Evaluating the efficacy of Radically Open Dialectical Behavior Therapy (RO-DBT) in patients with anorexia nervosa: study protocol for a randomized controlled clinical trial

Evaluating the efficacy of Radically Open Dialectical Behavior Therapy (RO-DBT) in patients with anorexia nervosa: study protocol for a randomized controlled clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Evaluating the efficacy of Radically Open Dialectical Behavior Therapy (RO-DBT) in patients with anorexia nervosa: study protocol for a randomized controlled clinical trial Aina Avila-Parcet, Ana Martín-Blanco, Leonor Gawron, Marta Cano, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4414466/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Apr, 2025 Read the published version in BMC Psychiatry → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Anorexia nervosa (AN) is a severe and disabling disorder, with relapse rates as high as 50% after the first episode, posing a significant challenge for clinicians. Most therapies excessively focus on nourishment, resulting in temporary weight restoration but with no improvements in general well-being and quality of life. Radically Open Dialectical Behavior Therapy (RO-DBT) is a transdiagnostic treatment designed to address overcontrol, a key aspect in the functioning of patients with AN. To date, no clinical trial (CT) has proven its efficacy in these patients or evaluated its neurobiological mechanism of action. Methods: A randomized CT in AN patients will be conducted, with one group receiving treatment as usual (TAU) and the other TAU plus RO-DBT, with the main outcome being quality of life. Secondary variables will include eating disorders (EDs) symptoms, overcontrol characteristics, autistic traits, and neuroimaging changes. Discussion: The results will address a gap in knowledge regarding AN treatment, with the expectation that patients receiving TAU with RO-DBT will exhibit improved quality of life and experience fewer relapses at the one-year follow-up. This is the first study examining neuroimaging changes in RO-DBT to better understand its underlying mechanisms. Trial registration: The study has been registered in ClinicalTrials.gov in September 22, 2023. It can be found in https://classic.clinicaltrials.gov/ct2/show/NCT06050421. Trial Registration Number: NCT06050421 Anorexia nervosa radically open dialectical behaviour therapy neuroimaging overcontrol efficacy. Figures Figure 1 Background Eating disorders (EDs) are severe psychiatric disorders associated with multiple physical and psychological problems( 1 ). The prevalence of these disorders is not negligible and continues to increase, with rates reaching up to 5% in their subclinical forms. As a result, they pose a growing health concern( 2 ). Among the different EDs, anorexia nervosa (AN) is the most severe and difficult to treat, with a lifetime prevalence of up to 0.5–0.6% ( 3 ). It frequently has a chronic course and is associated with mortality rates of up to 18% in longitudinal follow-up studies ( 4 ). In addition, numerous studies describe relapse rates over 25%, with some even documenting rates as high as 52% ( 4 ). It has been described that the period with the highest probability of relapse is during the first year following acute treatment ( 4 ). Regarding recovery, AN has long been considered a treatment-resistant disorder, making it a great challenge for clinicians to not only achieve physical weight recovery but also promote psychosocial recovery. A 20-year longitudinal study of AN patients revealed that, despite achieving physical recovery, the majority of patients did not achieve psychosocial recovery ( 5 ). To date, no psychological treatment has shown enough evidence to be considered the treatment of choice for adult patients with AN ( 6 ). Most medical centers specialized in treating EDs focus solely on re-nutrition, which seeks improvements in weight that are difficult to maintain over time, leading to high rates of relapse. In addition, the objectives of re-nutrition do not cover other core psychopathological domains such as psychosocial well-being (including psychosexual, socioeconomic, and social contacts and activities) or improvement of overall quality of life. This highlights the necessity for novel and more effective approaches/treatments that strive for comprehensive symptom relief. One of the reasons that could underlie the difficult recovery from EDs is their high comorbidity with features of autism spectrum disorder (ASD). The presence of comorbidity with ASD traits has been linked to a poorer initial social adjustment ( 7 ) and a worse prognosis in terms of eating symptoms ( 8 ) and psychosocial outcomes ( 9 ). Nielsen et al., in an 18-year follow-up study of a group of patients with AN, suggested a dose-dependent relationship between the presence of ASD traits and worse quality of life and psychosocial functioning ( 10 ). In this sense, clinical symptoms such as overcontrol, which is often shared between AN and ASD, may be a fundamental contributing mechanism to developing and maintaining AN. Overcontrol is defined as the tendency to inhibit emotional urges, impulses, and behaviors in order to follow long-term goals ( 11 ). AN, similarly to ASD, can be regarded as an overcontrol disorder characterized by low receptivity and openness, low flexible control, pervasive inhibited emotional expressiveness, low emotional awareness, and low social connectedness and intimacy with others ( 12 ). However, overcontrol is rarely addressed as a core element in treating AN ( 13 ). Thomas Lynch has created a promising treatment called Radically Open Dialectical Behavioral Therapy (RO-DBT) ( 14 ): a transdiagnostic intervention specifically designed to treat a spectrum of disorders characterized by excessive control such as resistant and chronic depression, avoidant and obsessive-compulsive personality disorders, AN and ASD. RO-DBT suggests that emotional well-being involves the confluence of three characteristics: openness, flexibility, and social connectedness. In the specific case of EDs, RO-DBT offers a different perspective regarding the aetiology and treatment of AN via a biosocial model that accounts for temperamental family/environment, perceptual and self-control tendencies. In this context, restrictive and ritualized eating is conceptualized as a symptom or consequence based on a maladaptive overcontrolled coping style that has been intermittently reinforced. Notwithstanding, only few authors have applied RO-DBT to AN patients. Lynch et al. ( 13 ) applied an adapted 8-week RO-DTB program to 47 inpatients diagnosed with restrictive AN, showing significant improvements in weight with a large effect size ( d = 1.71), but no follow-up data was recorded. Using an uncontrolled case series design, Baudinet et al. ( 15 ) evaluated the effect of RO-DBT group skills training as an add-on therapy to an intensive day treatment program for adolescents. Finally, two more studies implemented either RO-DBT group skills training added to standard Dialectical Behavioral Therapy (DBT) ( 11 ) or an individual RO-DBT program ( 16 ) in an outpatient setting for the treatment of AN. These studies provide promising results regarding the acceptability and feasibility of the treatment, but have some limitations, such as small sample sizes, the absence of a control group condition, and short follow-ups. Currently, no randomized controlled trial has proven the efficacy of RO-DBT in patients with AN. Moreover, none of the prior studies have investigated whether the presence of ASD traits interferes with the outcomes of this treatment. From a neurobiological perspective, overcontrol capacity has been closely related to a frontoparietal network control, specifically involving the dorsolateral prefrontal cortex (dlPFC) activity ( 17 ). Interestingly, Pauligk et al. explored whether overcontrol in AN, as measured by increased dlPFC activation, is associated with costs in the domain of affective processing. They found that higher activation of the dlPFC during emotion processing predicted increased amygdala reactivity, which, in turn, was associated with heightened self-reported momentary tension in everyday life during the following two weeks ( 18 ). Moreover, they observed a significant association between over-regulation of the reward system during a distancing emotional regulation task and increased body-related rumination, negative affect, and poorer treatment response. Therefore, overcontrolled behavior and negative affect states may reinforce each other, a mechanism that could potentially contribute to the maintenance of AN symptoms and, ultimately, diminish the quality of life of these patients ( 18 ). By unravelling the intricate workings of the brain mechanisms involved in RO-DBT for AN, novel targets for intervention will be pinpointed, leading to improved therapeutic outcomes and ultimately transforming the landscape of EDs treatment. However, no previous neuroimaging studies have investigated the specific impact of RO-DBT directly targeting brain-related overcontrolled behavior. The main objective of this study is to investigate the efficacy of RO-DBT in enhancing the quality of life of a group of weight-restored patients with AN. Secondary aims: (a) assess the effect of RO-DBT in reducing the number of relapses, (b) study the impact of RO-DBT in decreasing EDs symptoms, (c) analyze the influence of RO-DBT in reducing ASD traits, (d) investigate if ASD traits can modulate changes in quality of life after RO-DBT, (e) determine the impact of RO-DBT in reducing other symptoms that interfere with psychological well-being, (f) estimate the influence of RO-DBT in improving executive function, and (g) gain a deeper understanding of the underlying neurobiological mechanisms of RO-DBT. This is a novel approach to treating EDs, especially AN, as no other psychotherapy or pharmacotherapy has the therapeutic indication in AN. Our proposal is innovative and easily applicable to clinical practice, thus boosting the interest of clinicians in AN treatment. Methods and Design The present study is a randomized controlled clinical trial approved by the Research Ethics Board of the Hospital de la Santa Creu i Sant Pau ( HSCSP) . Two treatment arms will be compared (treatment as usual (TAU) and TAU + RO-DBT) in a sample of patients with AN. The impact of the intervention will be evaluated using clinical variables, clinical scales as well as structural, functional, and metabolic magnetic resonance imaging (MRI). Participants The EQUATOR network served as the basis for determining the required sample size in this study. With an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, each treatment arm should consist of 30 subjects for a statistically significant detection of a difference greater than or equal to 7 units in the quality of life scale employed. Based on previous literature, the common standard deviation is assumed to be 8 (19). Anticipating a drop-out rate of 35% based on our previous experience with extended group therapies in our EDs unit, and considering that the intervention is designed for groups of 8 individuals, we have decided to include 32 subjects per arm. The sample of patients will be recruited at the EDs Unit of the HSCSP , which is the main unit within the public health system treating EDs patients in the city of Barcelona. Inclusion criteria and exclusion criteria considered for the study are summarized in Table 1. Study Design Figure 1 and Table 2 present a comprehensive study schedule. Eligible patients will be assessed (V1) to ensure they fulfill all inclusion and exclusion criteria. Afterward, they will be invited to participate in the study. Detailed oral and written extensive information about the study will be provided to all eligible patients. If they wish to participate, informed consent (IC) will be signed by all participants (V1), and further appointments will be scheduled for the baseline assessment. After signing the IC, patients will be randomized into one of the two treatment arms. A detailed explanation of the treatment arms is provided below. Randomization will be carried out by an independent statistician from the Department of Epidemiology (HSCSP) using a computerized random number generation program. In order to ensure a balanced sample size across groups, a block randomization method will be used. The block size will be set to 16 so as to have 8 patients per arm in four consecutive blocks. Another experienced clinical researcher will assign participants to their corresponding intervention. A systematic and protocolled collection of sociodemographic and clinical variables of every participant will be held through a data collection notebook at two different times so as to avoid lengthen the exploration (V2.1 and V2.2). This will be carried out by a junior researcher who will be trained for the purposes of the study. Patients will undergo the first neuroimaging acquisition (V3) before starting the intervention. Clinical and neuroimaging assessments will be carried out in a maximum time period of one week per patient. The intervention will be conducted by two senior experienced psychologists who have completed training in RO-DBT. Supervision sessions will be taking place periodically in order to ensure therapy adherence. Compliance will be assessed by collecting attendance at treatment sessions and study visits. Changes in pharmacological treatment will be allowed when indicated under medical criteria and will be collected and considered as a possible confounding variable. Adverse effects derived from the psychotherapeutic intervention are not expected. However, in the case of any adverse event during participation in the study, these will be collected and further considered. During the intervention, both groups will have monthly appointments with the junior researcher in order to monitor body mass index (BMI), Eating Attitudes Test (EAT) scale, or prescribed medication changes (V4.1 to V4.6). The first post-intervention evaluation, including the data collection notebook (V5.1 and V5.2) and the second neuroimaging acquisition (V6), will occur within one week after the first month following the completion of RO-DBT therapy. A follow-up evaluation will take place 12 months after the completion of the intervention (V8.1 and 8.2) when patients will be again assessed by clinical scales included in the data collection notebook. As before, monthly appointments will be scheduled during the follow-up period with the junior researcher to maintain the monitoring of BMI, EAT scale, and prescribed medication changes (V7.1 to V7.12). Intervention Selected patients will be randomized to one of two treatment arms. Each patient randomization code will be maintained and identified in a separate document from the clinical data collection notebook. Both treatment arms have the same duration (30 weeks). TAU: The TAU condition will follow the standard treatment of the EDs Unit of the HSCSP for AN. This treatment consists of visits with a psychiatrist with a frequency decided according to the clinical situation and, in some cases, nursing follow-up and/or relapse prevention group that takes place twice per month. TAU + RO-DBT: In this treatment arm, a RO-DBT group skills training therapy will be added to TAU. Treatment and therapists: RO-DBT group skills training consists of a 30-week intervention program in which a set of skills specifically designed to treat overcontrol are taught on an ongoing basis. The duration of each session is 2 hours. Table 3 provides an overall summary of each skill training session content. Detailed information about the treatment can be found elsewhere (14,20). Three clinical psychologists and one psychiatrist will conduct the treatment, all of whom have undergone extensive training in RO-DBT. A maximum of two therapists will be in charge of each session, and the same two therapists will go throughout each group intervention. The team will be monitored by an approved RO-DBT supervisor who will evaluate adherence to the treatment. Demographic and clinical assessment Demographic variables: age, sex, gender, marital status, employment status, and maximum educational level. Clinical variables: Type of AN, BMI, severity and clinical course (including previous treatments, years of disease, maximum and minimum BMI), presence of comorbidities with other psychiatric or medical disorders not considered in exclusion criteria, family history of EDs or other psychiatric disorder, and current pharmacological treatment if present. Verbal Comprehension Index from Wechsler Adult Intelligence Scale version-IV (WAIS-IV) . Structured Clinical Interview for text revised fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) Axis II Personality Disorders (21). Childhood Trauma Questionnaire – Short Form, CTQ-SF (22). Zuckerman-Kuhlman Personality Questionnaire, ZKPQ (23). Outcome measures Principal outcome measure: Quality of Life Enjoyment and Satisfaction Questionnaire, Q-LES-Q (24). This questionnaire explores patient’s satisfaction in eight areas: physical health status, mood, work, home activities, academic tasks, leisure activities, social relationships, and general activities. Secondary clinical outcome measures: Summarized in Table 4. Neuroimaging variables: All the patients will be scanned two times: within two weeks before the first TAU or TAU + RO-DBT session (MRI1) and at 1-month follow-up after completion of the treatment protocol (MRI2). A 3.0-T Siemens MAGNETOM Prisma scanner (Munich, Germany) equipped with a 32-channel head coil will be used to acquire structural, functional, and metabolic magnetic resonance imaging. High-resolution T1-weighted anatomical sequence with repetition time, 2500 ms; echo time, 4.37 ms; flip angle, 7º; field of view, 256 x 256 mm; matrix size, 256 x 256 pixels; in-plane resolution, 1 x 1 mm 2 ; slice thickness, 1 mm; 176 slices; acquisition time, 3:47 minutes. High-resolution T2-weighted anatomical sequence with repetition time, 3200 ms; echo time, 405 ms; flip angle, 120º; field of view, 256 x 256 mm; matrix size, 256 x 256 pixels; in-plane resolution, 1 x 1 mm 2 ; slice thickness, 1 mm; 176 slices; acquisition time, 3:42 minutes. This sequence will be used to discard brain pathology. Diffusion-weighted multiband and multi-shell imaging sequence (repetition time, 3000 ms; echo time, 113 ms; flip angle, 90º; field of view, 224 x 224 mm; matrix size, 112 x 112 pixels; in-plane resolution, 2 x 2 mm 2 ; slice thickness, 2 mm; 76 slices; acquisition time: 7:40 minutes) with an acceleration factor = 4 and 3 diffusion-weighted shells at b -value = 500 s/mm 2 (6 volumes), b -value = 1000 s/mm 2 (64 volumes), and b -value = 2000 s/mm 2 (64 volumes). The sequence will include 14 interspersed b -value = 0 s/mm 2 volumes. A reverse phase-encode polarity sequence will be acquired for susceptibility distortion correction. Resting-state multiband functional sequence with acceleration factor, 8; repetition time, 800 ms; echo time, 37 ms; flip angle, 52º; field of view, 208 x 208 mm; matrix size, 104 x 104 pixels; in-plane resolution, 2 x 2 mm 2 ; slice thickness, 2 mm; 72 slices; 595 volumes; acquisition time, 8:06 minutes. A reverse phase-encode polarity sequence will be acquired for susceptibility distortion correction. Single-voxel Point-Resolved Spectroscopy sequence with repetition time, 2000 ms; echo time, 32 ms; 128 averages; acquisition time, 4:24 minutes. Unsuppressed water scans (16 averages) will be acquired alongside each scan. A total of 2048 data points will be collected over a spectral width of 2000 Hz. The volumes of interest will be adjusted to the individual left and right insula anatomy (37 x 13 x 21 mm 3 ). Several studies have emphasized the relevance of the insular cortex in the pathophysiology of anorexia nervosa (AN), acting as a central neural hub integrating information from different cortical and subcortical areas. The insula is involved in a variety of functions such as emotional awareness, sensorimotor processing, integration of interoception, information risk prediction, decision-making, and complex social processes such as empathy(37). Studies using magnetic resonance spectroscopy in AN show some consistent findings: Maier et al.(38) found insular metabolic alterations consisting of lower concentrations of N-acetyl aspartate (NAA) and Glutamate + Glutamine (Glx) in women with AN compared to those recovered. We considered this theoretical background in order to choose this brain region. End of study and discontinuation criteria The study will end 18 months after the inclusion of the last patient. No need for early discontinuation of the study is anticipated beyond: i) ineffectiveness of the treatment, ii) appearance of adverse events unknown to date or unrelated, iii) insufficient number of patients included in the study. Following the closure of the study, it is planned to call participating patients in the future to determine the long-term effects of the intervention. Data analyses Withdrawal from the trial will be triggered if a trial subject misses two or more consecutive therapy sessions or four or more non-consecutive therapy sessions, and they will be promptly notified via phone or email. However, these individuals will continue to receive follow-up care as deemed appropriate by medical professionals. Trial subjects will not be replaced, except in cases where they have not yet started treatment and are still in the phase of evaluation and MRI. Likewise, the absence at two or more control visits or four or more non-consecutive assessments will also be considered a withdrawal criterion in the case of participants assigned to the TAU group. The withdrawals in each group will be explicitly analyzed. We will use the statistical package SPSS 27.0 for Windows for statistical analyses. The following statistical tests will be carried out to evaluate the efficacy of the RO-DBT on quality of life and its impact on relapse prevention, EDs symptoms, ASD symptoms, executive function, and other psychological well-being variables. Two-factor mixed ANOVA tests will be performed with time as an intra-group variable and the different clinical scores as between-group variables. A statistical significance level of p<0.05 (Family-Wise Error corrected) will be used. We will do both intention to treat and per protocol analysis. MRIs will be pre-processed using FreeSurfer (i.e., T1-weighted and diffusion-weighted images), fMRIPrep (i.e., resting-state functional images), and jMRUI (i.e., spectroscopy images) following standardized protocols. T1-weighted pre-processed images will be used to optimize both diffusion-weighted and resting-state functional pre-processing procedures. For diffusion-weighted images, we will extract four diffusion measures: Fractional Anisotropy, Mean Diffusivity, Axial Diffusivity, and Radial Diffusivity of 42 reconstructed white-matter pathways using global probabilistic tractography as implemented in TRACULA (TRActs Constrained by UnderLying Anatomy) on FreeSurfer. Resting-state functional networks will be analyzed using a group probabilistic independent component analysis approach in MELODIC (Multivariate Exploratory Linear Optimized Decomposition into Independent Components) and computed at the individual level using a Dual Regression on FSL. Spectra processing will calculate NAA and Glx insular concentrations using jMRUI. Linear mixed-effects models will be conducted to evaluate the impact of the two different treatment strategies (i.e., TAU and TAU + RO-DBT) on the neuroimaging measures using SPSS (i.e., diffusion-weighted and spectroscopy images) and FSL (i.e., resting-state functional images). In addition, multiple regression analyses on the TAU + RO-DBT group will be performed to evaluate the potential relationship between clinical and neuroimaging variables (i.e., predictive and response biomarkers). Statistical significance will be set at a threshold of p<0.05 False Discovery Rate corrected. Discussion This study protocol presents the design of the first randomized controlled clinical trial evaluating the efficacy of RO-DBT in female weight-restored adults with AN. Despite extensive research on various treatments for EDs and AN in adults, there is currently no treatment supported by robust evidence that clearly outperforms others in terms of efficacy. With this study, we aim to address a severe and not-yet-resolved health problem: the need for a more effective treatment for AN focused not only on weight restoration but also on quality of life enhancement. In addition to its scientific significance, this study is motivated by the desire to expand the understanding of the neural mechanisms underlying this psychological intervention by incorporating neurobiological biomarkers such as neuroimaging signatures. Other strengths of this study include the large battery of secondary outcome measures that will be used. Finally, the follow-up will extend up to one year after the intervention is finished, thus allowing the possibility to draw conclusions about mid to long-term effects of RO-BDT in terms of relapse prevention and overall quality of life. The use of concomitant medication is allowed, which may interfere with the results, but changes in the prescription will be monitored, aiming to control for those potential confounder factors in the analysis. Cumulative evidence favoring RO-DBT for patients with AN may reduce the disorder-related costs by preventing relapse or modifying the tendency for the disorder to become chronic, generate new lines of research by applying it to a broader group of patients, and finally focus on patients’ real-life worries not only symptom reduction or weight restoration. Abbreviations EDs Eating Disorders AN Anorexia Nervosa ASD Autism Spectrum Disorder RO-DBT Radically Open Dialectical Behavioral Therapy DBT Dialectical Behavioral Therapy dlPDC dorsolateral prefrontal cortex HSCSP Hospital de la Santa Creu i Sant Pau TAU Treatment As Usual MRI Magnetic resonance imaging BMI Body Mass Index ASC-WP Assessing Styles of Coping – Word Pair BPD Borderline Personality Disorder IC Informed Consent EAT Eating Attitudes test WAIS-IV Wechsler Adult Intelligence Scale version-IV DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision CTQ-SF Childhood Trauma Questionnaire – Short Form ZKPQ Zuckerman-Kuhlman Personality Questionnaire EDI Eating Disorder Inventory AQ Autism-Spectrum Quotient RGSE Rosenberg General Self-Esteem Scale IIP Inventory of Interpersonal Problems SCS-R Social Connectedness Scale-Revised CEA Questionnaire Envy in Adults DASS Depression Anxiety Stress Scales INCOM-E Iowa-Netherlands Comparison Orientation Measure CORE-OM Clinical Outcomes in Routine Evaluation-Outcome Measure TMT Trail Making Test NAA N-acetyl aspartate Glx Glutamate + Glutamine. Declarations Ethics approval and consent to participate This study is approved by the Ethical Committee for Clinical Research (in Spanish, Comité Ético de Investigación Clínica) from the Hospital de la Santa Creu i Sant Pau , project number IIBSP-TDC-2022-123. Protocol version 3, 14th July 2023. Central Clinical Research and Clinical Trials Unit (CCRCTU), Research Institute of the Hospital de Sant Pau, will monitor through periodic visits the correct progression of the project, alerting from protocol deviations. They will be constantly aware of every single step of the project. All participants will receive extended information about the study and must give their written informed consent prior to participate in the study. This study does not pose any risk to the participants. Consent for publication Written informed consent from participants will be obtained prior to the inclusion to the study. Availability of data and materials This is an ongoing study and the investigators are currently collecting data. Therefore, any publication containing the results of this study has not been published. All the investigators collaborating in this study will have access to the final trial dataset. All writings and presentations will be performed by the members of the research team following the standard guidelines of dissemination policy. Competing interests Authors declare that they have no competing interests related to this study. Funding This study is financed by the Fundació La Marató de TV3 (project number 202231-10). This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. MC is funded by a “Sara Borrell” postdoctoral contract [CD20/00189] from the Carlos III Health Institute. VDA is funded by the Spanish Minsitry of Science, Innovation and Universities, State Research Agency, and the European Union-NextGenerationEU/PRTR (JDC2022-048445-I). Authors' contributions AAP drafted the manuscript which was critically reviewed by CCF, MC, AMB and MJP. CCF designed the study with the collaboration of MJP, AMB, AAP, JS, and MCS. CCF, AAP, LG, MCS and NC were involved in the set-up of the study, providing information upon the availability of facilities and clinical settings. CCF, AAP and MC reviewed the theoretical rationale for manuscript preparation. CCF, MJP and AMB defined the statistical approach for the manuscript. MC and VPA defined the neuroimaging variables and its statistical evaluation. All authors read and approved the final version manuscript . Acknowledgements We thank Dr. Ignasi Gich, from the Department of Epidemiology (Hospital de la Santa Creu i Sant Pau, Barcelona), for his help in the randomization process. 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Available from: https://pubmed.ncbi.nlm.nih.gov/33524917/ Hedgcock WM, Vohs KD, Rao AR. Reducing self-control depletion effects through enhanced sensitivity to implementation: Evidence from fMRI and behavioral studies. J Consum Psychol [Internet]. 2012 Oct 1 [cited 2023 Sep 27];22(4):486–95. Available from: https://onlinelibrary.wiley.com/doi/full/10.1016/j.jcps.2012.05.008 Pauligk S, Seidel M, Fürtjes S, King JA, Geisler D, Hellerhoff I, et al. The costs of over-control in anorexia nervosa: evidence from fMRI and ecological momentary assessment. Transl Psychiatry [Internet]. 2021 Jun 1 [cited 2023 Jul 13];11(1). Available from: https://pubmed.ncbi.nlm.nih.gov/34016948/ Demyttenaere K, Andersen HF, Reines EH. Impact of escitalopram treatment on Quality of Life Enjoyment and Satisfaction Questionnaire scores in major depressive disorder and generalized anxiety disorder. Int Clin Psychopharmacol [Internet]. 2008 Sep [cited 2023 May 31];23(5):276–86. Available from: https://pubmed.ncbi.nlm.nih.gov/18703937/ Lynch TR. The skills training manual for Radically open dialectical behavior therapy: a clinician’s guide for treating disorders of overcontrol. In: Oakland, CA: New Harbinger Publications. 2018. First, M. B., Gibbon, M., Spitzer, R. L., Williams, J. B. W., & Benjamin LS. Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Washington, DC Am Psychiatr Press Inc [Internet]. 1997 [cited 2023 May 16]; Available from: https://www.scirp.org/(S(351jmbntvnsjt1aadkposzje))/reference/referencespapers.aspx?referenceid=1302256 Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, et al. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry [Internet]. 1994 [cited 2023 May 16];151(8):1132–6. Available from: https://pubmed.ncbi.nlm.nih.gov/8037246/ Zuckerman M, Kuhlman DM, Joireman J, Teta P, Kraft M. A Comparison of Three Structural Models for Personality: The Big Three, the Big Five, and the Alternative Five. J Pers Soc Psychol. 1993;65(4):757–68. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull [Internet]. 1993 [cited 2023 May 16];29(2):321–6. Available from: https://pubmed.ncbi.nlm.nih.gov/8290681/ Garner DM, Garfinkel PE. The Eating Attitudes Test: an index of the symptoms of anorexia nervosa. Psychol Med [Internet]. 1979 [cited 2023 May 15];9(2):273–9. Available from: https://pubmed.ncbi.nlm.nih.gov/472072/ Garner DM, Olmstead MP, Polivy J. Development and validation of a multidimensional eating disorder inventory for anorexia nervosa and bulimia. Int J Eat Disord [Internet]. 1983 [cited 2023 May 15];2(2):15–34. Available from: https://www.researchgate.net/publication/238274320_Development_and_validation_ of_a_multidimensional_eating_disorder_inventory_of_anorexia_nervosa_and_bulimia/citation/download Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord [Internet]. 2001 [cited 2023 May 15];31(1):5–17. Available from: https://pubmed.ncbi.nlm.nih.gov/11439754/ Rosenberg M. Society and the adolescent self-image. Princenton, NJ Princent Univ Press. 1965;326. Horowitz LM, Rosenberg SE, Baer BA, Ureño G, et al. Inventory of interpersonal problems: psychometric properties and clinical applications. J Consult Clin Psychol [Internet]. 1988 [cited 2023 May 16];56(6):885–92. Available from: https://pubmed.ncbi.nlm.nih.gov/3204198/ Lee RM, Draper M, Lee S. Social connectedness, dysfunctional interpersonal behaviors, and psychological distress: Testing a mediator model. J Couns Psychol. 2001;48(3):310–8. Abad EV, Alfonso L, Larraz H, Pablo F, Tello H. Adaptation and Content Validity of the Child Envy Questionnaire to Adult Population. Acción Psicológica [Internet]. 2013 Jun 6 [cited 2023 May 16];10(2):59–72. Available from: https://revistas.uned.es/index.php/accionpsicologica/article/view/11824 Lovibond PF, Lovibond SH. The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behav Res Ther [Internet]. 1995 [cited 2023 May 16];33(3):335–43. Available from: https://pubmed.ncbi.nlm.nih.gov/7726811/ Gibbons FX, Buunk BP. Individual differences in social comparison: development of a scale of social comparison orientation. J Pers Soc Psychol [Internet]. 1999 [cited 2023 May 16];76(1):129–42. Available from: https://pubmed.ncbi.nlm.nih.gov/9972558/ Seretis D, Maguire T, Hempel R, Lynch T, Hart C. The Brief Overcontrol Scale. Univ Southampton. 2017; Evans C, Connell J, Barkham M, Margison F, McGrath G, Mellor-Clark J, et al. Towards a standardised brief outcome measure: psychometric properties and utility of the CORE-OM. Br J Psychiatry [Internet]. 2002 [cited 2023 May 16];180(JAN.):51–60. Available from: https://pubmed.ncbi.nlm.nih.gov/11772852/ Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills. 1958;8:271–6. Gogolla N. The insular cortex. Curr Biol [Internet]. 2017 Jun 19 [cited 2023 May 24];27(12):R580–6. Available from: https://pubmed.ncbi.nlm.nih.gov/28633023/ Maier S, Nickel K, Perlov E, Kukies A, Zeeck A, van Elst LT, et al. Insular Cell Integrity Markers Linked to Weight Concern in Anorexia Nervosa-An MR-Spectroscopy Study. J Clin Med [Internet]. 2020 May 1 [cited 2023 May 24];9(5). Available from: https://pubmed.ncbi.nlm.nih.gov/32365843/ Tables Tables 1 to 4 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files SPIRITFillablechecklist.doc Tables.docx Cite Share Download PDF Status: Published Journal Publication published 18 Apr, 2025 Read the published version in BMC Psychiatry → Version 1 posted Editorial decision: Revision requested 28 Aug, 2024 Submission checks completed at journal 02 Jun, 2024 Editor assigned by journal 02 Jun, 2024 First submitted to journal 13 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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16:42:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31276,"visible":true,"origin":"","legend":"\u003cp\u003eFlow of participants through the study.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4414466/v1/9ab7c36739c341358901cfbf.png"},{"id":81050809,"identity":"4c2b7747-5f39-49c9-85a7-a8bdcb78de87","added_by":"auto","created_at":"2025-04-21 16:05:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":663567,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4414466/v1/45d74504-7b05-4102-8587-820041d3cae9.pdf"},{"id":58515913,"identity":"fb7f1f01-9e8a-4af6-a338-b5bd7f1e40ea","added_by":"auto","created_at":"2024-06-17 16:42:39","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":125440,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFillablechecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-4414466/v1/d2cedc52099b573ab7d41f6e.doc"},{"id":58515911,"identity":"d601e98d-b5fd-421d-b6ed-a2947f2842a8","added_by":"auto","created_at":"2024-06-17 16:42:39","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":42499,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4414466/v1/c117d26ecf326921a0a8dd5f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluating the efficacy of Radically Open Dialectical Behavior Therapy (RO-DBT) in patients with anorexia nervosa: study protocol for a randomized controlled clinical trial","fulltext":[{"header":"Background","content":"\u003cp\u003eEating disorders (EDs) are severe psychiatric disorders associated with multiple physical and psychological problems(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The prevalence of these disorders is not negligible and continues to increase, with rates reaching up to 5% in their subclinical forms. As a result, they pose a growing health concern(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Among the different EDs, anorexia nervosa (AN) is the most severe and difficult to treat, with a lifetime prevalence of up to 0.5\u0026ndash;0.6% (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It frequently has a chronic course and is associated with mortality rates of up to 18% in longitudinal follow-up studies (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In addition, numerous studies describe relapse rates over 25%, with some even documenting rates as high as 52% (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). It has been described that the period with the highest probability of relapse is during the first year following acute treatment (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Regarding recovery, AN has long been considered a treatment-resistant disorder, making it a great challenge for clinicians to not only achieve physical weight recovery but also promote psychosocial recovery. A 20-year longitudinal study of AN patients revealed that, despite achieving physical recovery, the majority of patients did not achieve psychosocial recovery (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo date, no psychological treatment has shown enough evidence to be considered the treatment of choice for adult patients with AN (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Most medical centers specialized in treating EDs focus solely on re-nutrition, which seeks improvements in weight that are difficult to maintain over time, leading to high rates of relapse. In addition, the objectives of re-nutrition do not cover other core psychopathological domains such as psychosocial well-being (including psychosexual, socioeconomic, and social contacts and activities) or improvement of overall quality of life. This highlights the necessity for novel and more effective approaches/treatments that strive for comprehensive symptom relief. One of the reasons that could underlie the difficult recovery from EDs is their high comorbidity with features of autism spectrum disorder (ASD). The presence of comorbidity with ASD traits has been linked to a poorer initial social adjustment (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and a worse prognosis in terms of eating symptoms (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and psychosocial outcomes (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Nielsen et al., in an 18-year follow-up study of a group of patients with AN, suggested a dose-dependent relationship between the presence of ASD traits and worse quality of life and psychosocial functioning (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In this sense, clinical symptoms such as overcontrol, which is often shared between AN and ASD, may be a fundamental contributing mechanism to developing and maintaining AN.\u003c/p\u003e \u003cp\u003eOvercontrol is defined as the tendency to inhibit emotional urges, impulses, and behaviors in order to follow long-term goals (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). AN, similarly to ASD, can be regarded as an overcontrol disorder characterized by low receptivity and openness, low flexible control, pervasive inhibited emotional expressiveness, low emotional awareness, and low social connectedness and intimacy with others (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, overcontrol is rarely addressed as a core element in treating AN (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Thomas Lynch has created a promising treatment called Radically Open Dialectical Behavioral Therapy (RO-DBT) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e): a transdiagnostic intervention specifically designed to treat a spectrum of disorders characterized by excessive control such as resistant and chronic depression, avoidant and obsessive-compulsive personality disorders, AN and ASD. RO-DBT suggests that emotional well-being involves the confluence of three characteristics: openness, flexibility, and social connectedness. In the specific case of EDs, RO-DBT offers a different perspective regarding the aetiology and treatment of AN via a biosocial model that accounts for temperamental family/environment, perceptual and self-control tendencies. In this context, restrictive and ritualized eating is conceptualized as a symptom or consequence based on a maladaptive overcontrolled coping style that has been intermittently reinforced. Notwithstanding, only few authors have applied RO-DBT to AN patients. Lynch et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) applied an adapted 8-week RO-DTB program to 47 inpatients diagnosed with restrictive AN, showing significant improvements in weight with a large effect size (\u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.71), but no follow-up data was recorded. Using an uncontrolled case series design, Baudinet et al. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) evaluated the effect of RO-DBT group skills training as an add-on therapy to an intensive day treatment program for adolescents. Finally, two more studies implemented either RO-DBT group skills training added to standard Dialectical Behavioral Therapy (DBT) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) or an individual RO-DBT program (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) in an outpatient setting for the treatment of AN. These studies provide promising results regarding the acceptability and feasibility of the treatment, but have some limitations, such as small sample sizes, the absence of a control group condition, and short follow-ups. Currently, no randomized controlled trial has proven the efficacy of RO-DBT in patients with AN. Moreover, none of the prior studies have investigated whether the presence of ASD traits interferes with the outcomes of this treatment.\u003c/p\u003e \u003cp\u003eFrom a neurobiological perspective, overcontrol capacity has been closely related to a frontoparietal network control, specifically involving the dorsolateral prefrontal cortex (dlPFC) activity (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Interestingly, Pauligk et al. explored whether overcontrol in AN, as measured by increased dlPFC activation, is associated with costs in the domain of affective processing. They found that higher activation of the dlPFC during emotion processing predicted increased amygdala reactivity, which, in turn, was associated with heightened self-reported momentary tension in everyday life during the following two weeks (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Moreover, they observed a significant association between over-regulation of the reward system during a distancing emotional regulation task and increased body-related rumination, negative affect, and poorer treatment response. Therefore, overcontrolled behavior and negative affect states may reinforce each other, a mechanism that could potentially contribute to the maintenance of AN symptoms and, ultimately, diminish the quality of life of these patients (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). By unravelling the intricate workings of the brain mechanisms involved in RO-DBT for AN, novel targets for intervention will be pinpointed, leading to improved therapeutic outcomes and ultimately transforming the landscape of EDs treatment. However, no previous neuroimaging studies have investigated the specific impact of RO-DBT directly targeting brain-related overcontrolled behavior.\u003c/p\u003e \u003cp\u003eThe main objective of this study is to investigate the efficacy of RO-DBT in enhancing the quality of life of a group of weight-restored patients with AN. Secondary aims: (a) assess the effect of RO-DBT in reducing the number of relapses, (b) study the impact of RO-DBT in decreasing EDs symptoms, (c) analyze the influence of RO-DBT in reducing ASD traits, (d) investigate if ASD traits can modulate changes in quality of life after RO-DBT, (e) determine the impact of RO-DBT in reducing other symptoms that interfere with psychological well-being, (f) estimate the influence of RO-DBT in improving executive function, and (g) gain a deeper understanding of the underlying neurobiological mechanisms of RO-DBT. This is a novel approach to treating EDs, especially AN, as no other psychotherapy or pharmacotherapy has the therapeutic indication in AN. Our proposal is innovative and easily applicable to clinical practice, thus boosting the interest of clinicians in AN treatment.\u003c/p\u003e"},{"header":"Methods and Design","content":"\u003cp\u003eThe present study is a randomized controlled clinical trial approved by the Research Ethics Board of the \u003cem\u003eHospital de la Santa Creu i Sant Pau (\u003c/em\u003e\u003cem\u003eHSCSP)\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e Two treatment arms will be compared (treatment as usual (TAU) and TAU + RO-DBT) in a sample of patients with AN. The impact of the intervention will be evaluated using clinical variables, clinical scales as well as structural, functional, and metabolic magnetic resonance imaging (MRI).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe EQUATOR network served as the basis for determining the required sample size in this study. With an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, each treatment arm should consist of 30 subjects for a statistically significant detection of a difference greater than or equal to 7 units in the quality of life scale employed. Based on previous literature, the common standard deviation is assumed to be 8\u0026nbsp;(19). Anticipating a drop-out rate of 35% based on our previous experience with extended group therapies in our EDs unit, and considering that the intervention is designed for groups of 8 individuals, we have decided to include 32 subjects per arm. The sample of patients will be recruited at the EDs Unit of the \u003cem\u003eHSCSP\u003c/em\u003e, which is the main unit within the public health system treating EDs patients in the city of Barcelona.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInclusion criteria and exclusion criteria considered for the study are summarized in Table 1. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 and Table 2 present a comprehensive study schedule. Eligible patients will be assessed (V1) to ensure they fulfill all inclusion and exclusion criteria. Afterward, they will be invited to participate in the study. Detailed oral and written extensive information about the study will be provided to all eligible patients. If they wish to participate, informed consent (IC) will be signed by all participants (V1), and further appointments will be scheduled for the baseline assessment. After signing the IC, patients will be randomized into one of the two treatment arms. A detailed explanation of the treatment arms is provided below. Randomization will be carried out by an independent statistician from the Department of Epidemiology (HSCSP) using a computerized random number generation program. In order to ensure a balanced sample size across groups, a block randomization method will be used. The block size will be set to 16 so as to have 8 patients per arm in four consecutive blocks. Another experienced clinical researcher will assign participants to their corresponding intervention. A systematic and protocolled collection of sociodemographic and clinical variables of every participant will be held through a data collection notebook at two different times so as to avoid lengthen the exploration (V2.1 and V2.2). This will be carried out by a junior researcher who will be trained for the purposes of the study. Patients will undergo the first neuroimaging acquisition (V3) before starting the intervention. Clinical and neuroimaging assessments will be carried out in a maximum time period of one week per patient. The intervention will be conducted by two senior experienced psychologists who have completed training in RO-DBT. Supervision sessions will be taking place periodically in order to ensure therapy adherence. Compliance will be assessed by collecting attendance at treatment sessions and study visits. Changes in pharmacological treatment will be allowed when indicated under medical criteria and will be collected and considered as a possible confounding variable. Adverse effects derived from the psychotherapeutic intervention are not expected. However, in the case of any adverse event during participation in the study, these will be collected and further considered. During the intervention, both groups will have monthly appointments with the junior researcher in order to monitor body mass index (BMI), Eating Attitudes Test (EAT) scale, or prescribed medication changes (V4.1 to V4.6). The first post-intervention evaluation, including the data collection notebook (V5.1 and V5.2) and the second neuroimaging acquisition (V6), will occur within one week after the first month following the completion of RO-DBT therapy. A follow-up evaluation will take place 12 months after the completion of the intervention (V8.1 and 8.2) when patients will be again assessed by clinical scales included in the data collection notebook. As before, monthly appointments will be scheduled during the follow-up period with the junior researcher to maintain the monitoring of BMI, EAT scale, and prescribed medication changes (V7.1 to V7.12).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSelected patients will be randomized to one of two treatment arms. Each patient randomization code will be maintained and identified in a separate document from the clinical data collection notebook. Both treatment arms have the same duration (30 weeks).\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eTAU: The TAU condition will follow the standard treatment of the EDs Unit of the HSCSP for AN. This treatment consists of visits with a psychiatrist with a frequency decided according to the clinical situation and, in some cases, nursing follow-up and/or relapse prevention group that takes place twice per month.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTAU + RO-DBT: In this treatment arm, a RO-DBT group skills training therapy will be added to TAU. \u003cem\u003eTreatment and therapists:\u0026nbsp;\u003c/em\u003eRO-DBT group skills training consists of a 30-week intervention program in which a set of skills specifically designed to treat overcontrol are taught on an ongoing basis. The duration of each session is 2 hours. Table 3 provides an overall summary of each skill training session content. Detailed information about the treatment can be found elsewhere (14,20). Three clinical psychologists and one psychiatrist will conduct the treatment, all of whom have undergone extensive training in RO-DBT. A maximum of two therapists will be in charge of each session, and the same two therapists will go throughout each group intervention. The team will be monitored by an approved RO-DBT supervisor who will evaluate adherence to the treatment. \u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eDemographic and clinical assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cu\u003eDemographic variables:\u003c/u\u003e age, sex, gender, marital status, employment status, and maximum educational level.\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eClinical variables:\u003c/u\u003e Type of AN, BMI, severity and clinical course (including previous treatments, years of disease, maximum and minimum BMI), presence of comorbidities with other psychiatric or medical disorders not considered in exclusion criteria, family history of EDs or other psychiatric disorder, and current pharmacological treatment if present.\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eVerbal Comprehension Index from Wechsler Adult Intelligence Scale version-IV (WAIS-IV)\u003c/u\u003e.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eStructured Clinical Interview for text revised fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) Axis II Personality Disorders\u003c/u\u003e (21).\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eChildhood Trauma Questionnaire \u0026ndash; Short Form, CTQ-SF\u003c/u\u003e (22).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cu\u003eZuckerman-Kuhlman Personality Questionnaire, ZKPQ\u003c/u\u003e (23).\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrincipal outcome measure: \u003cu\u003eQuality of Life Enjoyment and Satisfaction Questionnaire, Q-LES-Q\u003c/u\u003e (24). This questionnaire explores patient\u0026rsquo;s satisfaction in eight areas: physical health status, mood, work, home activities, academic tasks, leisure activities, social relationships, and general activities.\u003c/p\u003e\n\u003cp\u003eSecondary clinical outcome measures: Summarized in Table 4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeuroimaging variables: All the patients will be scanned two times: within two weeks before the first TAU or TAU + RO-DBT session (MRI1) and at 1-month follow-up after completion of the treatment protocol (MRI2). A 3.0-T Siemens MAGNETOM Prisma scanner (Munich, Germany) equipped with a 32-channel head coil will be used to acquire structural, functional, and metabolic magnetic resonance imaging.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eHigh-resolution T1-weighted anatomical sequence with repetition time, 2500 ms; echo time, 4.37 ms; flip angle, 7\u0026ordm;; field of view, 256 x 256 mm; matrix size, 256 x 256 pixels; in-plane resolution, 1 x 1 mm\u003csup\u003e2\u003c/sup\u003e; slice thickness, 1 mm; 176 slices; acquisition time, 3:47 minutes.\u003c/li\u003e\n \u003cli\u003eHigh-resolution T2-weighted anatomical sequence with repetition time, 3200 ms; echo time, 405 ms; flip angle, 120\u0026ordm;; field of view, 256 x 256 mm; matrix size, 256 x 256 pixels; in-plane resolution, 1 x 1 mm\u003csup\u003e2\u003c/sup\u003e; slice thickness, 1 mm; 176 slices; acquisition time, 3:42 minutes. This sequence will be used to discard brain pathology.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDiffusion-weighted multiband and multi-shell imaging sequence (repetition time, 3000 ms; echo time, 113 ms; flip angle, 90\u0026ordm;; field of view, 224 x 224 mm; matrix size, 112 x 112 pixels; in-plane resolution, 2 x 2 mm\u003csup\u003e2\u003c/sup\u003e; slice thickness, 2 mm; 76 slices; acquisition time: 7:40 minutes) with an acceleration factor = 4 and 3 diffusion-weighted shells at \u003cem\u003eb\u003c/em\u003e-value = 500 s/mm\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e(6 volumes), \u003cem\u003eb\u003c/em\u003e-value = 1000 s/mm\u003csup\u003e2\u003c/sup\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e(64 volumes), and \u003cem\u003eb\u003c/em\u003e-value = 2000 s/mm\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e(64 volumes). The sequence will include 14 interspersed \u003cem\u003eb\u003c/em\u003e-value = 0 s/mm\u003csup\u003e2\u0026nbsp;\u003c/sup\u003evolumes. A reverse phase-encode polarity sequence will be acquired for susceptibility distortion correction.\u003c/li\u003e\n \u003cli\u003eResting-state multiband functional sequence with acceleration factor, 8; repetition time, 800 ms; echo time, 37 ms; flip angle, 52\u0026ordm;; field of view, 208 x 208 mm; matrix size, 104 x 104 pixels; in-plane resolution, 2 x 2 mm\u003csup\u003e2\u003c/sup\u003e; slice thickness, 2 mm; 72 slices; 595 volumes; acquisition time, 8:06 minutes. A reverse phase-encode polarity sequence will be acquired for susceptibility distortion correction.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSingle-voxel Point-Resolved Spectroscopy sequence with repetition time, 2000 ms; echo time, 32 ms; 128 averages; acquisition time, 4:24 minutes. Unsuppressed water scans (16 averages) will be acquired alongside each scan. A total of 2048 data points will be collected over a spectral width of 2000 Hz. The volumes of interest will be adjusted to the individual left and right insula anatomy (37 x 13 x 21 mm\u003csup\u003e3\u003c/sup\u003e). Several studies have emphasized the relevance of the insular cortex in the pathophysiology of anorexia nervosa (AN), acting as a central neural hub integrating information from different cortical and subcortical areas. The insula is involved in a variety of functions such as emotional awareness, sensorimotor processing, integration of interoception, information risk prediction, decision-making, and complex social processes such as empathy(37). \u0026nbsp;Studies using magnetic resonance spectroscopy in AN show some consistent findings: Maier et al.(38) found insular metabolic alterations consisting of lower concentrations of N-acetyl aspartate (NAA) and Glutamate + Glutamine (Glx) in women with AN compared to those recovered. We considered this theoretical background in order to choose this brain region.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eEnd of study and discontinuation criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will end 18 months after the inclusion of the last patient. No need for early discontinuation of the study is anticipated beyond: i) ineffectiveness of the treatment, ii) appearance of adverse events unknown to date or unrelated, iii) insufficient number of patients included in the study. Following the closure of the study, it is planned to call participating patients in the future to determine the long-term effects of the intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWithdrawal from the trial will be triggered if a trial subject misses two or more consecutive therapy sessions or four or more non-consecutive therapy sessions, and they will be promptly notified via phone or email. However, these individuals will continue to receive follow-up care as deemed appropriate by medical professionals. Trial subjects will not be replaced, except in cases where they have not yet started treatment and are still in the phase of evaluation and MRI. Likewise, the absence at two or more control visits or four or more non-consecutive assessments will also be considered a withdrawal criterion in the case of participants assigned to the TAU group. The withdrawals in each group will be explicitly analyzed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe will use the statistical package SPSS 27.0 for Windows for statistical analyses. The following statistical tests will be carried out to evaluate the efficacy of the RO-DBT on quality of life and its impact on relapse prevention, EDs symptoms, ASD symptoms, executive function, and other psychological well-being variables. Two-factor mixed ANOVA tests will be performed with time as an intra-group variable and the different clinical scores as between-group variables. A statistical significance level of p\u0026lt;0.05 (Family-Wise Error corrected) will be used. We will do both intention to treat and per protocol analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRIs will be pre-processed using FreeSurfer (i.e., T1-weighted and diffusion-weighted images), fMRIPrep (i.e., resting-state functional images), and jMRUI (i.e., spectroscopy images) following standardized protocols. T1-weighted pre-processed images will be used to optimize both diffusion-weighted and resting-state functional pre-processing procedures. For diffusion-weighted images, we will extract four diffusion measures: Fractional Anisotropy, Mean Diffusivity, Axial Diffusivity, and Radial Diffusivity of 42 reconstructed white-matter pathways using global probabilistic tractography as implemented in TRACULA (TRActs Constrained by UnderLying Anatomy) on FreeSurfer. Resting-state functional networks will be analyzed using a group probabilistic independent component analysis approach in MELODIC (Multivariate Exploratory Linear Optimized Decomposition into Independent Components) and computed at the individual level using a Dual Regression on FSL. Spectra processing will calculate NAA and Glx insular concentrations using jMRUI. Linear mixed-effects models will be conducted to evaluate the impact of the two different treatment strategies (i.e., TAU and TAU + RO-DBT) on the neuroimaging measures using SPSS (i.e., diffusion-weighted and spectroscopy images) and FSL (i.e., resting-state functional images). In addition, multiple regression analyses on the TAU + RO-DBT group will be performed to evaluate the potential relationship between clinical and neuroimaging variables (i.e., predictive and response biomarkers). Statistical significance will be set at a threshold of p\u0026lt;0.05 False Discovery Rate corrected.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study protocol presents the design of the first randomized controlled clinical trial evaluating the efficacy of RO-DBT in female weight-restored adults with AN. Despite extensive research on various treatments for EDs and AN in adults, there is currently no treatment supported by robust evidence that clearly outperforms others in terms of efficacy. With this study, we aim to address a severe and not-yet-resolved health problem: the need for a more effective treatment for AN focused not only on weight restoration but also on quality of life enhancement. In addition to its scientific significance, this study is motivated by the desire to expand the understanding of the neural mechanisms underlying this psychological intervention by incorporating neurobiological biomarkers such as neuroimaging signatures. Other strengths of this study include the large battery of secondary outcome measures that will be used. Finally, the follow-up will extend up to one year after the intervention is finished, thus allowing the possibility to draw conclusions about mid to long-term effects of RO-BDT in terms of relapse prevention and overall quality of life. The use of concomitant medication is allowed, which may interfere with the results, but changes in the prescription will be monitored, aiming to control for those potential confounder factors in the analysis. Cumulative evidence favoring RO-DBT for patients with AN may reduce the disorder-related costs by preventing relapse or modifying the tendency for the disorder to become chronic, generate new lines of research by applying it to a broader group of patients, and finally focus on patients\u0026rsquo; real-life worries not only symptom reduction or weight restoration.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEDs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEating Disorders\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAnorexia Nervosa\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAutism Spectrum Disorder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRO-DBT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadically Open Dialectical Behavioral Therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDBT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDialectical Behavioral Therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003edlPDC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edorsolateral prefrontal cortex\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSCSP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHospital de la Santa Creu i Sant Pau\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTAU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTreatment As Usual\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBody Mass Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASC-WP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAssessing Styles of Coping \u0026ndash; Word Pair\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBorderline Personality Disorder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInformed Consent\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEating Attitudes test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWAIS-IV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWechsler Adult Intelligence Scale version-IV\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSM-IV-TR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTQ-SF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChildhood Trauma Questionnaire \u0026ndash; Short Form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eZKPQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eZuckerman-Kuhlman Personality Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEDI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEating Disorder Inventory\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAutism-Spectrum Quotient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRGSE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRosenberg General Self-Esteem Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIIP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInventory of Interpersonal Problems\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSCS-R\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSocial Connectedness Scale-Revised\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCEA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQuestionnaire Envy in Adults\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDASS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDepression Anxiety Stress Scales\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eINCOM-E\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIowa-Netherlands Comparison Orientation Measure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCORE-OM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical Outcomes in Routine Evaluation-Outcome Measure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTMT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrail Making Test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNAA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eN-acetyl aspartate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGlx\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlutamate\u0026thinsp;+\u0026thinsp;Glutamine.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is approved by the Ethical Committee for Clinical Research (in Spanish, Comité Ético de Investigación Clínica) from the \u003cem\u003eHospital de la Santa Creu i Sant Pau\u003c/em\u003e, project number IIBSP-TDC-2022-123. Protocol version 3, 14th July 2023.\u003c/p\u003e\n\u003cp\u003eCentral Clinical Research and Clinical Trials Unit (CCRCTU), Research Institute of the Hospital de Sant Pau, will monitor through periodic visits the correct progression of the project, alerting from protocol deviations. They will be constantly aware of every single step of the project.\u003c/p\u003e\n\u003cp\u003eAll participants will receive extended information about the study and must give their written informed consent prior to participate in the study. This study does not pose any risk to the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent from participants will be obtained prior to the inclusion to the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is an ongoing study and the investigators are currently collecting data. Therefore, any publication containing the results of this study has not been published.\u003c/p\u003e\n\u003cp\u003eAll the investigators collaborating in this study will have access to the final trial dataset. All writings and presentations will be performed by the members of the research team following the standard guidelines of dissemination policy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare that they have no competing interests related to this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is financed by the \u003cem\u003eFundació La Marató de TV3\u003c/em\u003e (project number 202231-10). This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.\u003c/p\u003e\n\u003cp\u003eMC is funded by a “Sara Borrell” postdoctoral contract [CD20/00189] from the Carlos III Health Institute.\u003c/p\u003e\n\u003cp\u003eVDA is funded by the Spanish Minsitry of Science, Innovation and Universities, State Research Agency, and the European Union-NextGenerationEU/PRTR (JDC2022-048445-I).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAAP drafted the manuscript which was critically reviewed by CCF, MC, AMB and MJP. CCF designed the study with the collaboration of MJP, AMB, AAP, JS, and MCS. CCF, AAP, LG, MCS and NC were involved in the set-up of the study, providing information upon the availability of facilities and clinical settings. CCF, AAP and MC reviewed the theoretical rationale for manuscript preparation. CCF, MJP and AMB defined the statistical approach for the manuscript. MC and VPA defined the neuroimaging variables and its statistical evaluation. All authors read and approved the final version manuscript\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr. Ignasi Gich, from the Department of Epidemiology (Hospital de la Santa Creu i Sant Pau, Barcelona), for his help in the randomization process.\u003c/p\u003e\n\u003cp\u003eWe thank CERCA Program/Generalitat de Catalunya for institutional support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u0026Aacute;gh T, Kov\u0026aacute;cs G, Supina D, Pawaskar M, Herman BK, Vok\u0026oacute; Z, et al. 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Br J Psychiatry [Internet]. 2009 Feb [cited 2023 May 18];194(2):168\u0026ndash;74. Available from: https://pubmed.ncbi.nlm.nih.gov/19182181/\u003c/li\u003e\n \u003cli\u003eWestwood H, Eisler I, Mandy W, Leppanen J, Treasure J, Tchanturia K. Using the Autism-Spectrum Quotient to Measure Autistic Traits in Anorexia Nervosa: A Systematic Review and Meta-Analysis. J Autism Dev Disord [Internet]. 2016 Mar 1 [cited 2023 May 18];46(3):964\u0026ndash;77. Available from: https://pubmed.ncbi.nlm.nih.gov/26542816/\u003c/li\u003e\n \u003cli\u003eWestwood H, Tchanturia K. Autism Spectrum Disorder in Anorexia Nervosa: An Updated Literature Review. Curr Psychiatry Rep [Internet]. 2017 Jul 1 [cited 2023 May 18];19(7). Available from: https://pubmed.ncbi.nlm.nih.gov/28540593/\u003c/li\u003e\n \u003cli\u003eNielsen S, Anckars\u0026auml;ter H, Gillberg C, Gillberg C, R\u0026aring;stam M, Wentz E. 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Available from: https://pubmed.ncbi.nlm.nih.gov/29384459/\u003c/li\u003e\n \u003cli\u003eLynch TR, Gray KLH, Hempel RJ, Titley M, Chen EY, O\u0026rsquo;Mahen HA. Radically open-dialectical behavior therapy for adult anorexia nervosa: feasibility and outcomes from an inpatient program. BMC Psychiatry [Internet]. 2013 Nov 7 [cited 2023 May 18];13. Available from: https://pubmed.ncbi.nlm.nih.gov/24199611/\u003c/li\u003e\n \u003cli\u003eLynch TR. Radically Open Dialectical Behavior Therapy - Theory and Practice For Treating Disorders of Overcontrol. In: Oakland: Context Press/New Harbinger Publications [Internet]. 2018 [cited 2023 May 16]. p. 504. Available from: https://es.scribd.com/document/507746582/Thomas-R-Lynch-Radically-Open-Dialectical-Behavior-Therapy-Theory-and-Practice-for-Treating-Disorders-of-Overcontrol-Context-Press-2018#\u003c/li\u003e\n \u003cli\u003eBaudinet J, Stewart C, Bennett E, Konstantellou A, Parham R, Smith K, et al. Radically open dialectical behaviour therapy adapted for adolescents: a case series. BMC Psychiatry [Internet]. 2021 Dec 1 [cited 2023 May 18];21(1). Available from: https://pubmed.ncbi.nlm.nih.gov/34551741/\u003c/li\u003e\n \u003cli\u003eIsaksson M, Ghaderi A, Ramklint M, Wolf-Arehult M. Radically open dialectical behavior therapy for anorexia nervosa: A multiple baseline single-case experimental design study across 13 cases. J Behav Ther Exp Psychiatry [Internet]. 2021 Jun 1 [cited 2023 May 18];71. Available from: https://pubmed.ncbi.nlm.nih.gov/33524917/\u003c/li\u003e\n \u003cli\u003eHedgcock WM, Vohs KD, Rao AR. Reducing self-control depletion effects through enhanced sensitivity to implementation: Evidence from fMRI and behavioral studies. J Consum Psychol [Internet]. 2012 Oct 1 [cited 2023 Sep 27];22(4):486\u0026ndash;95. Available from: https://onlinelibrary.wiley.com/doi/full/10.1016/j.jcps.2012.05.008\u003c/li\u003e\n \u003cli\u003ePauligk S, Seidel M, F\u0026uuml;rtjes S, King JA, Geisler D, Hellerhoff I, et al. The costs of over-control in anorexia nervosa: evidence from fMRI and ecological momentary assessment. Transl Psychiatry [Internet]. 2021 Jun 1 [cited 2023 Jul 13];11(1). Available from: https://pubmed.ncbi.nlm.nih.gov/34016948/\u003c/li\u003e\n \u003cli\u003eDemyttenaere K, Andersen HF, Reines EH. Impact of escitalopram treatment on Quality of Life Enjoyment and Satisfaction Questionnaire scores in major depressive disorder and generalized anxiety disorder. Int Clin Psychopharmacol [Internet]. 2008 Sep [cited 2023 May 31];23(5):276\u0026ndash;86. Available from: https://pubmed.ncbi.nlm.nih.gov/18703937/\u003c/li\u003e\n \u003cli\u003eLynch TR. The skills training manual for Radically open dialectical behavior therapy: a clinician\u0026rsquo;s guide for treating disorders of overcontrol. In: Oakland, CA: New Harbinger Publications. 2018.\u003c/li\u003e\n \u003cli\u003eFirst, M. B., Gibbon, M., Spitzer, R. L., Williams, J. B. W., \u0026amp; Benjamin LS. Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Washington, DC Am Psychiatr Press Inc [Internet]. 1997 [cited 2023 May 16]; Available from: https://www.scirp.org/(S(351jmbntvnsjt1aadkposzje))/reference/referencespapers.aspx?referenceid=1302256\u003c/li\u003e\n \u003cli\u003eBernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, et al. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry [Internet]. 1994 [cited 2023 May 16];151(8):1132\u0026ndash;6. Available from: https://pubmed.ncbi.nlm.nih.gov/8037246/\u003c/li\u003e\n \u003cli\u003eZuckerman M, Kuhlman DM, Joireman J, Teta P, Kraft M. A Comparison of Three Structural Models for Personality: The Big Three, the Big Five, and the Alternative Five. J Pers Soc Psychol. 1993;65(4):757\u0026ndash;68.\u003c/li\u003e\n \u003cli\u003eEndicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull [Internet]. 1993 [cited 2023 May 16];29(2):321\u0026ndash;6. Available from: https://pubmed.ncbi.nlm.nih.gov/8290681/\u003c/li\u003e\n \u003cli\u003eGarner DM, Garfinkel PE. The Eating Attitudes Test: an index of the symptoms of anorexia nervosa. Psychol Med [Internet]. 1979 [cited 2023 May 15];9(2):273\u0026ndash;9. Available from: https://pubmed.ncbi.nlm.nih.gov/472072/\u003c/li\u003e\n \u003cli\u003eGarner DM, Olmstead MP, Polivy J. Development and validation of a multidimensional eating disorder inventory for anorexia nervosa and bulimia. Int J Eat Disord [Internet]. 1983 [cited 2023 May 15];2(2):15\u0026ndash;34. Available from: https://www.researchgate.net/publication/238274320_Development_and_validation_\u003cbr\u003eof_a_multidimensional_eating_disorder_inventory_of_anorexia_nervosa_and_bulimia/citation/download\u003c/li\u003e\n \u003cli\u003eBaron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord [Internet]. 2001 [cited 2023 May 15];31(1):5\u0026ndash;17. Available from: https://pubmed.ncbi.nlm.nih.gov/11439754/\u003c/li\u003e\n \u003cli\u003eRosenberg M. Society and the adolescent self-image. Princenton, NJ Princent Univ Press. 1965;326.\u003c/li\u003e\n \u003cli\u003eHorowitz LM, Rosenberg SE, Baer BA, Ure\u0026ntilde;o G, et al. Inventory of interpersonal problems: psychometric properties and clinical applications. J Consult Clin Psychol [Internet]. 1988 [cited 2023 May 16];56(6):885\u0026ndash;92. Available from: https://pubmed.ncbi.nlm.nih.gov/3204198/\u003c/li\u003e\n \u003cli\u003eLee RM, Draper M, Lee S. Social connectedness, dysfunctional interpersonal behaviors, and psychological distress: Testing a mediator model. J Couns Psychol. 2001;48(3):310\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eAbad EV, Alfonso L, Larraz H, Pablo F, Tello H. Adaptation and Content Validity of the Child Envy Questionnaire to Adult Population. Acci\u0026oacute;n Psicol\u0026oacute;gica [Internet]. 2013 Jun 6 [cited 2023 May 16];10(2):59\u0026ndash;72. Available from: https://revistas.uned.es/index.php/accionpsicologica/article/view/11824\u003c/li\u003e\n \u003cli\u003eLovibond PF, Lovibond SH. The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behav Res Ther [Internet]. 1995 [cited 2023 May 16];33(3):335\u0026ndash;43. Available from: https://pubmed.ncbi.nlm.nih.gov/7726811/\u003c/li\u003e\n \u003cli\u003eGibbons FX, Buunk BP. Individual differences in social comparison: development of a scale of social comparison orientation. J Pers Soc Psychol [Internet]. 1999 [cited 2023 May 16];76(1):129\u0026ndash;42. Available from: https://pubmed.ncbi.nlm.nih.gov/9972558/\u003c/li\u003e\n \u003cli\u003eSeretis D, Maguire T, Hempel R, Lynch T, Hart C. The Brief Overcontrol Scale. Univ Southampton. 2017;\u003c/li\u003e\n \u003cli\u003eEvans C, Connell J, Barkham M, Margison F, McGrath G, Mellor-Clark J, et al. Towards a standardised brief outcome measure: psychometric properties and utility of the CORE-OM. Br J Psychiatry [Internet]. 2002 [cited 2023 May 16];180(JAN.):51\u0026ndash;60. Available from: https://pubmed.ncbi.nlm.nih.gov/11772852/\u003c/li\u003e\n \u003cli\u003eReitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills. 1958;8:271\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eGogolla N. The insular cortex. Curr Biol [Internet]. 2017 Jun 19 [cited 2023 May 24];27(12):R580\u0026ndash;6. Available from: https://pubmed.ncbi.nlm.nih.gov/28633023/\u003c/li\u003e\n \u003cli\u003eMaier S, Nickel K, Perlov E, Kukies A, Zeeck A, van Elst LT, et al. Insular Cell Integrity Markers Linked to Weight Concern in Anorexia Nervosa-An MR-Spectroscopy Study. J Clin Med [Internet]. 2020 May 1 [cited 2023 May 24];9(5). Available from: https://pubmed.ncbi.nlm.nih.gov/32365843/\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anorexia nervosa, radically open dialectical behaviour therapy, neuroimaging, overcontrol, efficacy.","lastPublishedDoi":"10.21203/rs.3.rs-4414466/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4414466/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Anorexia nervosa (AN) is a severe and disabling disorder, with relapse rates as high as 50% after the first episode, posing a significant challenge for clinicians. Most therapies excessively focus on nourishment, resulting in temporary weight restoration but with no improvements in general well-being and quality of life. Radically Open Dialectical Behavior Therapy (RO-DBT) is a transdiagnostic treatment designed to address overcontrol, a key aspect in the functioning of patients with AN. To date, no clinical trial (CT) has proven its efficacy in these patients or evaluated its neurobiological mechanism of action.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A randomized CT in AN patients will be conducted, with one group receiving treatment as usual (TAU) and the other TAU plus RO-DBT, with the main outcome being quality of life. Secondary variables will include eating disorders (EDs) symptoms, overcontrol characteristics, autistic traits, and neuroimaging changes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThe results will address a gap in knowledge regarding AN treatment, with the expectation that patients receiving TAU with RO-DBT will exhibit improved quality of life and experience fewer relapses at the one-year follow-up. This is the first study examining neuroimaging changes in RO-DBT to better understand its underlying mechanisms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u0026nbsp;\u003c/strong\u003eThe study has been registered in ClinicalTrials.gov in September 22, 2023.\u003c/p\u003e\n\u003cp\u003eIt can be found in\u0026nbsp;https://classic.clinicaltrials.gov/ct2/show/NCT06050421.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration Number: \u003c/strong\u003eNCT06050421\u003c/p\u003e","manuscriptTitle":"Evaluating the efficacy of Radically Open Dialectical Behavior Therapy (RO-DBT) in patients with anorexia nervosa: study protocol for a randomized controlled clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-17 16:42:35","doi":"10.21203/rs.3.rs-4414466/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-28T06:02:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-02T12:52:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-02T12:52:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2024-05-13T16:24:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"53ac81d3-db74-4cf6-b889-d9d595a1f759","owner":[],"postedDate":"June 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-21T15:59:49+00:00","versionOfRecord":{"articleIdentity":"rs-4414466","link":"https://doi.org/10.1186/s12888-025-06854-9","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2025-04-18 15:57:19","publishedOnDateReadable":"April 18th, 2025"},"versionCreatedAt":"2024-06-17 16:42:35","video":"","vorDoi":"10.1186/s12888-025-06854-9","vorDoiUrl":"https://doi.org/10.1186/s12888-025-06854-9","workflowStages":[]},"version":"v1","identity":"rs-4414466","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4414466","identity":"rs-4414466","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}