*J. Clin. Med.* **2019**, *8* , 153

#### 3.2.3. Nutritional Management

For adults: The WFSBP guideline [47] suggests that nasogastric feeding is effective for malnourished patients, however, does not address risks associated with refeeding, or provide any specific nutritional or weight gain recommendations. All remaining guidelines, (excluding the Danish guideline [40]), recommend nasogastric feeding for severely malnourished patients, when oral feeding is not an option [14,38,39,41,43,44,46,48]. These guidelines address the risk of refeeding syndrome, recommending that treatment is administered by experienced staff. The APA guideline [43] recommends nasogastric feeding over parenteral feeding, and the British guideline [38] explicitly recommends against parenteral nutrition. The German guideline also discusses the use of percutaneous endoscopic gastronomy feeding as a potential alternative, when patients will not tolerate nasogastric feeding [14]. The Danish guideline does not provide any recommendations regarding refeeding, nutritional intake or weight restoration.

In the original German guideline [15], an initial food intake of approximately 30 to 40 kcal/kg per day was recommended for highly underweight patients (see Table 1), which, upon revision, was considered too strict. The revised German guideline [14], as well as the Danish [40], French [44] and WFSBP guidelines [47], do not give specific recommendations regarding energy intake during refeeding. Both the British [38] and MARSIPAN guidelines [48] recommend commencing refeeding at 5 to 10 kcal/kg/day for severely underweight patients, and gradually increasing to 20 kcal/kg/day within 2 days. The British Columbia guideline [46] also recommends beginning refeeding at 5 to 10 kcal/kg/day if severity factors (e.g., nasogastric feeding) are involved. In the absence of severity factors, intake of 20 to 25 kcal/kg/day is recommended, and intake should not exceed 70 to 80 kcal/kg/day. The Spanish guideline [45] recommends a slightly higher caloric intake of 25 to 30 kcal/kg/day for severely malnourished patients, and they also provide a recommended upper limit of 1000 kcal/day. The APA guideline [43] recommends initiating refeeding at 30 to 40 kcal/kg/day, and also suggests that males may require a significantly higher energy intake to gain weight. The Dutch guideline has an even higher recommended refeeding starting point of 40 to 60 kcal/kg/day for severely underweight patients [39]. The Australian and New Zealand guideline [41] does not provide a recommended nutritional intake based on weight, but instead recommends a specific starting intake of 1433 kcal/day, with increases of 478kcal every 2 to 3 days.

Several guidelines also provide recommendations regarding appropriate weekly weight gain goals in inpatient and outpatient settings. Five guidelines recommend a minimum weight gain of 0.5 kg/week in an inpatient setting; the German [14], French [44] and Spanish guidelines [45] recommend weight gain ranging between 0.5 and 1 kg/week, the Australian and New Zealand guideline [41] recommends weight gain between 0.5 and 1.4 kg/week, and the Dutch guideline suggests weight gain ranging between 0.5 and 1.5 kg/week [39]. In contrast, the British Columbia guideline [46] suggests a higher minimum weight gain ranging from 0.8 to 1.4 kg/week, and the APA guideline [43] suggests a minimum weight gain ranging from 0.9 to 1.4 kg/week. The remaining guidelines [38,40,47,48] do not provide specific weight gain recommendations. Only four of the guidelines provide recommendations regarding weight gain per week in an outpatient setting. The French guideline recommends a weight gain of 0.25 kg/week, while the German, APA guidelines and Dutch recommend a weekly gain of between 0.2 to 0.5 kg [39].

For children and adolescents: The British guideline for the management of severely ill young people with AN (Junior MARSIPAN) [48,50] advocates to commence refeeding at about 40 kcal/kg/day and increase the meal plan by 200 kcal/day, while the others do not explicitly give calorie specifications for children and adolescents. Almost all guidelines recommend nasogastric tube feeding, if a meal plan and supplement drink tops are not managed [14,41,43,45,50].

The French, Danish and German guidelines emphasise the necessity of achieving a target weight at which menstruation can reoccur [14,40,44]. While the French guideline does not give any threshold criteria, the German guideline defines the 25th age-adapted BMI-percentile (with the 10th percentile as a minimum) in contrast to the Danish guideline with the 50th weight-for height percentile as target weight.

Supplementary nutritional counselling is advised by the British, Spanish and German guidelines for children and adolescents and their carers to help young people meet their dietary needs for pubertal development and growth [14,38,45]. According to these guidelines, growth and pubertal development should be regularly monitored in this age group.

#### 3.2.4. Psychopharmacology

For adults: Use of pharmacotherapy is addressed in all treatment guidelines excluding the Danish guideline [40]. All of these guidelines emphasise the lack of evidence surrounding medication use for AN, and most guidelines emphasise that caution must be taken when administering medication, due to the physical complications associated with AN (e.g., cardiac problems). The Spanish [45], APA [43] and British guidelines [38] explicitly state that medication should not be used as the sole treatment. The British guideline also states that there is no proven benefit of combined treatment over psychotherapy alone in treating patients without comorbidities. All guidelines excluding the MARSIPAN [48], Danish and British guidelines give cautious recommendations for the use of antipsychotic medications. The French guideline [44] provides a cautionary recommendation, without addressing specific medications or effects. The remaining guidelines all make specific reference to the antipsychotic olanzapine; the German [14], WFSBP [47], Dutch [39], Australian and New Zealand [41], and APA guidelines recommended it to assist with anxious and obsessional thoughts, the WFSBP and Spanish guidelines suggest that it may be useful for improving general psychological symptoms, and the British Columbian [46], Spanish and APA guideline cautiously recommended it for improvements in weight gain. In contrast, the German guideline recommends against the use of antipsychotics for weight gain. The German guideline states there is no conclusive evidence to recommend the use of antidepressants for the core symptoms of AN, and the Dutch guideline also explicitly recommends against the use of selective serotonin reuptake inhibitors (SSRIs) [39]. In contrast, antidepressants are cautiously recommended by the French, WFSBP and APA guidelines, to assist with co-occurring symptoms of depression, obsessive–compulsive or anxiety disorder. Specifically, the APA guideline discusses the advantages of using selective serotonin reuptake inhibitors in combination with psychotherapy to address persistent depressive or anxiety symptoms, but recommends against the use of monoamine oxidase inhibitors and bupropion, due to adverse reactions and health risks. The APA guideline cautiously recommends the use of pro-motility agents for use against bloating, and use of antianxiety agents before eating for some patients. Similarly, the MARSIPAN guideline [48] discusses the use of benzodiazepines for particularly anxious patients. The WFSBP and APA guidelines discuss potential weight gain benefits of taking zinc supplements, while the German guideline suggests restricting zinc supplementation to cases with proven zinc deficiency.

For children and adolescents: With the exception of hormone replacement therapy the German and most other international guidelines do not give any specific recommendations for this age group. The Junior MARSIPAN guideline concludes that it 'may be necessary to prescribe regular sedative antipsychotic medication, such as olanzapine', if the patients are extremely agitated and resist refeeding [48]. It also gives clear recommendations for ECG monitoring if antipsychotics are applied. Hormone replacement therapy: In several guidelines including the German guideline the prescription of an oral contraceptive is not recommended [38,41,43]. The British guideline suggests considering a bone mineral density scan after one year of underweight in children and adolescents. Moreover—in correspondence to the German guideline—the British guideline suggests to consider transdermal estrogen replacement in combination with cyclic progesterone application in girls with a bone age over 15 years and long-term underweight as well as incremental physiological doses of estrogen in those below 15 years [14,38]. Similar indications are mentioned in the APA and the Australian and New Zealand guidelines [41,43].

#### **4. Discussion**

This review provides an overview of the newly revised and published German S3-guideline for eating disorders [14]. In particular, it highlights the changes in recommendations regarding the treatment of AN since the publication of the original guideline in 2011 [15]. In summary, family-based therapy approaches are recommended for adolescents, whereas individual approaches are suggested for adults. There is no evidence indicating the superiority of one specialised approach over another. In more intensive settings, as well as in adolescents, higher weight gains can be expected. To date, there is no convincing evidence for the positive effect of pharmacotherapy regarding the core symptoms of AN.

The revised German guideline is currently the most recent eating disorder treatment guideline internationally. Recommendations are, therefore, based on the most up to date research findings and evidence available. The development of this guideline involved a rigorous process, including a comprehensive literature review and analysis, and consultation and contribution by many experts in the eating disorder field. The findings of the literature review and network analysis are also available in English [18].

The German guideline also includes an easily comprehensible guide for sufferers with eating disorders and their relatives [17], which has been developed with the help of patient representatives. The German guideline, hereby, stresses the necessity of providing information and support to significant others, who often bear a high emotional burden, but also play an important role in helping patients to overcome the eating disorder. The guideline has been published in two different formats—as a scientific book (only the original version so far) and on the website of the Association of the Scientific Medical Societies in Germany (AWMF, awmf.org [14]), where it is freely available.

Similar to the Dutch guideline, the original version of the German guideline has been published in German only, which limits its distribution and implementation to Germany, Austria and Switzerland. An English translation of the revised version, which is currently in preparation, is, therefore, an invaluable step towards increasing the utility of this guideline.

The review also explores the similarities and differences between the German guideline and other existing international guidelines. There is significant homogeneity among the international guidelines in the recommendations derived from the existing evidence. All agree that there is no superior treatment for AN, if specialised approaches are compared. There are, however, some inconsistencies regarding aspects, such as medication and nutritional management. Most guidelines implemented a thorough methodology. We think there is a need for European research initiatives which aim to enhance the evidence base and clinical guidance regarding AN across the different participating countries. Recommendations must, however, take into account the specificities of the national health care systems.

Overall, evidence for treatment of AN has increased, yet even in the latest German guideline, many of the recommendations are still based on expert opinion. Guidelines do not only mirror the current state of research but also point out gaps that need to be bridged. There is still a need for more research in the field of eating disorders, particularly in AN. In view of the so-called 'research-practice gap', it needs to be mentioned that guidelines are not designed to propagate conformist standard therapy, or to restrict clinicians' individual willingness to learn and innovate. They should not be seen as directives, but as advice.

## **5. Conclusions**

The German S3-guideline is, at present, the most recently revised evidence-based treatment guideline for AN. Based on newly available evidence, several amendments have been made regarding treatment recommendations, since the original guideline publication in 2011. Overall, the recommendations provided in the German guideline are fairly consistent with those provided in other international evidence-based eating disorder guidelines. Adult and adolescent patients should be distinguished in terms of treatment response and the most suitable treatment approach. Although the

existing guidelines provide a sound base of information, which can be used by healthcare professionals to guide diagnosis and treatment decisions, further research regarding the treatment of AN is still urgently needed.

**Author Contributions:** Conceptualisation, G.R. and A.Z.; methodology, A.Z.; investigation, G.R.; writing—original draft preparation, G.R., S.H., B.H.-D. and A.Z.; writing–review and editing, G.R.

**Funding:** The S3-guideline was funded by the Christina Barz-Stiftung in the Association of German Academic Foundations.

**Acknowledgments:** The support of the publication fund of the University Hospital Tuebingen was greatly appreciated. We would also like to thank all contributors to the German S3-guideline and the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). The authors would like to thank Brigid Kennedy for her help in preparing this manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
