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Recent advances in therapies for eating disorders

Recent advances in therapies for eating disorders   Invited Reviewers Eating disorders are serious psychiatric illnesses with high rates of 1   2 morbidity and mortality. Effective treatments have traditionally included behaviorally focused therapies as well as several medication strategies. version 1 Recent years have seen promising developments in these treatments, published including additional support for family-based approaches for children and 26 Sep 2019 adolescents, new evidence for “third-wave” behavioral therapies, and new support for the use of lisdexamfetamine for binge eating disorder and F1000 Faculty Reviews are written by members of olanzapine for anorexia nervosa. Case study and pilot data are beginning to show limited support for neuromodulatory interventions targeting brain the prestigious F1000 Faculty. They are regions thought to be involved in eating disorders. This review summarizes commissioned and are peer reviewed before treatment developments over the last several years and points towards publication to ensure that the final, published version future directions for the field. is comprehensive and accessible. The reviewers Keywords who approved the final version are listed with their Eating disorders names and affiliations. Anja Hilbert, University of Leipzig Medical Center, Leipzig, Germany James Lock, Stanford University, Stanford, USA Any comments on the article can be found at the end of the article. Page 1 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Corresponding author: Evelyn Attia (ea12@cumc.columbia.edu) Author roles: Davis LE: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Attia E: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: Evelyn Attia receives royalty payments from UpToDate and serves as a consultant to Weight Watchers International. Lauren E. Davis declares that she has no competing interests. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2019 Davis LE and Attia E. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Davis LE and Attia E. Recent advances in therapies for eating disorders [version 1; peer review: 2 approved] F1000Research 2019, 8(F1000 Faculty Rev):1693 (https://doi.org/10.12688/f1000research.19847.1) First published: 26 Sep 2019, 8(F1000 Faculty Rev):1693 (https://doi.org/10.12688/f1000research.19847.1)  Page 2 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Introduction decreased across both groups but with a significantly greater Eating disorders, including anorexia nervosa (AN), bulimia change among those randomized to CBT-E. A greater pro- nervosa (BN), binge eating disorder (BED), and avoidant- portion of patients who received CBT-E achieved remission restrictive food intake disorder (ARFID), are serious psychiatric while in treatment (as defined by a global eating disorder illnesses associated with high rates of morbidity and mortality. examination score below 1.74) and a greater percentage of Recent epidemiological data from a United States population patients in CBT-E versus IPT (44.8% versus 21.7%) reported estimated lifetime prevalence rates of 0.80% (AN), 0.28% no binge eating, vomiting, or laxative misuse post-treatment. (BN), and 0.85% (BED), though estimates vary across These findings strengthen the evidence base for using 1,2 studies . Treatments are frequently multi-faceted, with psycho- cognitive-behavioral treatments for BN and BED and begin therapy and pharmacotherapy being commonly utilized across to support its use in higher-weight patients with binge eating a range of treatment settings. Recent treatment advances in psy- and purging behaviors. chotherapies were previously highlighted in a review , focusing 6,7 on the advancement of cognitive-behavioral treatments for BN Two recent meta-analyses have further supported the use of and BED as well as family-based therapy (FBT) for chil- CBT for the treatment of both BN and BED. Hilbert and col- dren and adolescents with AN. Since then, behavioral thera- leagues found that for BED, RCTs comparing CBT to inac- pies have continued to flourish and expand, integrating the tive control groups found a significantly reduced number of transdiagnostic model of cognitive-behavioral therapy (CBT) binge eating episodes as well as abstinence from binge eating into clinical practice. While BN has the most empirical overall in individuals undergoing CBT. When examining support for pharmacologic interventions, recent studies have RCTs that used active control groups, there was no clear treat- shown support for medications involved in the treatment of BED ment that appeared to be superior at reducing episodes of and AN, including one FDA-approved drug to treat BED. binge eating. For BN, Svaldi et al. found through a search of 79 RCTs including 5,775 participants that CBT had the most Across the spectrum of eating disorders, there is still much to effect on primary outcome variables (including remission be learned about their etiology, their development, and ways from binge eating and compensatory behaviors, and reduc- in which they can be effectively managed and treated. Recent tions in symptom severity). These meta-analyses support the developments in neuroscience and neuroimaging have begun use of CBT to treat BN and BED while indicating a need for to identify possible treatment targets for eating and other further research into CBT for BED to interpret its utility above psychiatric disorders. The neurocircuitry that may be respon- and beyond general psychotherapy. sible for disturbances in eating behavior has provided the field with new ideas about contributing factors to the devel - The transdiagnostic approach to conceptualizing treatment for opment and maintenance of eating disorders and possible eating disorders has continued to expand with increased rec- treatments for these disturbances. ognition for previously under-identified diagnoses. ARFID is one such example. A newly defined diagnosis in the Diag - This review aims to summarize findings from recent studies nostic and Statistical Manual of Mental Disorders, Fifth Edi- of psychological, medicinal, and other adjunctive treatments tion (DSM-5) , ARFID expanded upon DSM-IV’s “Feeding that have been used for individuals with eating disorders. Ran- and Eating Disorder of Early Childhood” to better describe the domized controlled trials (RCTs) as well as more preliminary condition of avoidant or restrictive eating not associated with reports including open series will be described. body weight and shape concerns that may present across the lifespan. The new diagnostic category has led clinicians to begin data collection regarding assessment and treatment Psychotherapies of individuals who meet criteria for ARFID. Thomas and The transdiagnostic approach to understanding core cognitive Eddy adapted the CBT model to ARFID and developed and behavioral features co-occurring across eating disorder diag- a treatment specifically tailored for the disorder, recently noses continues to shape the various psychotherapies in practice published in a formalized treatment manual. This model is today. In recent years, Fairburn and colleagues built upon currently being studied in treatment settings and shows initial case their initial work developing and studying CBT for BN and study support . By employing the transdiagnostic CBT model BED, creating a transdiagnostic version of CBT (CBT-E) . in designing treatments, researchers have been able to address This manualized treatment uses many of the familiar princi- a wider variety of eating disorder needs, including those of ples of CBT (e.g. food monitoring, cognitive challenges, etc.) more recently defined disorders, such as ARFID. but includes treatment components that specifically target different eating behaviors in order to have relevance across the range of different eating disorders. For adolescents with AN, FBT remains a first-choice therapy owing to its demonstrated efficacy in the treatment of young patients . Earlier evidence reported that early response to A 2015 study randomized 130 transdiagnostic patients (includ- treatment, specifically initial weight gain, likely predicts end- ing patients with BN, BED, and “other eating disorder”) to 12,13 of-treatment (EOT) remission and treatment outcomes . either CBT-E or interpersonal psychotherapy (IPT). Levels of The growing empirical literature continues to suggest that early general and eating disorder-specific psychopathology were intervention and weight gain can vastly improve outcomes assessed post-treatment, along with BMI and presence of binge for adolescents with AN. As a result of FBT’s demonstrated eating/purging behaviors. Overall, levels of psychopathology Page 3 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 effectiveness, research is now building upon it and extend- for binge-eating frequency). Data suggest that CBT deliv- ing its reach to various other clinical settings and populations, ered in an online group chat setting may be an acceptable alter- with positive support. native to in-person group CBT, but it may involve a slower trajectory of change than traditional CBT. This online for- mat for treatment may have value for those who otherwise Recently, Le Grange and colleagues demonstrated that among would not have access to care, as well as those with less comor- 121 adolescents with AN, early weight gain predicted improved bid psychopathology, owing to longer time to improvement outcome at EOT in an RCT comparing FBT and individual as well as less direct therapist interaction. adolescent-focused therapy (AFT) . The authors found that weight gain of 5.8 pounds by session three of FBT and 7.1 pounds by session four of AFT predicted remission status at EOT. For adolescents with BN, FBT has also been shown to be Early weight gain did not predict remission at 6- and 12-month an effective therapy . In a recently conducted RCT of 130 post-treatment follow-up for either treatment, but a survival patients with BN or partial BN, participants randomized to analysis of weight gain showed FBT to be superior to AFT FBT achieved significantly higher binge eating and purg - at 12 months post-treatment. Initial weight gain continues ing abstinence rates (39% versus 20%) than participants to be a predictive marker of treatment trajectory for ado- receiving CBT adapted for adolescents (CBT-A). This statis- lescents with AN, with FBT maintaining strong empirical tically significant difference remained at 6-month follow-up, support for use in outpatient settings. although abstinence rates were not significantly different by 12-month follow-up. Although FBT was originally developed to be delivered in an outpatient setting, recent evidence has supported using the Preliminary evidence has also been put forth applying FBT to model within treatment programs offered at higher levels of presentations of ARFID. Lock et al. published a case report 15–20 care . Matthews et al. reported that 49 hospitalized partici- indicating that the favorable principles of FBT (e.g. parental pants receiving an FBT-guided intervention gained significantly empowerment, externalization, and reinforcement of serious more weight at 3- and 6-months post-discharge (P <0.05 medical and developmental consequences) are applicable to and P <0.01, respectively) than a group of 44 patients exam- patients with ARFID as well. A feasibility study was also 21 26 ined retrospectively who received treatment as usual (TAU) . conducted by Lock et al. of 28 patients with ARFID who were Patients who received FBT while hospitalized were also enrolled in either FBT or TAU to examine the appropriateness of less likely to be re-hospitalized in the 6 months following conducting an RCT as well as differences in effect size between discharge. Though this was only a pilot study and slightly groups on clinical outcomes. In terms of weight gain, research- limited by the retrospective TAU design, evidence for FBT is ers found that both underweight and normal-weight patients indicative of clinical utility at all levels of treatment, not just gained more weight in FBT-ARFID (Cohen’s d = –0.90 and in the outpatient setting. –0.69, respectively) than in TAU. ARFID severity scores, accord- ing to the Pica, ARFID, and Rumination Disorder Interview (PARDI), showed a greater reduction in severity (d = 0.83). While the evidence base for FBT in adolescents with AN grows, Results also showed strong differences for change in parental many patients are still unable to access this intervention for self-efficacy favoring FBT-ARFID (d = –1.49). These results, reasons that may include regional differences in numbers of taken with other supporting evidence for FBT in a variety of FBT-trained clinicians. In an effort to address this accessibil- settings and across diagnoses, reinforce the need for contin- ity gap, Le Grange et al. conducted a small study examining ued study as well as more large-scale RCTs to promote the the feasibility of delivering FBT via a Telehealth platform. The use of FBT in clinical settings. authors reported that among 10 adolescents with AN or atypi- cal AN, weight increased significantly from baseline to EOT as well as from baseline to 6-month follow-up. Meas- Third-wave behavioral therapies such as dialectical behavior ures of eating disorder severity also showed statistically therapy (DBT) and acceptance and commitment therapy (ACT) significant changes during the study period. have also been adapted to treat eating disorders and in recent years have been accumulating data to support their use in treatment. Although originally developed for the treatment of As online-based platforms for delivering or augmenting treat- borderline personality disorder (BPD) , DBT for eating disor- ment grow in popularity, research continues to test how treat- ders relies on both theory and evidence of emotion dysregula- ment can be delivered most effectively for patients. One recent tion in eating disorder patients to suggest its utility . Recent study examined an internet-based manualized version of CBT data support the use of DBT in the treatment of BN and BED, but, group therapy for BN delivered in a group chat setting and com- as yet, there have been no RCTs of DBT for AN . pared it to CBT delivered face-to-face in group therapy . The authors hypothesized that the online therapeutic group chat would not be inferior to the face-to-face group and tested ACT has not yet gathered enough empirical support to be this hypothesis in 149 adults with BN. Results showed that regarded as an evidence-based treatment for eating disorders . at EOT, the online group chat was inferior to face-to-face The ACT formulation appears to be well suited to addressing therapy at reducing the frequency of binge eating and purg- some of the underlying maladaptive cognitions and behaviors ing but by 12-month follow-up the online group chat was mostly that are associated with eating disorders . Yet, despite earlier not inferior to the face-to-face group (it remained inferior case studies with preliminary support for the treatment , more Page 4 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 recent evidence has not shown ACT to perform above and While antidepressant medications, including fluoxetine, are 33 34 beyond TAU . In 2017, Juarascio et al. published results moderately helpful to individuals with BED in decreasing the of a pilot study examining the effects of an ACT adapta- frequency of binge eating, they are not associated with weight tion for BED. The ACT formulation, which also incorporated change effects, leaving many overweight and obese patients elements of both CBT and DBT, showed favorable results, with BED interested in adjunctive strategies for their symptoms. although reported rates of binge-eating abstinence were simi- BED has been described and studied since its inclusion in lar to those observed with CBT alone. Before existing as a DSM-IV as a diagnosis in need of further research but was only stand-alone treatment, ACT needs further development and recently identified as a formal clinical diagnosis with the 8,47 evidence for use in eating disorder populations. publication of DSM-5, in 2013 , and, with this renewed introduction, became the subject of additional investigations to identify helpful strategies for its management. Among these Another meta-analysis took interest in examining the effects lines of investigation, lisdexamfetamine, a stimulant medication of psychotherapy on self-esteem in BN and BED . Individuals with US FDA indications for the treatment of attention defi - with eating disorders are often conceptualized as having defi - cit hyperactivity disorder (ADHD), was examined for possible cits in self-esteem, which has been regarded as a potential main- utility in BED. In a randomized double-blind, parallel-group, taining mechanism of the disorders themselves . The authors forced dose titration, placebo-controlled clinical trial at 30 sites, wanted to understand how self-esteem might be improved 514 individuals with BED received lisdexamfetamine dime- following treatment and which, if any, current psychotherapies sylate at dosages of 30, 50, and 70 mg or placebo over an produce significant improvements in self-esteem. Initially, 11-week study period . At week 11, statistically significant the authors found modest improvements in self-esteem for differences in binge eating days/week decreased with the BN and BED across 34 RCTs (g = 0.44 and 0.20, respec- 50 mg/day and 70 mg/day groups but not the 30 mg/day com- tively), although the authors reported that there was some pared with placebo. Adverse effects were consistent with the evidence that the effect sizes were overestimated because of known safety profile of the medication. Additionally, the mean publication bias. In contrast to some previous results indicat- (SD) change in body weight was –0.1 (3.09) for the placebo ing the utility of CBT, this meta-analysis found no evidence group, –3.1 (3.64) kg for the 30 mg/day treatment group, –4.9 to support CBT over non-CBT interventions for improving (4.43) kg for the 50 mg/day treatment group, –4.9 (3.93) kg for self-esteem. The study was limited by its lack of statistical the 70 mg/day treatment group, and –4.3 (4.09) kg for the com- power, so further studies examining the effect of psychotherapy bined treatment group (0.001 for each dose versus placebo on self-esteem are still indicated. group comparison in post hoc analysis). Additional studies have confirmed the efficacy of 50 and 70 mg doses in binge The empirical findings supporting the use of psychothera - eating days and associated symptoms, leading to approval pies in the treatment of eating disorders have been reflected in by the FDA for the treatment of BED. the National Institute for Health and Care Excellence (NICE) guidelines, published in 2017 . They recommend group In contrast to BN and BED, AN has posed more of a or individual CBT for AN, BN, and BED as well as family clinical challenge in medication trials. In efforts to treat symp- therapy (when indicated) for adolescents with AN and BN. toms frequently associated with AN, including low mood, As the evidence base accumulates for efficacious interven - anxiety, and obsessionality, and the eating behavioral symptoms tions, clinical recommendations will refine to reflect empirically that overlap with those seen in BN, antidepressant and other indicated practices. medications have been examined in multiple RCTs without success. Medications Since the identification of distinct categories of eating disor - With the development and use of atypical antipsychotic medi- ders, pharmacologic interventions have been considered, and cations that help with psychiatric symptoms including severe RCTs have been conducted to examine the potential benefit of anxiety, and are associated with weight gain in other clinical various classes of medication on the core symptoms of eating populations including those with psychotic disorders, there has disorders. The evidence base for antidepressant medications in been interest in the eating disorders field about whether these the treatment of BN and BED has been robust, with outcomes agents may be helpful for individuals with AN. After several including significant decrease of binge eating and purging small pilot studies suggesting possible benefit of olan - behaviors. While fluoxetine is the only medication to have 49–53 zapine in AN , Attia et al. examined the effects of 16 undergone the US FDA approval process that concluded with a weeks of olanzapine versus placebo among 152 outpatients specific indication for treatment of BN, many other antidepres - with AN across five clinical sites in North America . The sants, from both the SSRI and TCA medication classes, have authors found that at 16 weeks following randomization, demonstrated statistically and clinically significant superior - olanzapine was associated with a statistically significant ity compared to placebo at decreasing the frequency of binge 38–45 increase in BMI over time compared with that seen in eating and purging behaviors . Notably, in a study of 387 the olanzapine group (0.256 [SD = 0.051] compared with women with BN, 60 mg fluoxetine demonstrated improved 0.095 [SD = 0.052] per month). The group did not find outcome compared with placebo while 20 mg did not , sug- psychological symptom differences between groups using gesting that a higher dose than that commonly utilized for Yale-Brown Obsessive Compulsive Scale (YBOCS), Center for depression is needed in the treatment of BN symptoms. Page 5 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Epidemiologic Studies Depression Scale (CES-D), Zung Anxi- rTMS, patients repeated the FCT and VAS, along with meas- ety Inventory, or Eating Disorders Examination (EDE) but ures of temporal discounting and saliva samples. Primary out- did find statistically significant symptom changes associated comes were measured by the VAS and described as “core with olanzapine on a somatic symptom inventory, with trouble AN symptoms”: urges to restrict, levels of feeling full, and concentrating, difficulty sitting still, trouble falling asleep, levels of feeling fat. Results indicated a trend for group and trouble staying asleep being rated as more problematic differences in the effects of rTMS on core AN symptoms in the placebo group than the group receiving olanzapine. (P = 0.056). While notably the effects of TMS are transient in comparison to other therapeutic interventions, initial evidence provides modest support that TMS may allow for symptom Neuromodulation and neuroimaging reduction in patients with AN. Advances in the understanding of the neurocircuitry involved in eating disorders has led to an increased interest in using The more intensive intervention, DBS, has been used in an neuromodulation as a possible treatment, especially for open series of 16 patients with treatment-refractory AN and those with severe illness, including those who may be resist- promising results have been reported . DBS treatment tar- ant to other established treatments . Recent research has geting the subcallosal cingulate cortex was associated with begun to identify neural circuits that are thought to be altered 56,57 improved anxiety, depression, emotion regulation, and BMI among individuals with eating disorders . Specifically, neu - at 12 months post-surgery. Other case reports of DBS for rocognitive and neuroimaging data have implicated circuits 58–61 62,63 AN have described similarly promising results, but control- involved in reward learning , decision making , stress, 64,65 66,67 led studies of this intervention are needed to determine the affect and negative valence , appetite regulation , and 71–73 58,67 impact of this strategy . self-regulatory control . Understanding these circuits and their locations in the brain has been critical for identifying treat- Many of these data come from preliminary studies in the field, ment targets that may be used for treatment development with with mixed results suggesting that the clinical utility of these neuromodulation technologies. interventions has yet to be fully understood. With the advance- ment of neuroimaging data enhancing our knowledge of Current methods for neuromodulation range from relatively the neurobiological underpinnings of psychiatric illnesses, non-invasive modalities like repetitive transcranial magnetic neuromodulatory targets will continue to be explored. stimulation (rTMS) to more intensive/invasive types such as deep brain stimulation (DBS). Conclusion There have been considerable advances in therapies for eat- rTMS has been examined as both a probe to test neurobiologi- ing disorders within the past few years alone. Relying on the cal hypotheses and a possible therapeutic intervention. One 2016 recent transdiagnostic CBT-E model of eating disorders , CBTs case series of five adult women with AN measured changes in continue to show support for patients with BN and BED . visual analogue scales (VAS), EDE-Q scores, and BMI before Empirical data indicate that the model can be formulated to and after 20 sessions of rTMS to the left dorsolateral prefron- fit diagnoses, with promising results . FBT for adolescents 15–22 tal cortex (l-DLPFC) . Results showed overall lower VAS has been studied across a variety of contexts and multiple 14,24,26 scores across levels of stress, anxiety, urges to restrict, and diagnoses with favorable results, underscoring its clini- feelings of fullness post-TMS. There was no notable change cal utility in young patients. Medication trials have led to the in BMI from pre- to post-treatment for the patients, but FDA approval of lisdexamfetamine for the treatment of BED , eating disorder symptomatology (as measured by the EDE-Q) and there is promise for olanzapine as an adjunctive treatment 49–54 improved and persisted up to the 12-month follow-up. for weight gain in AN . Neuroimaging studies have laid the This case study was followed by a larger RCT of 49 patients groundwork for understanding underlying brain mechanisms with AN who were randomized to receive either real or sham that may contribute to the development and perpetuation of rTMS to the l-DLPFC . Patients filled out baseline meas - eating disorders, with neuromodulatory therapies currently 68–70 ures of eating disorder and general psychopathology and being piloted as possible targeted interventions . Further then were asked to complete a food challenge task (FCT), research and development are still needed to refine the which involved watching a video of people eating palat- clinical utility of many treatments, but favorable outcomes able foods with those same foods in the room, before filling out point in the direction of progress toward empirically defined, VAS and receiving the real or sham rTMS treatment. After the effective eating disorder treatments. F1000 recommended References prevalence and mortality rates. Curr Psychiatry Rep. 2012; 14(4): 406–14. 1. Udo T, Grilo CM: Prevalence and Correlates of DSM-5-Defined Eating PubMed Abstract Publisher Full Text Free Full Text | | Disorders in a Nationally Representative Sample of U.S. Adults. Biol Psychiatry. 3. Waller G: Recent advances in psychological therapies for eating disorders 2018; 84(5): 345–354. [version 1; peer review: 2 approved]. F1000Res. 2016; 5: pii: F1000 Faculty Rev-702. 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PubMed Abstract Publisher Full Text Free Full Text 71. Blomstedt P, Naesström M, Bodlund O: Deep brain stimulation in the bed | | nucleus of the stria terminalis and medial forebrain bundle in a patient with major 57. Dunlop KA, Woodside B, Downar J: Targeting Neural Endophenotypes of Eating depressive disorder and anorexia nervosa. Clin Case Rep. 2017; 5(5): 679–84. Disorders with Non-invasive Brain Stimulation. Front Neurosci. 2016; 10: 30. PubMed Abstract Publisher Full Text Free Full Text F1000 Recommendation | | | PubMed Abstract Publisher Full Text Free Full Text | | 72. Lipsman N, Woodside DB, Giacobbe P, et al.: Neurosurgical treatment of 58. Berner LA, Marsh R: Frontostriatal circuits and the development of bulimia anorexia nervosa: review of the literature from leucotomy to deep brain nervosa. Front Behav Neurosci. 2014; 8: 395. stimulation. Eur Eat Disord Rev. 2013; 21(6): 428–35. PubMed Abstract Publisher Full Text Free Full Text | | PubMed Abstract Publisher Full Text 59. Frank GK: Altered brain reward circuits in eating disorders: chicken or egg? 73. McClelland J, Bozhilova N, Campbell I, et al.: A systematic review of the effects Curr Psychiatry Rep. 2013; 15(10): 396. of neuromodulation on eating and body weight: evidence from human and PubMed Abstract Publisher Full Text Free Full Text | | animal studies. Eur Eat Disord Rev. 2013; 21(6): 436–55. 60. O'Hara CB, Campbell IC, Schmidt U: A reward-centred model of PubMed Abstract Publisher Full Text Page 8 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Open Peer Review Current Peer Review Status: Editorial Note on the Review Process F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. The reviewers who approved this article are: Version 1 James Lock  Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, USA Competing Interests: No competing interests were disclosed. Anja Hilbert  Department of Medical Psychology and Medical Sociology, Department of Psychosomatic Medicine and Psychotherapy, University of Leipzig Medical Center, Leipzig, Germany Competing Interests: No competing interests were disclosed. The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias You can publish traditional articles, null/negative results, case reports, data notes and more The peer review process is transparent and collaborative Your article is indexed in PubMed after passing peer review Dedicated customer support at every stage For pre-submission enquiries, contact research@f1000.com  Page 9 of 9 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png F1000Research Pubmed Central

Recent advances in therapies for eating disorders

F1000Research , Volume 8 – Sep 26, 2019

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References (75)

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Pubmed Central
Copyright
Copyright: © 2019 Davis LE and Attia E
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2046-1402
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2046-1402
DOI
10.12688/f1000research.19847.1
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Abstract

  Invited Reviewers Eating disorders are serious psychiatric illnesses with high rates of 1   2 morbidity and mortality. Effective treatments have traditionally included behaviorally focused therapies as well as several medication strategies. version 1 Recent years have seen promising developments in these treatments, published including additional support for family-based approaches for children and 26 Sep 2019 adolescents, new evidence for “third-wave” behavioral therapies, and new support for the use of lisdexamfetamine for binge eating disorder and F1000 Faculty Reviews are written by members of olanzapine for anorexia nervosa. Case study and pilot data are beginning to show limited support for neuromodulatory interventions targeting brain the prestigious F1000 Faculty. They are regions thought to be involved in eating disorders. This review summarizes commissioned and are peer reviewed before treatment developments over the last several years and points towards publication to ensure that the final, published version future directions for the field. is comprehensive and accessible. The reviewers Keywords who approved the final version are listed with their Eating disorders names and affiliations. Anja Hilbert, University of Leipzig Medical Center, Leipzig, Germany James Lock, Stanford University, Stanford, USA Any comments on the article can be found at the end of the article. Page 1 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Corresponding author: Evelyn Attia (ea12@cumc.columbia.edu) Author roles: Davis LE: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Attia E: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: Evelyn Attia receives royalty payments from UpToDate and serves as a consultant to Weight Watchers International. Lauren E. Davis declares that she has no competing interests. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2019 Davis LE and Attia E. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Davis LE and Attia E. Recent advances in therapies for eating disorders [version 1; peer review: 2 approved] F1000Research 2019, 8(F1000 Faculty Rev):1693 (https://doi.org/10.12688/f1000research.19847.1) First published: 26 Sep 2019, 8(F1000 Faculty Rev):1693 (https://doi.org/10.12688/f1000research.19847.1)  Page 2 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Introduction decreased across both groups but with a significantly greater Eating disorders, including anorexia nervosa (AN), bulimia change among those randomized to CBT-E. A greater pro- nervosa (BN), binge eating disorder (BED), and avoidant- portion of patients who received CBT-E achieved remission restrictive food intake disorder (ARFID), are serious psychiatric while in treatment (as defined by a global eating disorder illnesses associated with high rates of morbidity and mortality. examination score below 1.74) and a greater percentage of Recent epidemiological data from a United States population patients in CBT-E versus IPT (44.8% versus 21.7%) reported estimated lifetime prevalence rates of 0.80% (AN), 0.28% no binge eating, vomiting, or laxative misuse post-treatment. (BN), and 0.85% (BED), though estimates vary across These findings strengthen the evidence base for using 1,2 studies . Treatments are frequently multi-faceted, with psycho- cognitive-behavioral treatments for BN and BED and begin therapy and pharmacotherapy being commonly utilized across to support its use in higher-weight patients with binge eating a range of treatment settings. Recent treatment advances in psy- and purging behaviors. chotherapies were previously highlighted in a review , focusing 6,7 on the advancement of cognitive-behavioral treatments for BN Two recent meta-analyses have further supported the use of and BED as well as family-based therapy (FBT) for chil- CBT for the treatment of both BN and BED. Hilbert and col- dren and adolescents with AN. Since then, behavioral thera- leagues found that for BED, RCTs comparing CBT to inac- pies have continued to flourish and expand, integrating the tive control groups found a significantly reduced number of transdiagnostic model of cognitive-behavioral therapy (CBT) binge eating episodes as well as abstinence from binge eating into clinical practice. While BN has the most empirical overall in individuals undergoing CBT. When examining support for pharmacologic interventions, recent studies have RCTs that used active control groups, there was no clear treat- shown support for medications involved in the treatment of BED ment that appeared to be superior at reducing episodes of and AN, including one FDA-approved drug to treat BED. binge eating. For BN, Svaldi et al. found through a search of 79 RCTs including 5,775 participants that CBT had the most Across the spectrum of eating disorders, there is still much to effect on primary outcome variables (including remission be learned about their etiology, their development, and ways from binge eating and compensatory behaviors, and reduc- in which they can be effectively managed and treated. Recent tions in symptom severity). These meta-analyses support the developments in neuroscience and neuroimaging have begun use of CBT to treat BN and BED while indicating a need for to identify possible treatment targets for eating and other further research into CBT for BED to interpret its utility above psychiatric disorders. The neurocircuitry that may be respon- and beyond general psychotherapy. sible for disturbances in eating behavior has provided the field with new ideas about contributing factors to the devel - The transdiagnostic approach to conceptualizing treatment for opment and maintenance of eating disorders and possible eating disorders has continued to expand with increased rec- treatments for these disturbances. ognition for previously under-identified diagnoses. ARFID is one such example. A newly defined diagnosis in the Diag - This review aims to summarize findings from recent studies nostic and Statistical Manual of Mental Disorders, Fifth Edi- of psychological, medicinal, and other adjunctive treatments tion (DSM-5) , ARFID expanded upon DSM-IV’s “Feeding that have been used for individuals with eating disorders. Ran- and Eating Disorder of Early Childhood” to better describe the domized controlled trials (RCTs) as well as more preliminary condition of avoidant or restrictive eating not associated with reports including open series will be described. body weight and shape concerns that may present across the lifespan. The new diagnostic category has led clinicians to begin data collection regarding assessment and treatment Psychotherapies of individuals who meet criteria for ARFID. Thomas and The transdiagnostic approach to understanding core cognitive Eddy adapted the CBT model to ARFID and developed and behavioral features co-occurring across eating disorder diag- a treatment specifically tailored for the disorder, recently noses continues to shape the various psychotherapies in practice published in a formalized treatment manual. This model is today. In recent years, Fairburn and colleagues built upon currently being studied in treatment settings and shows initial case their initial work developing and studying CBT for BN and study support . By employing the transdiagnostic CBT model BED, creating a transdiagnostic version of CBT (CBT-E) . in designing treatments, researchers have been able to address This manualized treatment uses many of the familiar princi- a wider variety of eating disorder needs, including those of ples of CBT (e.g. food monitoring, cognitive challenges, etc.) more recently defined disorders, such as ARFID. but includes treatment components that specifically target different eating behaviors in order to have relevance across the range of different eating disorders. For adolescents with AN, FBT remains a first-choice therapy owing to its demonstrated efficacy in the treatment of young patients . Earlier evidence reported that early response to A 2015 study randomized 130 transdiagnostic patients (includ- treatment, specifically initial weight gain, likely predicts end- ing patients with BN, BED, and “other eating disorder”) to 12,13 of-treatment (EOT) remission and treatment outcomes . either CBT-E or interpersonal psychotherapy (IPT). Levels of The growing empirical literature continues to suggest that early general and eating disorder-specific psychopathology were intervention and weight gain can vastly improve outcomes assessed post-treatment, along with BMI and presence of binge for adolescents with AN. As a result of FBT’s demonstrated eating/purging behaviors. Overall, levels of psychopathology Page 3 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 effectiveness, research is now building upon it and extend- for binge-eating frequency). Data suggest that CBT deliv- ing its reach to various other clinical settings and populations, ered in an online group chat setting may be an acceptable alter- with positive support. native to in-person group CBT, but it may involve a slower trajectory of change than traditional CBT. This online for- mat for treatment may have value for those who otherwise Recently, Le Grange and colleagues demonstrated that among would not have access to care, as well as those with less comor- 121 adolescents with AN, early weight gain predicted improved bid psychopathology, owing to longer time to improvement outcome at EOT in an RCT comparing FBT and individual as well as less direct therapist interaction. adolescent-focused therapy (AFT) . The authors found that weight gain of 5.8 pounds by session three of FBT and 7.1 pounds by session four of AFT predicted remission status at EOT. For adolescents with BN, FBT has also been shown to be Early weight gain did not predict remission at 6- and 12-month an effective therapy . In a recently conducted RCT of 130 post-treatment follow-up for either treatment, but a survival patients with BN or partial BN, participants randomized to analysis of weight gain showed FBT to be superior to AFT FBT achieved significantly higher binge eating and purg - at 12 months post-treatment. Initial weight gain continues ing abstinence rates (39% versus 20%) than participants to be a predictive marker of treatment trajectory for ado- receiving CBT adapted for adolescents (CBT-A). This statis- lescents with AN, with FBT maintaining strong empirical tically significant difference remained at 6-month follow-up, support for use in outpatient settings. although abstinence rates were not significantly different by 12-month follow-up. Although FBT was originally developed to be delivered in an outpatient setting, recent evidence has supported using the Preliminary evidence has also been put forth applying FBT to model within treatment programs offered at higher levels of presentations of ARFID. Lock et al. published a case report 15–20 care . Matthews et al. reported that 49 hospitalized partici- indicating that the favorable principles of FBT (e.g. parental pants receiving an FBT-guided intervention gained significantly empowerment, externalization, and reinforcement of serious more weight at 3- and 6-months post-discharge (P <0.05 medical and developmental consequences) are applicable to and P <0.01, respectively) than a group of 44 patients exam- patients with ARFID as well. A feasibility study was also 21 26 ined retrospectively who received treatment as usual (TAU) . conducted by Lock et al. of 28 patients with ARFID who were Patients who received FBT while hospitalized were also enrolled in either FBT or TAU to examine the appropriateness of less likely to be re-hospitalized in the 6 months following conducting an RCT as well as differences in effect size between discharge. Though this was only a pilot study and slightly groups on clinical outcomes. In terms of weight gain, research- limited by the retrospective TAU design, evidence for FBT is ers found that both underweight and normal-weight patients indicative of clinical utility at all levels of treatment, not just gained more weight in FBT-ARFID (Cohen’s d = –0.90 and in the outpatient setting. –0.69, respectively) than in TAU. ARFID severity scores, accord- ing to the Pica, ARFID, and Rumination Disorder Interview (PARDI), showed a greater reduction in severity (d = 0.83). While the evidence base for FBT in adolescents with AN grows, Results also showed strong differences for change in parental many patients are still unable to access this intervention for self-efficacy favoring FBT-ARFID (d = –1.49). These results, reasons that may include regional differences in numbers of taken with other supporting evidence for FBT in a variety of FBT-trained clinicians. In an effort to address this accessibil- settings and across diagnoses, reinforce the need for contin- ity gap, Le Grange et al. conducted a small study examining ued study as well as more large-scale RCTs to promote the the feasibility of delivering FBT via a Telehealth platform. The use of FBT in clinical settings. authors reported that among 10 adolescents with AN or atypi- cal AN, weight increased significantly from baseline to EOT as well as from baseline to 6-month follow-up. Meas- Third-wave behavioral therapies such as dialectical behavior ures of eating disorder severity also showed statistically therapy (DBT) and acceptance and commitment therapy (ACT) significant changes during the study period. have also been adapted to treat eating disorders and in recent years have been accumulating data to support their use in treatment. Although originally developed for the treatment of As online-based platforms for delivering or augmenting treat- borderline personality disorder (BPD) , DBT for eating disor- ment grow in popularity, research continues to test how treat- ders relies on both theory and evidence of emotion dysregula- ment can be delivered most effectively for patients. One recent tion in eating disorder patients to suggest its utility . Recent study examined an internet-based manualized version of CBT data support the use of DBT in the treatment of BN and BED, but, group therapy for BN delivered in a group chat setting and com- as yet, there have been no RCTs of DBT for AN . pared it to CBT delivered face-to-face in group therapy . The authors hypothesized that the online therapeutic group chat would not be inferior to the face-to-face group and tested ACT has not yet gathered enough empirical support to be this hypothesis in 149 adults with BN. Results showed that regarded as an evidence-based treatment for eating disorders . at EOT, the online group chat was inferior to face-to-face The ACT formulation appears to be well suited to addressing therapy at reducing the frequency of binge eating and purg- some of the underlying maladaptive cognitions and behaviors ing but by 12-month follow-up the online group chat was mostly that are associated with eating disorders . Yet, despite earlier not inferior to the face-to-face group (it remained inferior case studies with preliminary support for the treatment , more Page 4 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 recent evidence has not shown ACT to perform above and While antidepressant medications, including fluoxetine, are 33 34 beyond TAU . In 2017, Juarascio et al. published results moderately helpful to individuals with BED in decreasing the of a pilot study examining the effects of an ACT adapta- frequency of binge eating, they are not associated with weight tion for BED. The ACT formulation, which also incorporated change effects, leaving many overweight and obese patients elements of both CBT and DBT, showed favorable results, with BED interested in adjunctive strategies for their symptoms. although reported rates of binge-eating abstinence were simi- BED has been described and studied since its inclusion in lar to those observed with CBT alone. Before existing as a DSM-IV as a diagnosis in need of further research but was only stand-alone treatment, ACT needs further development and recently identified as a formal clinical diagnosis with the 8,47 evidence for use in eating disorder populations. publication of DSM-5, in 2013 , and, with this renewed introduction, became the subject of additional investigations to identify helpful strategies for its management. Among these Another meta-analysis took interest in examining the effects lines of investigation, lisdexamfetamine, a stimulant medication of psychotherapy on self-esteem in BN and BED . Individuals with US FDA indications for the treatment of attention defi - with eating disorders are often conceptualized as having defi - cit hyperactivity disorder (ADHD), was examined for possible cits in self-esteem, which has been regarded as a potential main- utility in BED. In a randomized double-blind, parallel-group, taining mechanism of the disorders themselves . The authors forced dose titration, placebo-controlled clinical trial at 30 sites, wanted to understand how self-esteem might be improved 514 individuals with BED received lisdexamfetamine dime- following treatment and which, if any, current psychotherapies sylate at dosages of 30, 50, and 70 mg or placebo over an produce significant improvements in self-esteem. Initially, 11-week study period . At week 11, statistically significant the authors found modest improvements in self-esteem for differences in binge eating days/week decreased with the BN and BED across 34 RCTs (g = 0.44 and 0.20, respec- 50 mg/day and 70 mg/day groups but not the 30 mg/day com- tively), although the authors reported that there was some pared with placebo. Adverse effects were consistent with the evidence that the effect sizes were overestimated because of known safety profile of the medication. Additionally, the mean publication bias. In contrast to some previous results indicat- (SD) change in body weight was –0.1 (3.09) for the placebo ing the utility of CBT, this meta-analysis found no evidence group, –3.1 (3.64) kg for the 30 mg/day treatment group, –4.9 to support CBT over non-CBT interventions for improving (4.43) kg for the 50 mg/day treatment group, –4.9 (3.93) kg for self-esteem. The study was limited by its lack of statistical the 70 mg/day treatment group, and –4.3 (4.09) kg for the com- power, so further studies examining the effect of psychotherapy bined treatment group (0.001 for each dose versus placebo on self-esteem are still indicated. group comparison in post hoc analysis). Additional studies have confirmed the efficacy of 50 and 70 mg doses in binge The empirical findings supporting the use of psychothera - eating days and associated symptoms, leading to approval pies in the treatment of eating disorders have been reflected in by the FDA for the treatment of BED. the National Institute for Health and Care Excellence (NICE) guidelines, published in 2017 . They recommend group In contrast to BN and BED, AN has posed more of a or individual CBT for AN, BN, and BED as well as family clinical challenge in medication trials. In efforts to treat symp- therapy (when indicated) for adolescents with AN and BN. toms frequently associated with AN, including low mood, As the evidence base accumulates for efficacious interven - anxiety, and obsessionality, and the eating behavioral symptoms tions, clinical recommendations will refine to reflect empirically that overlap with those seen in BN, antidepressant and other indicated practices. medications have been examined in multiple RCTs without success. Medications Since the identification of distinct categories of eating disor - With the development and use of atypical antipsychotic medi- ders, pharmacologic interventions have been considered, and cations that help with psychiatric symptoms including severe RCTs have been conducted to examine the potential benefit of anxiety, and are associated with weight gain in other clinical various classes of medication on the core symptoms of eating populations including those with psychotic disorders, there has disorders. The evidence base for antidepressant medications in been interest in the eating disorders field about whether these the treatment of BN and BED has been robust, with outcomes agents may be helpful for individuals with AN. After several including significant decrease of binge eating and purging small pilot studies suggesting possible benefit of olan - behaviors. While fluoxetine is the only medication to have 49–53 zapine in AN , Attia et al. examined the effects of 16 undergone the US FDA approval process that concluded with a weeks of olanzapine versus placebo among 152 outpatients specific indication for treatment of BN, many other antidepres - with AN across five clinical sites in North America . The sants, from both the SSRI and TCA medication classes, have authors found that at 16 weeks following randomization, demonstrated statistically and clinically significant superior - olanzapine was associated with a statistically significant ity compared to placebo at decreasing the frequency of binge 38–45 increase in BMI over time compared with that seen in eating and purging behaviors . Notably, in a study of 387 the olanzapine group (0.256 [SD = 0.051] compared with women with BN, 60 mg fluoxetine demonstrated improved 0.095 [SD = 0.052] per month). The group did not find outcome compared with placebo while 20 mg did not , sug- psychological symptom differences between groups using gesting that a higher dose than that commonly utilized for Yale-Brown Obsessive Compulsive Scale (YBOCS), Center for depression is needed in the treatment of BN symptoms. Page 5 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Epidemiologic Studies Depression Scale (CES-D), Zung Anxi- rTMS, patients repeated the FCT and VAS, along with meas- ety Inventory, or Eating Disorders Examination (EDE) but ures of temporal discounting and saliva samples. Primary out- did find statistically significant symptom changes associated comes were measured by the VAS and described as “core with olanzapine on a somatic symptom inventory, with trouble AN symptoms”: urges to restrict, levels of feeling full, and concentrating, difficulty sitting still, trouble falling asleep, levels of feeling fat. Results indicated a trend for group and trouble staying asleep being rated as more problematic differences in the effects of rTMS on core AN symptoms in the placebo group than the group receiving olanzapine. (P = 0.056). While notably the effects of TMS are transient in comparison to other therapeutic interventions, initial evidence provides modest support that TMS may allow for symptom Neuromodulation and neuroimaging reduction in patients with AN. Advances in the understanding of the neurocircuitry involved in eating disorders has led to an increased interest in using The more intensive intervention, DBS, has been used in an neuromodulation as a possible treatment, especially for open series of 16 patients with treatment-refractory AN and those with severe illness, including those who may be resist- promising results have been reported . DBS treatment tar- ant to other established treatments . Recent research has geting the subcallosal cingulate cortex was associated with begun to identify neural circuits that are thought to be altered 56,57 improved anxiety, depression, emotion regulation, and BMI among individuals with eating disorders . Specifically, neu - at 12 months post-surgery. Other case reports of DBS for rocognitive and neuroimaging data have implicated circuits 58–61 62,63 AN have described similarly promising results, but control- involved in reward learning , decision making , stress, 64,65 66,67 led studies of this intervention are needed to determine the affect and negative valence , appetite regulation , and 71–73 58,67 impact of this strategy . self-regulatory control . Understanding these circuits and their locations in the brain has been critical for identifying treat- Many of these data come from preliminary studies in the field, ment targets that may be used for treatment development with with mixed results suggesting that the clinical utility of these neuromodulation technologies. interventions has yet to be fully understood. With the advance- ment of neuroimaging data enhancing our knowledge of Current methods for neuromodulation range from relatively the neurobiological underpinnings of psychiatric illnesses, non-invasive modalities like repetitive transcranial magnetic neuromodulatory targets will continue to be explored. stimulation (rTMS) to more intensive/invasive types such as deep brain stimulation (DBS). Conclusion There have been considerable advances in therapies for eat- rTMS has been examined as both a probe to test neurobiologi- ing disorders within the past few years alone. Relying on the cal hypotheses and a possible therapeutic intervention. One 2016 recent transdiagnostic CBT-E model of eating disorders , CBTs case series of five adult women with AN measured changes in continue to show support for patients with BN and BED . visual analogue scales (VAS), EDE-Q scores, and BMI before Empirical data indicate that the model can be formulated to and after 20 sessions of rTMS to the left dorsolateral prefron- fit diagnoses, with promising results . FBT for adolescents 15–22 tal cortex (l-DLPFC) . Results showed overall lower VAS has been studied across a variety of contexts and multiple 14,24,26 scores across levels of stress, anxiety, urges to restrict, and diagnoses with favorable results, underscoring its clini- feelings of fullness post-TMS. There was no notable change cal utility in young patients. Medication trials have led to the in BMI from pre- to post-treatment for the patients, but FDA approval of lisdexamfetamine for the treatment of BED , eating disorder symptomatology (as measured by the EDE-Q) and there is promise for olanzapine as an adjunctive treatment 49–54 improved and persisted up to the 12-month follow-up. for weight gain in AN . Neuroimaging studies have laid the This case study was followed by a larger RCT of 49 patients groundwork for understanding underlying brain mechanisms with AN who were randomized to receive either real or sham that may contribute to the development and perpetuation of rTMS to the l-DLPFC . Patients filled out baseline meas - eating disorders, with neuromodulatory therapies currently 68–70 ures of eating disorder and general psychopathology and being piloted as possible targeted interventions . Further then were asked to complete a food challenge task (FCT), research and development are still needed to refine the which involved watching a video of people eating palat- clinical utility of many treatments, but favorable outcomes able foods with those same foods in the room, before filling out point in the direction of progress toward empirically defined, VAS and receiving the real or sham rTMS treatment. After the effective eating disorder treatments. F1000 recommended References prevalence and mortality rates. Curr Psychiatry Rep. 2012; 14(4): 406–14. 1. Udo T, Grilo CM: Prevalence and Correlates of DSM-5-Defined Eating PubMed Abstract Publisher Full Text Free Full Text | | Disorders in a Nationally Representative Sample of U.S. Adults. Biol Psychiatry. 3. Waller G: Recent advances in psychological therapies for eating disorders 2018; 84(5): 345–354. [version 1; peer review: 2 approved]. F1000Res. 2016; 5: pii: F1000 Faculty Rev-702. 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Frank GK: Altered brain reward circuits in eating disorders: chicken or egg? 73. McClelland J, Bozhilova N, Campbell I, et al.: A systematic review of the effects Curr Psychiatry Rep. 2013; 15(10): 396. of neuromodulation on eating and body weight: evidence from human and PubMed Abstract Publisher Full Text Free Full Text | | animal studies. Eur Eat Disord Rev. 2013; 21(6): 436–55. 60. O'Hara CB, Campbell IC, Schmidt U: A reward-centred model of PubMed Abstract Publisher Full Text Page 8 of 9 F1000Research 2019, 8(F1000 Faculty Rev):1693 Last updated: 26 SEP 2019 Open Peer Review Current Peer Review Status: Editorial Note on the Review Process F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. The reviewers who approved this article are: Version 1 James Lock  Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, USA Competing Interests: No competing interests were disclosed. Anja Hilbert  Department of Medical Psychology and Medical Sociology, Department of Psychosomatic Medicine and Psychotherapy, University of Leipzig Medical Center, Leipzig, Germany Competing Interests: No competing interests were disclosed. The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias You can publish traditional articles, null/negative results, case reports, data notes and more The peer review process is transparent and collaborative Your article is indexed in PubMed after passing peer review Dedicated customer support at every stage For pre-submission enquiries, contact research@f1000.com  Page 9 of 9

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