Ulrich Voderholzer ^1,2,3* Barbara B. Barton ¹ Matthias Favreau ¹ Eva M. Zisler ^1,2 Winfried Rief ⁴ Marcel Wilhelm ⁴ Elisabeth Schramm ³

• ¹ LMU Munich University Hospital, Munich, Germany
• ² Schoen Clinic Roseneck, Prien am Chiemsee, Germany
• ³ University of Freiburg, Freiburg, Baden-Wurttemberg, Germany
• ⁴ University of Marburg, Marburg, Hesse, Germany

Introduction: Although depressive disorders are frequently associated with relapses, the sustained efficacy of therapies after their termination has been insufficiently investigated.Objective: The aim of this study was to evaluate the current evidence of enduring effects of psychotherapy, antidepressants and their combination after the end of treatment. Methods: PubMed and PsychINFO were systematically screened according to PRISMA guidelines (except for preregistration)) resulting in 17 eligible RCTs with a total of 1154 participants. Only randomized controlled trials (RCTs) between 1980 and 2022 comparing the efficacy of psychotherapy, antidepressants and their combination in adult depression regarding relapse, recurrence or rehospitalization rates at follow-up at least 12 months after termination of therapy, which could be either acute phase, maintenance or relapse prevention therapy, were included. Risk of bias was assessed by using the Cochrane risk of bias tool. Results: ) In total 19 RCTs with a total of 1154 participants were included. In total 19 RCTS were identified.Psychotherapy was significantly superior to pharmacotherapy regarding relapse rates and Beck Depression Inventory scores at follow-up after acute treatment in two of nine RCTs. Combined treatment performed significantly better than pharmacotherapy, but not psychotherapy, regarding relapse and remission in five out of nine RCTs at least 12 months after treatment termination. Pairwise meta-analyses indicated a superiority of combined treatment compared to pharmacotherapy alone regarding relapse, recurrence, and rehospitalization rates (RR=0.60, 95%-CI: 0.37-0.97, p=.041) and for psychotherapy compared to pharmacotherapy alone regarding relapse and recurrence rates (RR=0.58, 95%-CI: 0.38-0.89, p=.023), however comparative treatment effects between psychotherapy and combined treatment were insignificant. Conclusions: Current findings suggest a superiority of psychotherapy and combined treatment over pharmacotherapy alone in major depressive disorder unipolar Formatted: Not Highlight Formatted: English (United States) Formatted: Not Highlight 4 depression. Major limitations were a of this study may be the overall low number of studies reporting follow-up data after termination of study periods and a high variance heterogeneity in definitions of treatment outcomes. Practice guidelines and participatory decision-making processes for the choice of treatment should consider the current knowledge on long-term effects of antidepressant therapy methods more than has been the case to date.