Bulimia Nervosa and Binge Eating Disorder: Comparing Therapeutic Strategies

Study Overview
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Brief Summary
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This study aims to assess the effectiveness of new neurostimulation techniques in patients with eating disorders. The primary aim of our proposal is to test a reduction in symptoms of alteration of eating behaviors, such as always thinking about food or binge eating, in a sample of 30 patients, aged between 18 and 65, with diagnosis of Bulimia Nervosa or Binge Eating Disorder. Of these patients, 10 will undergo to a protocol of vagal transcutaneous stimulation in the ear (tVNS) and targeted cognitive-behavioral therapy (CBT-E), another 10 to a protocol of transcranial magnetic stimulation (rtms) and CBT-E and another 10 to a protocol of only tergeted CBT-E, comparing the results obtained in the three groups under study. Secondary purposes of this project are the assessment of the effects of auricular vagal transcutaneous stimulation and of transcranial magnetic stimulation on depressive symptoms associated with eating disorder, on the inflammatory profile, on cardiovascular autonomic control, neuronal excitability, functional connectivity and on the quality of life of these patients. In order to achieve the objectives of this research project, we will perform a national, interventional on a medical device, monocentric study, controlled in 3 parallel and randomized groups with a 1:1:1 allocation ratio. 30 patients will be recruited at the Day Hospital of the Psychiatry Unit of the Fondazione.

Detailed Description
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This study aims to assess the effectiveness of new neurostimulation techniques in patients with eating disorders. To date, the management of these disorders is still difficult and few treatments have proven their effectiveness. According to most guidelines, management is typically multidisciplinary. The best validated and most frequently used treatment is the cognitive behavioral therapy enanched (CBT-E), a highly individualized psychological treatment designed to treat all diagnostic categories of eating disorders, addressing the common cognitive-behavioural mechanisms of maintaining shared and evolving psychopathology of eating disorders. For Bulimia Nervosa (BN) and Binge Eating Disorder (BED), the serotoninergic antidepressants are the most frequently used pharmacological option (considering the frequent recurrence of depressive symptoms in comorbidity in the clinical population with eating disorders), which may improve symptoms in the medium term, but not allow complete remission. In this context, the development of alternative therapeutic strategies is crucial. Recently, several studies have described the important contribution of neurostimulation techniques (such as repetitive transcranial magnetic stimulation (rTMS), and vagal nerve stimulation (VNS)). Following the proven effectiveness, both rTMS and VNS have received official approval for the treatment of depression in Europe and United States. Neuroimaging studies have revealed that both of these neurostimulation techniques modulate the frontal-vagal network, the one with a top-down mechanism (rTMS) and the other with a bottom-up mechanism (VNS). The neuromodulation influencing the functioning of the central nervous system (CNS) and the emotional/alimentary behavior, would offer an alternative (or complementary) intervention to psychotropic drugs and different psychological and nutritional approaches. Studies in the literature, conducted on patients with BN and BED, showed a significant improvement in symptomatology, in terms of binge eating, after rTMS stimulation of the left dorsolateral prefrontal cortex (DLPFC). Instead, the effectiveness of vagal stimulation in the treatment of ED lies in the fact that the vagus nerve plays a fundamental role in mood and appetite regulation. Human studies report how tVNS stimulation produces a reduction in the effect of food cravings. Moreover, currently, in patients with ED, the determined effects of vagal non-invasive neurostimulation have not been compared with the effects of repetitive transcranial magnetic stimulation. Therefore, the primary aim of our proposal is to test a reduction in symptoms of alteration of eating behaviors, such as always thinking about food or binge eating, in a sample of 30 patients, aged between 18 and 65, with diagnosis of Bulimia Nervosa or Binge Eating Disorder, according to the diagnostic criteria of DSM-V, and with a psychopathological framework of depression in comorbidity (cut-off ≥ 8 of the Hamilton Depression Rating Scale, HAM-D). Of these patients, 10 will undergo to a protocol of vagal transcutaneous stimulation in the ear (tVNS) and targeted cognitive-behavioral therapy (CBT-E), another 10 to a protocol of transcranial magnetic stimulation (rtms) and targeted cognitive-behavioral therapy (CBT-E) and another 10 to a protocol of only tergeted cognitive-behavioral therapy (CBT-E), comparing the results obtained in the three groups under study. Secondary purposes of this project are the assessment of the effects of auricular vagal transcutaneous stimulation and of transcranial magnetic stimulation on depressive symptoms associated with eating disorder, on the inflammatory profile, on cardiovascular autonomic control, neuronal excitability, functional connectivity and on the quality of life of these patients. In order to achieve the objectives of this research project, we will perform a national, interventional on a medical device, monocentric study, controlled in 3 parallel and randomized groups with a 1:1:1 allocation ratio. 30 patients will be recruited at the Day Hospital of the Psychiatry Unit of the Fondazione. Patients will be assigned by randomization to 3 different groups/treatments: tVNS+CBT-E group: 10 patients will be instructed to perform tVNS at home for 4 non-consecutive hours per day for 12 weeks with the tVNS VITOS device (already used in the Fondazione for the study tVNS2019 approved by the Milan Area 2 Ethics Committee on 19.02.2019 and with code 158_2019bis); rTMS+CBT-E group: 10 patients will participate in a total of 20 rTMS sessions lasting 40 minutes (5 sessions per week for 4 weeks) that will take place at the Day Hospital of the Psychiatry Unit of the Fondazione; CBT-E only group: 10 patients will proceed with only targeted cognitive behavioral therapy (CBT-E), following the CBT-E protocol CG Fairburn - 2010. During the screening visit, provided by normal clinical practice, the inclusion and exclusion criteria and the diagnosis of Bulimia Nervosa and Binge Eating Disorder will be verified through a structured clinical interview planned for DSM-5 and personality disorders (by administration of the SCID-5 CV and PD scales by the physician). All patients will then be evaluated during 5 extra standard care visits. At each visit dietary behavior and any depressive symptoms will be evaluated through scales validated in Italian (Eating Disorder Examination, Eating Disorder Inventory, Eating Disorder Examination Questionnaire, Hamilton Depression Rating Scale and Beck Depression Inventory); cardiovascular variables will be recorded during clinostatism and orthostatism; a resting EEG and a during acute administration of transcranial magnetic stimulation EEG (TMS-EEG) will be recorded; participants will be asked to self-compile 2 questionnaires on the quality of life linked to health; finally a blood sample will be taken for the analysis of the inflammatory profile. For each patientd an Holter-ECG will be recorded lasting 72h following each visit. All the devices used in the study have already been purchased with university funds and have been taken over, labelled and coded by the Clinical Engineering of the Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico di Milano.

Official Title
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Bulimia Nervosa e Binge Eating Disorder: Strategie Terapeutiche a Confronto

Conditions
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Bulimia Nervosa, Binge-Eating Disorder

Intervention / Treatment
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* Device: tVNS
* Device: rTMS
* Behavioral: CBT-E


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients diagnosed with Bulimia Nervosa or Binge Eating Disorder, according to the diagnostic criteria of DSM-V, with a psychopathological framework of depression in comorbidity (cut-off ≥ 8 of the Hamilton Depression Rating Scale, HAM-D), aged between 18 and 65 years. Exclusion Criteria: Previous TMS sessions with significant side effects; Conditions leading to an increased risk of epilepsy or side effects in the context of transcranial magnetic stimulation (including personal or family history of epilepsy, cerebral ischemic events, neurological pathologies, neurosurgical interventions, orthopedic or vascular interventions in the head-neck district, major head trauma, migraine or severe headache); Presence of pacemakers, defibrillators, infusion pumps, neurostimulation implants (DBS, VNS), endovascular implants in the head-neck district, cochlear implants, cerebrospinal shunts, metal implants in the head-neck area ; Exposure to penetration of metal chips in the head-neck area; Presence of non-removable metal in the head-neck area (including tattoos, permanent make-up, piercing, excluding dental implants); Unstable sinus rhythm at ECG (Pace-Maker rhythm, atrial fibrillation, supra-/ventricular extrasystole); Chronic intake of β-blocker; Heart, respiratory, renal or hepatic failure and immunosuppression; Current hospitalization; State of pregnancy or lactation; Vestibular or balance problems; Positive personal history of schizophrenia or schizoaffective disorder; Substance or alcohol abuse in the last 6 months; Positive personal history of intellectual disability (mental retardation); Refusal of informed consent by the patient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In order to achieve the objectives of the research project, we will perform a national, monocentric interventional on a medical device study, controlled in 3 parallel and randomized groups with a 1:1:1 allocation ratio.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tVNS + CBT-E group<br>N=10 Interventional group with transcutaneous stimulation of the auricular branch of the vagus nerve associated with targeted cognitive-behavioral therapy (following the CBT-E protocol, CG Fairburn - 2010. | Device: tVNS<br>* An electric current with a frequency of 25 Hz (Figure 2) will be applied to the cymba conca of the left ear through a specific device (VITOS, Cerbomed, Germany; CE marking). The stimulation intensity will be customized between 0.1 and 5 mA according to the sensitivity threshold of each participant. Patients will be instructed to perform tVNS at home for 4 non-consecutive hours per day for 12 weeks, in accordance with the protocol reported in the literature for the treatment of major depression.<br>* Other names: Transcutaneous stimulation of the auricular branch of the vagus nerve associated;Behavioral: CBT-E<br>* Targeted cognitive-behavioral therapy following the CBT-E protocol (CG Fairburn - 2010. La terapia cognitivo-comportamentale dei disturbi dell'alimentazione. Firenze, Eclipsi; 2010.)<br>* Other names: Cognitive-behavioral therapy - enanched;|
| Experimental: rTMS + CBT-E group<br>N=10 Interventional group with repetitive transcranial magnetic stimulation associated with targeted cognitive-behavioral therapy (following the CBT-E protocol, CG Fairburn - 2010.). | Device: rTMS<br>* The stimulation will be carried out with a TMS STM9000 system (Ates, Medica Device s.r.l., Italy) equipped with a 70 mm butterfly cooled coil. The stimulation protocol followed will be the one approved by the FDA for major depression, that is, a stimulation at the level of the left dorsolateral prefrontal cortex at an intensity equal to 120% of the motor threshold, at the frequency of 10hz. Each stimulation session will last 37.5 minutes, and will consist of 75 trains lasting 4 seconds, with a 26-second break between each train. During each session, a total of 3000 stimuli will be administered. The sessions will take place 5 days a week, from Monday to Friday, for 4 weeks, and for a total of 20 sessions of stimulation.<br>* Other names: Repetitive transcranial magnetic stimulation;Behavioral: CBT-E<br>* Targeted cognitive-behavioral therapy following the CBT-E protocol (CG Fairburn - 2010. La terapia cognitivo-comportamentale dei disturbi dell'alimentazione. Firenze, Eclipsi; 2010.)<br>* Other names: Cognitive-behavioral therapy - enanched;|
| Experimental: Only CBT-E group<br>N=10 Group with only cognitive-behavioral therapy of eating disorders. | Behavioral: CBT-E<br>* Targeted cognitive-behavioral therapy following the CBT-E protocol (CG Fairburn - 2010. La terapia cognitivo-comportamentale dei disturbi dell'alimentazione. Firenze, Eclipsi; 2010.)<br>* Other names: Cognitive-behavioral therapy - enanched;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changing in dietary behaviour in terms of changes in Eating Disorder Examination scale score at T3 | Effectiveness in changing dietary behaviour in terms of the EDE (Eating Disorder Examination) score difference between groups at T3. Great differences mean better clinical outcome. | 6 months from the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute effects of treatments in terms of difference between pre- and post-treatment | Incidence of acute effects of treatment with tVNS+CBT-E, rTMS+CBT-E or only CBT-E in patients with Eating Disorders in terms of difference between pre- and post-treatment for: Variations in EDE-Q (Eating Disorder Examination Questionnaire) validated questionnaire scores. Depressive symptoms: change in HAM-D and BDI-II scores. Change in the systemic inflammatory profile: values of inflammatory serum proteins (IL-6, IL-1β, IL-4, IL-10, TNF-α and PCR) and microvesicles. Changes in cardiovascular autonomic control: spectral power (ms2) and percentage (normalized units), over 250 beats, of the following frequency classes: very low frequency (VLF), low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.40 Hz). Percentage on 250 beats, of pattern 0V, 2LV and 2UV (symbolic analysis). For TMS+EEG: variation of neuronal excitability patterns and functional connectivity and changes in quality of life in terms of total score of the CIA 3.0, PSQI validated questionnaires. | After 4 weeks of stimulation (T1) | 
| Incidence of acute effects of treatments in terms of difference between pre- and post-treatment | Incidence of acute effects of treatment with tVNS+CBT-E, rTMS+CBT-E or only CBT-E in patients with Eating Disorders in terms of difference between pre- and post-treatment for: Variations in EDE-Q (Eating Disorder Examination Questionnaire) validated questionnaire scores. Depressive symptoms: change in HAM-D and BDI-II scores. Change in the systemic inflammatory profile: values of inflammatory serum proteins (IL-6, IL-1β, IL-4, IL-10, TNF-α and PCR) and microvesicles. Changes in cardiovascular autonomic control: spectral power (ms2) and percentage (normalized units), over 250 beats, of the following frequency classes: very low frequency (VLF), low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.40 Hz). Percentage on 250 beats, of pattern 0V, 2LV and 2UV (symbolic analysis). For TMS+EEG: variation of neuronal excitability patterns and functional connectivity and changes in quality of life in terms of total score of the CIA 3.0, PSQI validated questionnaires. | After 12 weeks of stimulation (T2) | 
| Incidence of long-term effects in terms of relapses and difference between T0 and T4. | Incidence of long-term effects of the three treatments (tVNS + CBT-E, rtms + CBT-E and CBT-E) in patients with BN and BED in terms of relapses and difference between T0 and T4 for the following indices: Dietary behaviour: change in EDE and EDE-Q scores. Depressive symptoms: change in HAM-D and BDI-II scores Change in the systemic inflammatory profile: values of inflammatory serum proteins (IL-6, IL-1β, IL-4, IL-10, TNF-α and PCR) and microvesicles. Changes in cardiovascular autonomic control: spectral power (ms2) and percentage (normalized units), over 250 beats, of the following three frequency classes: very low frequency (VLF), low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.40 Hz). Percentage on 250 beats, of pattern 0V, 2LV and 2UV (symbolic analysis). TMS + EEG: Variation of neuronal excitability patterns and functional connectivity. Changes in quality of life: total score of PSQI and CIA 3.0 validated questionnaires. | After 12 months (T4) from enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EEG, Bulimia Nervosa, Eating disorders, rTMS, CBT-E, tVNS