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Binge eating as a core diagnostic symptom in eating disorders (ED), is characterized by consuming unusual large amount of food in a short time, associated with sense of loss of control during eating [1]. By definition of Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5), binge eating disorder (BED) refers to recurrent episodes of binge eating at least once a week during past three months followed by noticeable amount of distress. BED is not accompanied by any compensatory behaviors (e.g., purging, intensive exercise or dietary restriction) and associates with three or more of the following features about eating: 1) in time of not physically hungry, 2) occurrence in privacy due to embarrassment about amount of eaten food, 3) rapidly, 4) until uncomfortably full and the feeling of disgusted, depressed or guilty afterwards [2].
Life-time prevalence of this disorder is estimated 1.9% worldwide as the most common ED [3]. This concept is attributed to variety of health areas [4] that can lead to multiple adverse effects on physical and mental health [5]. Obesity, metabolic syndrome, mood disorders, anxiety and substance use, are common comorbidities among this population [6]. A study revealed that approximately 80% of affected individuals have at least one psychiatric disorder [7].
Sadly, individuals with BED mostly seek treatment for comorbidities and adverse effects in order to disorder itself [8]. In fact, only one tenth of patient gets treatment for BED [9]. In addition, BED usually remains unrecognized, hence, untreated by healthcare professionals [10]. Non-pharmacological treatments such as cognitive-behavioral therapy, interpersonal therapy and behavioral weight loss therapy, as the first-line therapeutic options are suggested [11]. However, pharmacological treatment can also be beneficial for whom with insufficient response or no access to psychotherapy [12].
Different neurotransmitters such as dopamine, norepinephrine and glutamate seem to be involved in pathogenesis of BED [13]. Lisdexamfetamine dimesylate (LDX); the only drug approved treatment for moderate to severe BED [14] is a D-amphetamine prodrug that blocks dopamine and norepinephrine reuptake [13]. Hence, it leads to reduce in sense of palatable food, rewarding and severity of binge eating [14].
Topiramate (TPM) is an anticonvulsant and a glutamate receptor antagonist which causes appetite suppression and decreases food intake by inhibitory effect on lateral hypothalamus glutamate pathway [15]. TPM seems to reduce episodes of BED and improve the quality of life in these patients [16]. Additionally it is the only tested treatment of BED, which can cause significant reduction in both binge eating and weight [17], hence, there is evidence to support off-label use of TPM for treatment of BED [18]. Due to restricted pharmacological options with evidence-based efficiency in treatment of BED and also urgent need for novel approved drugs, as the first survey, we conducted this study to evaluate efficacy and tolerability of LDX plus TPM compared to LDX for treatment of BED in adults age in the range of 18−55 years in Shiraz, Iran.
The current study had two major objectives; first, to assess efficacy of combination therapy with LDX and TPM in improvement of binge eating scale (BES) in BED compared to monotherapy with LDX. Second, to compare adverse events and tolerability when using LDX plus TPM or LDX alone. We also assessed some parameters of metabolic and lipid profile in both groups.
While many studies have evaluated the effect of TPM or LDX on BED, to our knowledge, there is no study about combinatory effects of these drugs in improvement of BES.
The present randomized control trial was performed from January to September 2022 among patients who were referred to medical clinics of Shiraz metropolitan city, Iran.
Participants aged 18−55 years old meeting the diagnostic criteria for BED according to DSM-5, were enrolled in our study. The diagnosis was made by the second author who is a well experienced psychiatrist through a systematic interview and filling up the Gormally questionnaire. The participants did not have any regular physical activities or dietary habits before or after enrolling the study. The inclusion criteria were: 1) negative history of other major psychiatric disorders assessed by psychiatrist 2) negative history of cardiovascular diseases, thyroid disturbances or gastrointestinal diseases 3) not using medications interfering with metabolism recently 4) no known sensitivity to LDX or TPM. The exclusion criteria were: 1) participants with unwillingness to fill the questionnaire, participate in study interview or take study medications 2) loss of contact during study period.
According to the objectives and type of study, taking into account the assumptions: 5% error, 80% power and, mean difference = 2 which pertained to primary outcome changes in BED; the main variable of the study; and standard deviation = 3.2 with a one-to-one ratio using the formula:
42 patients were estimated in each group. Due to the drop out of 10%, the final sample size was 93. These samples were selected from among the patients using the convenience sampling method.
After eligibility was assessed, 93 participants were assigned using permuted block randomization method with blocks of 4 to LDX or LDX plus TPM for 12 weeks. In the first group (n = 48), LDX was started with low dose (30 mg/day) orally in the morning and increased to 50 mg/day if tolerated. The average dose of this group was fairly 37.5 mg/day. Forty-five patients in the second group received LDX as the same (average dose 38 mg/day) plus TPM with starting dose of 25 mg/day and if tolerated, followed by max dose of 150 mg/day (average dose of TPM 77.7 mg/day) every night. The method of drug titration was made according to revisit (regular follow up every three weeks), investigation of drug efficacy, absence of drug side-effects and probable drug intolerance in the patients.
Prior to administration, all participants were informed about most common side effects of study medications (e.g., restlessness by LDX, paresthesia and drowsiness by TPM) and also rare side effects (e.g., nausea by LDX, headache by TPM). In such cases they would report the side effects, medication would be stopped and subjects could leave the study if no longer interested.
For data gathering, the research team visited sample clinics and the required data was collected by filling questionnaire through clinical interviews or referring to medical records of patients. The randomization in the sampling of population was guided by the second author (psychiatrist). Data collection was performed before and 3 months after interventional procedure, during three phases.
In the first phase, the required data on demographic characteristics including age, sex, weight and height was obtained through self-administrated questionnaire.
Next, to determine BED severity, we used BES of Gormally; constructed of 16-item questionnaire [19], which was adopted among Iranian population [20] with similar internal consistency compared to original scale (0.85), reliability of 0.71, sensitivity of 84.6% and specificity of 80.8%. Similar versions were adopted among Iranian population as a reliable measure to assess eating beliefs [21,22]. According to this scaling, patients were categorized in to three groups: non-binge eaters for score less than 17, moderate binge eaters for score between 18 and 26 and severe binge eaters for those with score 27 or more.
In the last phase, laboratory characteristics of subjects including lipid profile, fasting blood sugar (FBS) and liver transaminases was measured. After overnight fasting, 10 ml of blood samples were obtained from each participant to perform laboratory tests. To measure glucose and triglyceride (TG), after centrifugation, we used kits from Biorexfars company. We analyzed total cholesterol, low density lipo-protein (LDL), high density lipo-protein (HDL), serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) with Pars Azmoon kits (Pars Azmoon Co.). All the laboratory measurements were analyzed by biochemical autoanalyzer (Hitachi 717; Roche).
Statistical analysis of the data was performed using Statistical Package for Social Sciences (SPSS) version 16 (SPSS Inc.). The results related to continuous variables were presented as mean ± standard deviation (SD), and those related to the quantitative or categorical data were shown as numbers and percentages. The statistical tests used in this study were chi-square, Independent ttest and analysis of covariance (ANCOVA). pvalue < 0.05 was considered a significant level.
Present study with clinical trial of IRCT20230910059396N1 was performed according to Declaration of Helsinki with ethical code IR.IAU.KAU.REC.1400.177 approved by ethic committee of Kazeroon branch of Islamic Azad University of Medical Sciences.
The number of 104 patients were enrolled and randomized to receive study medications. Eleven subjects were removed from the study due to medication non-adherence or intolerance and finally ninety-three subjects completed the survey. The age range of our study sample was between 20−49 years old with mean age of 32.87 ± 6.54 year. Most of our study participants were female (65.6%). In terms of age and sex, no significant difference was obtained between the two groups (p = 0.167 and p = 0.822, respectively) (Table 1). There was no significant difference in baseline variables between the two groups except for body mass index (BMI), LDL and cholesterol.
Eleven subjects left the study due to adverse effects of medications. Severe restlessness with LDX and paresthesia with LDX and TPM were the most common adverse effects that made participants leave the study (Table 2).
By observing the reduction between the two groups, we came to this conclusion that the reduction in both groups was significantly different (p < 0.001 and p < 0.001, respectively). In other words, in one BMI was reduced approximately by 4.4 (out of 30) while in the group the drop in BMI was approximately 6.4 (out of 32). Therefore, the combination of these two drugs (LDX plus TPM) had affected statistically significant different influence compare to use of a single drug (LDX) (Table 3).
Before intervention there was no significant difference in TG in both groups. After three months, subjects of both groups achieved significant reduction in TG whereas this difference was not exactly significant between both groups (p = 0.052) but the difference was near to be meaningful. However, the LDX plus TPM group experienced statistically significant greater reduction in TG at the end of follow up period compared to the LDX group (mean: 73.68 vs. 58.97 respectively, p = 0.024).
Low density lipo-proteinFrom baseline to month three, difference in LDL remained significant between the two groups (p < 0.001). By last month, LDL reduced significantly in both groups; however, subjects of the LDX plus TPM group, reached statistically greater significant decline in this index (mean: 9.66 vs. 5.16 respectively, p < 0.001).
High density lipo-proteinHDL level was increased by a greater extent in combinative regimen at the end; however, it was not statistically significant (p = 0.266).
Total cholesterolEvaluation of total cholesterol before and after intervention showed significant difference between the two groups (p = 0.008 and p = 0.021, respectively); however, three months of taking TPM or TPM plus LDX were equally effective in reducing total cholesterol (p = 0.363).
Analysis of lipid profile parameters is shown below (Table 4).
Fasting blood sugarFBS was reduced over three months in both groups (Table 5). Nonetheless it did not reach a significant difference statistically (p = 0.543).
Serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminaseAfter three months, subjects receiving LDX or LDX plus TPM had insignificant (p = 0.829) reduction in level of serum transaminases and the LDX group showed slightly greater reduction which was not statistically significant (p = 0.413) (Table 6).
Binge eating scaleThe comparison of the prevalence of overeating in two groups is shown in Table 7. In terms of the prevalence of binge eating disorder, before the intervention, there was no statistically significant difference between the two groups (p = 0.060). Also, after the intervention, there was no statistically significant difference between the two groups (p = 0.422). On the other hand, a significant decrease was seen in both groups (p < 0.001).
The main focus in BED trials is to reduce the frequency of episodes; however, decrease in body weight or appetite come after that as safety and tolerability assessments [23]. Before treatment, the problems of BED patients should be evaluated in three main areas: eating-related psychopathology, psychiatric disorders and obesity thereafter personalized treatment should be performed [24].
The present study is the first to examine efficacy of combination therapy with TPM plus LDX compared to LDX in treatment of BED. Ninety-three patients with BED were treated with LDX or LDX plus TPM for 12 weeks. We observed that by this novel investigational combination therapy, subjects showed greater improvement in frequency of episode. According to what previously was shown in Table 7, based on BES of Gormally total scores, before intervention, most of the subjects in both groups were severe binge eaters while after intervention, low binge eaters were the majority. We also found that adding TPM to LDX in BED, significantly improved BMI and lipid profile and reduced adverse effects of using LDX alone such as insomnia, paresthesia, confusion and ataxia. Considering palpitation and increase in blood pressure, we suggest checking vital sign and neurological examination in each visit. Also to prevent dental side effects, patients should be aware of bruxism and if happen should report it to their psychiatrist.
While LDX is a US Food and Drug Administration approved drug for BED patients, some other agents that are commonly used to treat depression, epilepsy and obesity have been tested and used as off-label interventions for BED [11]. By considering impulsivity as a feature in BED, TPM as an anti-convulsant that is used widely to treat impulse control disorders, seems to be effective in BED patients. This can be explained by the hypothesis that TPM as an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist can facilitate inhibition. This study also revealed that positive effect of TPM on impulsivity might be greater by using higher doses and sufficient longer duration of this drug [24]. In line with our results, some previous studies of TPM in binge eating disorder, indicated that this drug, induced significant reduction in frequency of binge eating [25-28]. In contrast, in a study by Claudino [29], subjects treated with TPM did not reach any significant difference in BES score or binge frequencies compared to placebo additionally binge remission was significantly more prevalent among TPM-treated group. Twelve-week treatment with phentermine-topiramate, demonstrated significant decrease in frequency of binge eating episodes, weight and BMI associated with no serious adverse effects, misuse or withdrawal [30]. In accordance with our result, McElroy et al. [27] evaluated efficacy of TPM in obese adults with BED. In this study, sixteen weeks treatment with TPM was well tolerated and caused significant reduction in the number of binge-eating days and episodes per week also concomitant improvement in weight and BMI was seen [27]. On the other hand, a review by Heal et al. [23] revealed that TPM should not be used as monotherapy in BED because of cognitive deficits, risk of obesity and type-II diabetes mellitus. Another review reported that dizziness and concentration problems were some adverse effects with TPM that caused higher rate of discontinuation in study group compared to placebo [31].
Dopamine has a wide distribution in parts of brain responsible for craving food, making decision, executive function and impulsive behaviors; the main risk factors that lead to binge eating. Furthermore, majority of studies demonstrated that altered dopamine availability, activity or affinity (hypo or hyperdopaminergic state) plays role in BED, hence, manipulation of dopamine level or activity seems to be efficient in treatment of this disorder [32]. LDX plays a role in this pathway [13]. In a study on 22 females with BED, reduction in self-reported appetite rating, impulsive responding and increase in sustained attention was observed by taking 50 mg single dose of LDX [33]. This appetite reduction is in line with our achieved results. In another study single (20 mg/day) and multiple doses (20, 50, 70 mg/day) of LDX were well tolerated among healthy Japanese and Caucasian individuals; however, 72.7% and 80%, respectively experienced at least one mild or moderate treatment emergent adverse events. In addition, most adverse events occurred by 50 mg dose [34]. On the other hand, in a randomized double-blind trial, Guerdjikova et al. [35] evaluated the effect of 20−70 mg/day LDX for 12 weeks. In the primary analysis, no significant greater reduction was seen in binge eating score and episodes per week; however, in the secondary analysis, significant decreased occurred in patients received LDX compared to placebo. In addition, weight, BMI and TG level were significantly improved in both analysis.
The limitations of this study can be summarized as follows: first of all, at the time of performing this study, the pharmacies of our city were faced with scarcity of LDX hence providing LDX for all referred patients with BED was not possible which limited the sample size for the study and subgroup analysis. Second, some of the questionnaires were filled incompletely and some participants left the study due to adverse events of drugs and we could not include their information in our study. Third, although baseline BMI was not an inclusion criteria in our study, all of the referred subjects to our clinic had obesity as well as BED hence the results of this study may not be generalizable to non-obese BED populations.
In conclusion, in BED patients, combinative treatment with LDX plus TPM is more effective in modulating binge eating severity, lipid profile and BMI rather than LDX alone. TPM plus LDX is well tolerated, safe and have lesser adverse events for these patients; however, more studies with larger samples are needed to clarify efficacy the combination of TPM plus LDX compared to using these drugs separately.
The present article derived from M.D thesis of Dr. Farnoosh Mokhtari.
No potential conflict of interest relevant to this article was reported.
Conceptualization: Mahsa Taghavi. Data acquisition: Farnoosh Mokhtari, Mina Mashayekh. Formal analysis: Mahsa Taghavi, Farnoosh Mokhtari. Supervision: Mahsa Taghavi. Writing—original draft: Farnoosh Mokhtari, Mina Mashayekh. Writing—review & editing: Mahsa Taghavi, Farnoosh Mokhtari, Mina Mashayekh.
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