more recently, it has been found that stimulation of kainite receptors, but not AMPA receptors, elicits feeding behavior [23]. The clinical efficacy of topiramate has been suggested by case series and open-label trials [24,25]; however, until 2003, there had been no randomized clinical trial to support this result. Clinical trials here revised the different topiramate doses used. The usual schedule was to predetermine an objective dose, begin with 25 mg/24 h and progressively increase topiramate until the objective dose had been reached; some minor variations in dose schedule have been applied in some trials. Data in Tables 1 and 2 do not suggest any clear relationship between topiramate dose and efficacy; nevertheless, no trial targeting dose-dependent efficacy has been published. Three weak points should be discussed: small sample sizes, dropouts and duration of follow-up. First of all, four of the five trials we have revised included fewer than 75 patients; therefore, the mean results displayed in Table 2 are largely conditioned by the only trial that included almost 400 patients. Interestingly, except for a trial on sibutramine efficacy [16], which included 304 patients, clinical trials on other pharmacological treatments for BED also had small sample sizes, with the range being 29–89 [12,14,15,17,18]. Second, the percentages of dropouts were 19–47% in the topiramate groups and 20–44% in the placebo groups; although there are no relevant differences in withdrawals between both groups, generalizations would be limited by such high figures. Third, all five trials we have considered were short term; BED and BN would require long-term treatment, so additional trials would be needed. In fact, the trial performed by McElroy et al. [13] had an open-label continuation [26], suggesting that topiramate would also be efficacious in longterm treatments. Only one trial on orlistat efficacy in BED
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
[12] and another trial on sibutramine efficacy [16] followed patients for as long as 24 weeks. The remaining studies on pharmacological treatment for BED had follow-up periods ranging between 10 and 16 weeks [14,15,17,18]; therefore, there is lack of evidence for choosing the best pharmacological long-term treatment for BED. An important limitation in our review should be reported. Our initial interest was to perform a meta-analysis; however, this was impossible because several trials did not report a variability measure (e.g., standard deviation) on result variables (changes in binge frequency or changes in weight). Of note, all trials described standard deviations in basal measures of clinical variables; however, surprisingly, when displaying the main results, a number of articles only reported the average changes from basal measurements. Providing standard deviations or confidence intervals for result variables would be an improvement in reporting results from clinical trials [27], as it may make the reader's interpretation of results easier; generalization of results also requires information on how much variability exists. In summary, randomized clinical trials indicate that topiramate is useful for short-term treatment of BED and BN, as it improves binge frequency and decreases weight. Openlabel studies also suggest that topiramate would be efficacious in the long term; however, additional trials are required to prove this and to determine the optimal effective dose.
References [1] van Passel L, Arif H, Hirsch LJ. Topiramate for the treatment of epilepsy and other nervous system disorders. Expert Rev Neurotherapeutics 2006;6:19–31. [2] Johnson BA, Ait-Daoud N, Akhtar FZ, et al. Oral topiramate reduces the consequences of drinking and improves the quality of life of alcoholdependent individuals: a randomized controlled trial. Arch Gen Psychiatry 2004;61:905–12. [3] Johnson BA, Rosenthal N, Capèce JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007;298: 1641–51. [4] Johannessen Landmark C. Targets for antiepileptic drugs in the synapse. Med Sci Monit 2007;13:1–7. [5] Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med 2004;10:685–92. [6] Johannessen Landmark C. Relations between mechanisms of action and clinical efficacy of antiepileptic drugs in non-epilepsy conditions. CNS Drugs 2008;22:27–47. [7] Bray GA, Hollander P, Klein S, et al. A 6-month randomized, placebocontrolled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003;1:722–33. [8] Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord 2004;28:1399–410.
475
[9] Hettes SR, Gonaga J, Heyming TW, et al. Dual roles in feeding for AMPA/kainite receptors: receptor activation or inactivation within distinct hypothalamic regions elicits feeding behavior. Brain Res 2003; 992:167–78. [10] Nickel C, Tritt K, Muehlbacher M, et al. Topiramate treatment in bulimia nervosa patients: a randomized, double-blind, placebo-controlled trial. Int J Eat Disord 2005;38:295–300. [11] Carter WP, Hudson JI, Lalonde JK, et al. Pharmacologic treatment of binge eating disorder. Int J Eat Disord 2003;34(suppl):S74–S88. [12] Grilo CM, Masheb RM, Salant SL. Cognitive behavioral therapy guided self-help and orlistat for the treatment of binge eating disorder: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry 2005;57:1193–201. [13] McElroy SL, Arnold LM, Shapira NA, et al. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:255–61. [14] Milano W, Petrella C, Casella A, et al. Use of sibutramine, an inhibitor of the reuptake of serotonin and noradrenalin, in the treatment of binge eating disorder: a placebo-controlled study. Adv Ther 2005;22:25–31. [15] Appolinario JC, Bacaltchuk J, Sichieri R, et al. A randomized, doubleblind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder. Arch Gen Psychiatry 2003;60:1109–16. [16] Wilfley DE, Crow SJ, Hudson JI, et al. Efficacy of sibutramine for the treatment of binge eating disorder: a randomized multicenter placebocontrolled double-blind study. Am J Psychiatry 2008;165:51–8. [17] McElroy SL, Kotwal R, Guerdjikova A, et al. Zonisamide in the treatment of binge eating disorder with obesity: a placebo-controlled trial. J Clin Psychiatry 2006;67:1897–906. [18] McElroy SL, Guerdjikova A, Kotwal R, et al. Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry 2007;68:390–8. [19] McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry 2007;61:1039–48. [20] Claudino AM, Oliveira IR, Appolinario JC, et al. Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive–behavior therapy in binge-eating disorder. J Clin Psychiatry 2007;68:1324–32. [21] Hoopes SP, Reimherr FW, Hedges DW, et al. Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebocontrolled trial: Part 1. Improvement in binge and purge measures. J Clin Psychiatry 2003;64:1335–41. [22] Stanley BG, Ha LH, Spears LC, et al. II. Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5methyl-isoxazole propionic or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats. Brain Res 1993;613:88–95. [23] Hettes SR, Heyming TW, Stanley BG. Stimulation of lateral hypothalamic kainate receptors selectively elicits feeding behavior. Brain Res 2007;1184:178–85. [24] Shapira NA, Goldsmith TD, McElroy SL. Treatment of binge-eating disorder with topiramate: a clinical case series. J Clin Psychiatry 2000; 61:368–72. [25] Appolinario JC, Fontenelle LF, Papelbaum M, Bueno JR, Coutinho W. Topiramate use in obese patients with binge eating disorder: an open study. Can J Psychiatry 2002;47:271–3. [26] McElroy SL, Shapira NA, Arnold LM, et al. Topiramate in the longterm treatment of binge-eating disorder associated with obesity. J Clin Psychiatry 2004;65:1463–9. [27] Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357:1191–4.
General Hospital Psychiatry 30 (2008) 471 – 475
Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review Beatriz Arbaizar, M.D. a , Inés Gómez-Acebo, B.Sc.b,c , Javier Llorca, M.D., Ph.D.b,c,⁎ a
Unit of Mental Health, Hospital de Laredo, 39770-Laredo (Cantabria), Spain b CIBER Epidemiología y Salud Pública (CIBERESP), Spain c Group of Epidemiology and Computational Biology, University of Cantabria, 39011 Santander, Spain Received 19 January 2008; accepted 12 February 2008
Abstract Objective: The objective of this review was to establish the efficacy of topiramate as treatment for eating disorders associated with obesity. Methods: We reviewed all five published controlled clinical trials that tested the efficacy of topiramate in treating bulimia nervosa (BN) or binge-eating disorder (BED). Two trials involving 128 patients studied topiramate efficacy in BN, and three trials (528 patients) studied patients with BED. Data on the number of participants, weeks of follow-up, dropouts, binge frequency and weight were extracted. Results: Short-term treatment with topiramate is more effective than treatment with placebo in decreasing binge episodes per week (overall result: topiramate group: −5.0±0.6; placebo group: −3.3±1.2), binge days per week (topiramate group: −3.5±0.6; placebo group: −2.3±0.7) and corporal weight (topiramate group: −4.6±2.3; placebo group: −0.5±0.6) in both BN and BED. The high number of withdrawals and the small sample sizes in four of the five controlled clinical trials limit the generalizability of this result. Conclusion: Topiramate is effective in the short-term treatment of eating disorders associated with obesity. Additional studies are needed to prove its efficacy in the long term and to determine the optimal effective dose. © 2008 Elsevier Inc. All rights reserved. Keywords: Binge-eating disorder; Bulimia nervosa; Controlled clinical trial; Topiramate
1. Introduction Topiramate is an anticonvulsant that is currently indicated for therapy in tonic–clonic seizures, as well as for migraine prophylaxis [1]; recently, it has been used to treat some addictive behaviors, mainly alcohol dependence [2,3]. Its proposed mechanisms of action include inhibition of voltagegated sodium and calcium channels, activation of γ-aminobutyric acid A receptors, inhibition of enzyme carbonic anhydrase and blockade of kainite/amino-3-hydroxy5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors [4].It has been found to be effective in migraine prophylaxis, essential tremor, neuropathic pain and other neurological or psychiatric disorders [5,6]. Mechanisms of action for the treatment of nonepileptic conditions have been described by Rogawski and Löscher [5]. A number of ⁎ Corresponding author. Medicina Preventiva y Salud Pública, Faculdad de Medicina, Avda. Herrera Oria s/n, 39011 Santander, Spain. Tel.: +34 942201993; fax: +34 942201903. E-mail address: [email protected] (J. Llorca). 0163-8343/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2008.02.002
randomized clinical trials support its efficacy in decreasing appetite and weight [7,8]. Its effect on the kainite/AMPA glutamate receptors is the rationale for suggesting that it may be effective in eating disorders associated with obesity, such as bulimia nervosa (BN) and binge-eating disorder (BED) [9]. Until now, the possible treatments tested for BN had been nonpharmacological (such as cognitive–behavioral therapy and interpersonal therapy) and pharmacological (such as tricyclic antidepressants and selective serotonin reuptake inhibitors) strategies; although these approaches have beneficial effects, they are not good enough for most patients to obtain total remission [10]. The same strategies are available for BED; however, it appears that treatments that are useful for weight loss are not effective for reducing binge frequency and vice versa [11,12]. Lately, a group of new drugs, such as topiramate [13], sibutramine [14–16], orlistat plus cognitive–behavioral therapy [12], zonisamide [17] and atomoxetine [18], has demonstrated efficacy in reducing both binge frequency and weight in controlled clinical trials. Nowadays, there is no consensus on the first-line treatment of eating disorders associated with obesity. In
472
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
this report, we review the published randomized controlled clinical trials on the efficacy of topiramate in BN or BED. 2. Methods 2.1. Data sources We searched the MEDLINE database for articles reporting controlled clinical trials on the efficacy of topiramate in BN or BED. The search keywords used were “topiramate” AND “binge-eating disorder” and “topiramate” AND “bulimia nervosa”; the last search was performed on January 2, 2008. Abstracts were revised to identify original articles on controlled clinical trials; these articles were obtained in full. 2.2. Extracting information Data on the number of patients in both intervention and control (i.e., placebo) groups, weeks of follow-up, withdrawals, topiramate doses, number of binge episodes per week, days with binge episodes per week, weight, body mass index and several psychological scores (as Clinical Global Impression—Severity Scale, Hamilton—Anxiety and Hamilton—Depression) were extracted. We also recorded changes in clinical and ponderal characteristics after the intervention. 2.3. Summary measures The main measures for efficacy were changes in the number of binge episodes per week, days with binge episodes per week and weight. 3. Results We found five randomized clinical trials on the use of topiramate in eating disorders associated with obesity; three trials had been performed on BED [13,19,20], and the remaining two had been performed on BN [10,21]. All five trials were placebo controlled. A description of the main clinical and demographic base data appears in Table 1. 3.1. Topiramate in BN Two clinical trials involving 129 patients have been published; the period of follow-up in both trials was 10 weeks. Hoopes et al. [21] randomly assigned 34 BN patients to topiramate (dose: 25–400 mg/day) and 34 patients to placebo. Nine patients from the topiramate group and 15 patients from the placebo group dropped out of the study; the reasons for withdrawal were as follows: lost to follow-up (8 topiramate/4 placebo), adverse events (1 topiramate/ 2 placebo), patient choice (1 topiramate/7 placebo), lack of efficacy (0 topiramate/2 placebo) or others (2 topiramate/ 1 placebo). Adverse events included the following: fatigue (11 topiramate/8 placebo), influenza-like symptoms (10 topiramate/6 placebo), paresthesia (8 topiramate/2 placebo), hypoesthesia (7 topiramate/1 placebo), nausea (6 topiramate/3 placebo), constipation (5 topiramate/2 placebo), difficulty with concentration (5 topiramate/2 placebo), head-
ache (4 topiramate/5 placebo) and nervousness (4 topiramate/ 2 placebo). The mean age at recruitment was about 30 years (Table 1). Before the intervention, patients reported about 11 binge episodes/week, on average, and 4.8 binge days/ week. After 10 weeks of follow-up, binge episodes per week decreased more in the topiramate group (−5.3) than in the placebo group (−3.2); the decrease in binge days per week and the decrease in corporal weight were also greater in the topiramate group (Table 2). The other clinical trial on BN [10] assigned 30 patients to both groups (topiramate and placebo); only 5 patients in the topiramate group and 6 patients in the placebo group withdrew from the study (no reasons were reported). Adverse events were not more frequent in the topiramate group; they included sedation (2 topiramate/3 placebo), dizziness (1 topiramate/2 placebo), headache (3 topiramate/2 placebo) and paresthesia (2 topiramate/2 placebo). Patients were younger than in the Hoopes et al. study (21 years, on average) and suffered fewer binge episodes per week (8.0) (Table 1). Binge frequency dropped by −3.4 binge episodes/week in the topiramate group, while it remained constant in the placebo group. Corporal weight fell by −4.0 kg in the intervention group and −0.3 kg in the control group (Table 2). 3.2. Topiramate in BED A total of 528 patients have participated in three trials on topiramate efficacy in BED treatment; nevertheless, this figure is strongly influenced by the largest study performed: about four of five patients participated in the study published by McElroy et al. [19]. The first trial on BED and topiramate was published in 2003 [13]. It involved 61 patients [31 received topiramate (50–600 mg/day) and 30 took placebo]; withdrawals were frequent, although without any relevant difference between the groups (14 with topiramate and 12 with placebo). Reasons for withdrawing from the study were as follows: adverse events [6 topiramate (3 headache, 2 paresthesia, 1 amenorrhea)/ 3 placebo (1 leg cramps, 1 sedation, 1 testicular soreness)]; lack of efficacy (1 topiramate/2 placebo); nonadherence to protocol (6 topiramate/7 placebo); and exacerbation of previous medical condition (1 topiramate/0 placebo). The more frequent adverse events included the following: paresthesia (21 topiramate/3 placebo), dry mouth (13 topiramate/9 placebo), headache (12 topiramate/7 placebo), dyspepsia (9 topiramate/7 placebo), somnolence (8 topiramate/8 placebo), nervousness (7 topiramate/3 placebo), language problems (6 topiramate/1 placebo) and taste perversion (6 topiramate/0 placebo). The mean age was about 41 years, and patients reported about 6 binge episodes/week and 4.5 binge days/week, on average (Table 1). After 14 weeks of follow-up, greater declines in binge episodes per week (−4.2 in the topiramate group vs. −2.9 in the placebo group), binge days per week (−3.4 in the topiramate group vs. −2.0 in the placebo group) and weight (−5.9 kg in the topiramate group vs. −1.2 kg in the placebo group) were observed in the topiramate group (Table 2).
Reference
Hoopes et al. [21] Nickel et al. [10] McElroy et al. [13] McElroy et al. [19] Claudino et al. [20]
Diagnosis
n (topiramate/ placebo)
Weeks of follow-up
Withdrawals (topiramate/ placebo) [n (%)]
Age range (years)
Mean age in years (topiramate/ placebo)
16–50
29.0/29.6
33/1
N18
21.5/21.1
30/0
Binge episodes/week (topiramate/ placebo)
Binge days/week (topiramate/ placebo)
Clinical Global Impression— Severity Scale score (topiramate/placebo)
Range of topiramate dose (mg/24 h) a
34/0
10.8/11.3
4.8/4.7
4.9/4.6
30/0
8.0/8.0
NA/NA
NA/NA
25–400 (median: 100) 250
–
5.3/6.3
4.3/4.8
4.7/4.9
300–600
Women/men (n) Topiramate
Placebo
BN
34/34
10
13 (37)/16 (47)
BN
30/30
10
5 (17)/6 (20)
BED
30/31
14
14 (47)/12 (39)
18–60
40.9/40.7
52/8 b
BED
195/199
16
57 (29)/61 (31)
18–65
44.0/45.0
170/32
170/32
6.6/6.6
4.6/4.6
4.8/4.8
400
BED
37/36
21
7 (19)/10 (28)
NA
41.1/35.4
36/1
34/2
4.7/3.8
4.2/3.4
NA/NA
200–300
NA: not available. a All studies began with a dose of 25 mg/24 h, which progressively increased until the objective dose had been reached. b No detailed data for topiramate and placebo groups.
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
Table 1 Description of studies included in this revision
473
474
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
Table 2 Changes in clinical variables Reference
Hoopes et al. [21] Nickel et al. [10] McElroy et al. [13] McElroy et al. [19] Claudino et al. [20] Mean of two studies on BN b Mean of three studies on BED b Mean of five studies b
Conclusion a
Binge episodes/week
Binge days/week
Weight
Topiramate
Placebo
Topiramate
Placebo
Topiramate
Placebo
−5.3 −3.4 −4.2 −5.3 −4.7 −4.4±1.3 −5.2±0.3 −5.0±0.6
−3.2 −0.1 −2.9 −3.8 −3.5 −1.7±2.2 −3.7±0.4 −3.3±1.2
−2.3 NA −3.4 −3.5 −4.2 – −3.7±0.4 −3.5±0.6
−1.8 NA −2.0 −2.5 −3.3 – −2.5±0.3 −2.3±0.7
−1.8 −4.0 −5.9 NA −6.8 −2.8±1.6 −6.4±0.6 −4.6±2.3
+0.2 −0.3 −1.2 NA −0.9 −0.03±0.35 −1.0±0.2 −0.5±0.6
+/+ ++/++ +/++ +/? +/++ ++/++ +/++ +/++
NA: not available. a The first sign represents effect on binges; the second sign represents effect on weight. b Weighting by the number of participants; standard deviations represent interstudy variability rather than interpatient variability.
Three hundred ninety-four patients participated in the largest controlled clinical trial performed on BED and topiramate [19]. One hundred ninety-five patients were randomly assigned to the topiramate group, and 199 patients were randomly assigned to the placebo group; 118 patients withdrew from the study [57 topiramate (12, subject choice; 29, adverse event; 1, lack of efficacy; 13, lost to follow-up; 2, other reasons) vs. 61 placebo (21, subject choice; 16, adverse events; 3, lack of efficacy; 17, lost to follow-up; 4, other reasons)]. Some adverse events were more frequent in the topiramate group: paresthesia (113 in the topiramate group vs. 25 in the placebo group), upper respiratory tract infection (37 in the topiramate group vs. 20 in the placebo group), taste perversion (28 in the topiramate group vs. 2 in the placebo group), difficulty with concentration/attention (26 in the topiramate group vs. 5 in the placebo group) and difficulty with memory (25 in the topiramate group vs. 12 in the placebo group). Patient age was 45 years, on average, and the patients reported 6.6 binge episodes/week and 4.6 binge days/week (Table 1). After a 16-week follow-up, a larger reduction was found in binge episodes per week (−5.3 vs. −3.8) and in binge days per week (−3.5 vs. −2.5) in the topiramate group (Table 2). The last published controlled clinical trial on topiramate in BED enrolled 73 patients (37 were allocated to topiramate plus cognitive–behavioral therapy and 36 were allocated to placebo) [20]; there were 17 dropouts (7 topiramate, 10 placebo). Topiramate patients were older (41.1 vs. 35.4 years, on average), had a higher number of binge episodes per week (4.7 vs. 3.8) and had a higher number of binge days per week (4.2 vs. 3.4) (Table 1). Patients were followed for 21 weeks. A dramatic decrease in weight was observed in the topiramate group (−6.8 kg); less improvements were found in binge episodes per week and binge days per week (Table 2). 4. Discussion Topiramate enhances the main clinical variables in eating disorders associated with obesity. This improvement consistently occurs in binge episodes per week, binge days per week and, especially, corporal weight. This result is steady when treating BED or BN.
Topiramate has several mechanisms of action: increase in GABAergic activity, blockade of glutamatergic neurotransmission and inhibition of voltage-gated calcium and sodium channels. Its efficacy in the treatment of eating disorders was suggested because of its inhibitor effect on kainate/AMPA glutamate receptors [9]. Kainate/AMPA agonists produced an intense dose-dependent increase in food intake in animal models [22]; more recently, it has been found that stimulation of kainite receptors, but not AMPA receptors, elicits feeding behavior [23]. The clinical efficacy of topiramate has been suggested by case series and open-label trials [24,25]; however, until 2003, there had been no randomized clinical trial to support this result. Clinical trials here revised the different topiramate doses used. The usual schedule was to predetermine an objective dose, begin with 25 mg/24 h and progressively increase topiramate until the objective dose had been reached; some minor variations in dose schedule have been applied in some trials. Data in Tables 1 and 2 do not suggest any clear relationship between topiramate dose and efficacy; nevertheless, no trial targeting dose-dependent efficacy has been published. Three weak points should be discussed: small sample sizes, dropouts and duration of follow-up. First of all, four of the five trials we have revised included fewer than 75 patients; therefore, the mean results displayed in Table 2 are largely conditioned by the only trial that included almost 400 patients. Interestingly, except for a trial on sibutramine efficacy [16], which included 304 patients, clinical trials on other pharmacological treatments for BED also had small sample sizes, with the range being 29–89 [12,14,15,17,18]. Second, the percentages of dropouts were 19–47% in the topiramate groups and 20–44% in the placebo groups; although there are no relevant differences in withdrawals between both groups, generalizations would be limited by such high figures. Third, all five trials we have considered were short term; BED and BN would require long-term treatment, so additional trials would be needed. In fact, the trial performed by McElroy et al. [13] had an open-label continuation [26], suggesting that topiramate would also be efficacious in longterm treatments. Only one trial on orlistat efficacy in BED
B. Arbaizar et al. / General Hospital Psychiatry 30 (2008) 471–475
[12] and another trial on sibutramine efficacy [16] followed patients for as long as 24 weeks. The remaining studies on pharmacological treatment for BED had follow-up periods ranging between 10 and 16 weeks [14,15,17,18]; therefore, there is lack of evidence for choosing the best pharmacological long-term treatment for BED. An important limitation in our review should be reported. Our initial interest was to perform a meta-analysis; however, this was impossible because several trials did not report a variability measure (e.g., standard deviation) on result variables (changes in binge frequency or changes in weight). Of note, all trials described standard deviations in basal measures of clinical variables; however, surprisingly, when displaying the main results, a number of articles only reported the average changes from basal measurements. Providing standard deviations or confidence intervals for result variables would be an improvement in reporting results from clinical trials [27], as it may make the reader's interpretation of results easier; generalization of results also requires information on how much variability exists. In summary, randomized clinical trials indicate that topiramate is useful for short-term treatment of BED and BN, as it improves binge frequency and decreases weight. Openlabel studies also suggest that topiramate would be efficacious in the long term; however, additional trials are required to prove this and to determine the optimal effective dose.
References [1] van Passel L, Arif H, Hirsch LJ. Topiramate for the treatment of epilepsy and other nervous system disorders. Expert Rev Neurotherapeutics 2006;6:19–31. [2] Johnson BA, Ait-Daoud N, Akhtar FZ, et al. Oral topiramate reduces the consequences of drinking and improves the quality of life of alcoholdependent individuals: a randomized controlled trial. Arch Gen Psychiatry 2004;61:905–12. [3] Johnson BA, Rosenthal N, Capèce JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007;298: 1641–51. [4] Johannessen Landmark C. Targets for antiepileptic drugs in the synapse. Med Sci Monit 2007;13:1–7. [5] Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med 2004;10:685–92. [6] Johannessen Landmark C. Relations between mechanisms of action and clinical efficacy of antiepileptic drugs in non-epilepsy conditions. CNS Drugs 2008;22:27–47. [7] Bray GA, Hollander P, Klein S, et al. A 6-month randomized, placebocontrolled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003;1:722–33. [8] Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord 2004;28:1399–410.
475
[9] Hettes SR, Gonaga J, Heyming TW, et al. Dual roles in feeding for AMPA/kainite receptors: receptor activation or inactivation within distinct hypothalamic regions elicits feeding behavior. Brain Res 2003; 992:167–78. [10] Nickel C, Tritt K, Muehlbacher M, et al. Topiramate treatment in bulimia nervosa patients: a randomized, double-blind, placebo-controlled trial. Int J Eat Disord 2005;38:295–300. [11] Carter WP, Hudson JI, Lalonde JK, et al. Pharmacologic treatment of binge eating disorder. Int J Eat Disord 2003;34(suppl):S74–S88. [12] Grilo CM, Masheb RM, Salant SL. Cognitive behavioral therapy guided self-help and orlistat for the treatment of binge eating disorder: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry 2005;57:1193–201. [13] McElroy SL, Arnold LM, Shapira NA, et al. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:255–61. [14] Milano W, Petrella C, Casella A, et al. Use of sibutramine, an inhibitor of the reuptake of serotonin and noradrenalin, in the treatment of binge eating disorder: a placebo-controlled study. Adv Ther 2005;22:25–31. [15] Appolinario JC, Bacaltchuk J, Sichieri R, et al. A randomized, doubleblind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder. Arch Gen Psychiatry 2003;60:1109–16. [16] Wilfley DE, Crow SJ, Hudson JI, et al. Efficacy of sibutramine for the treatment of binge eating disorder: a randomized multicenter placebocontrolled double-blind study. Am J Psychiatry 2008;165:51–8. [17] McElroy SL, Kotwal R, Guerdjikova A, et al. Zonisamide in the treatment of binge eating disorder with obesity: a placebo-controlled trial. J Clin Psychiatry 2006;67:1897–906. [18] McElroy SL, Guerdjikova A, Kotwal R, et al. Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry 2007;68:390–8. [19] McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry 2007;61:1039–48. [20] Claudino AM, Oliveira IR, Appolinario JC, et al. Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive–behavior therapy in binge-eating disorder. J Clin Psychiatry 2007;68:1324–32. [21] Hoopes SP, Reimherr FW, Hedges DW, et al. Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebocontrolled trial: Part 1. Improvement in binge and purge measures. J Clin Psychiatry 2003;64:1335–41. [22] Stanley BG, Ha LH, Spears LC, et al. II. Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5methyl-isoxazole propionic or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats. Brain Res 1993;613:88–95. [23] Hettes SR, Heyming TW, Stanley BG. Stimulation of lateral hypothalamic kainate receptors selectively elicits feeding behavior. Brain Res 2007;1184:178–85. [24] Shapira NA, Goldsmith TD, McElroy SL. Treatment of binge-eating disorder with topiramate: a clinical case series. J Clin Psychiatry 2000; 61:368–72. [25] Appolinario JC, Fontenelle LF, Papelbaum M, Bueno JR, Coutinho W. Topiramate use in obese patients with binge eating disorder: an open study. Can J Psychiatry 2002;47:271–3. [26] McElroy SL, Shapira NA, Arnold LM, et al. Topiramate in the longterm treatment of binge-eating disorder associated with obesity. J Clin Psychiatry 2004;65:1463–9. [27] Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357:1191–4.