Journal Article

Safe discontinuation of antidepressants in individuals with clinically remitted depressive disorders: study protocol for a randomised controlled trial

Barbui, Corrado, Ostuzzi, Giovanni, Gastaldon, Chiara, Tedeschi, Federico, de Filippis, Renato, D’Agostino, Armando, Novara, Caterina, Bartoli, Francesco, Amaddeo, Francesco, Zaccoletti, Debora, Riboldi, Ilaria, Carrà, Giuseppe, Gottardi, Carolina, Papola, Davide, Belnome, Giulia, De Fazio, Pasquale, Cavallotti, Simone, Cristea, Ioana

2026

Overview

IntroductionAntidepressant overprescribing and unnecessary long-term use are common and can increase the risk of adverse effects and withdrawal symptoms on discontinuation. Although gradual tapering strategies have been proposed, empirical evidence from randomised trials is lacking. This study will compare the efficacy of two antidepressant discontinuation strategies—linear and hyperbolic tapering—in adults with remitted depressive disorders.Methods and analysisThis pragmatic, multicentre, open-label, parallel-group superiority randomised controlled trial will recruit adults (≥18 years) with remitted depressive disorders who have been taking an antidepressant for at least 6 months. During an 8-month recruitment period, participants in outpatient psychiatric and primary care settings will be randomised (1:1) to (a) linear tapering (dose reduced by 50% of the minimum effective dose every 2 weeks until cessation) or (b) hyperbolic tapering (dose reduced by 20–25% every 2 weeks until cessation). The primary outcome is the proportion of participants who fail to discontinue the antidepressant by the end of the predefined tapering schedule or who re-initiate antidepressant therapy within 16 weeks of discontinuation. Secondary outcomes include safety, tolerability (including withdrawal symptoms), acceptability, clinical effectiveness, social functioning, quality of life and cost-effectiveness. Recruiters and participants will be aware of their treatment allocation; however, outcome assessors and the biostatistician will remain blinded throughout follow-up. Validated rating scales measuring depression, anxiety, withdrawal symptoms and social functioning will be administered at baseline and at scheduled follow-up visits up to 36 weeks. Based on observational data, we aim to recruit 150 participants (75 per arm).Ethics and disseminationThe study was approved by institutional Ethics Committees and regulatory authorities. Written informed consent will be obtained from all participants and data processed in accordance with General Data Protection Regulation. Study insurance and pharmacovigilance procedures are in place. Findings will be published in open-access journals, presented at scientific meetings and communicated to policy and regulatory stakeholders.Trial registrationNCT07393919.

• Publisher: British Medical Journal Publishing Group,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adult / Adult psychiatry / Antidepressants / Antidepressive Agents - administration & dosage / Antidepressive Agents - adverse effects / Antidepressive Agents - therapeutic use / Anxiety disorders / Clinical medicine / Depression & mood disorders / Depressive Disorder - drug therapy / Drug Tapering - methods / Equivalence Trials as Topic / Female / Humans / Male / Mental depression / Mental Health / Meta-analysis / Multicenter Studies as Topic / Patients / Pragmatic Clinical Trials as Topic / Primary Health Care / Protocol / Quality of Life / Questionnaires / Randomized Controlled Trial / Substance Withdrawal Syndrome / Treatment Interruption