BACKGROUND: Anorexia nervosa (AN) is a severe eating disorder. With a lifetime prevalence of 1.4% in women and 0.2% in men, an increasing incidence and the highest mortality rate of all mental disorders, it is recognized as a major public health threat. Although the number of available treatments is increasing worldwide, the comparative efficacy and safety of different treatment options have not been investigated systematically. In this systematic review with network meta-analysis (NMA), we aim to assess the efficacy and safety of pharmacological and non-pharmacological interventions in adolescents and adults with AN.

METHODS: We will consider randomized controlled trials investigating pharmacological (e.g., antidepressants) and non-pharmacological (e.g., cognitive behavioral therapy) interventions compared to each other and to relevant control groups (e.g., no treatment, treatment as usual, waiting list) in adolescents (≥ 10 years) and/or adults (≥ 18 years) with AN. Eligible outcomes will include physiological (e.g., body weight) and psychological (e.g., depressive symptoms) outcomes prioritized by various interest-holders, including patients and healthcare professionals. Six electronic databases will be searched (Ovid MEDLINE, Scopus, WHO Global Index Medicus, Cochrane Central Register of Controlled Trials, Science Citation Index Expanded [Web of Science], Ovid APA PsycINFO). We will additionally search for grey literature and unpublished trials in further sources. Study selection, data extraction and the risk of bias assessment (Cochrane RoB 2 tool), will be performed independently by two reviewers. We will synthesize the data using a random-effects network meta-analysis and component network meta-analysis, if appropriate. We will assess inconsistency using a random-effects design-by-treatment interaction model. As effect measures, the risk ratio will be used for dichotomous outcomes, while the (standardized) mean difference will be utilized for continuous outcomes. Subgroup analyses, sensitivity analyses, and an assessment of publication bias are planned. The certainty of evidence derived from NMA will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

DISCUSSION: Our NMA will provide important findings on the efficacy and safety of (non-)pharmacological interventions, offering valuable insights to inform clinical guidelines for the treatment of AN. The findings will inform various interest-holders including patients, their families, and clinical decision-makers.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2025 CRD420250654515.