Discontination of Antidepressants in Remitted Depression

Starting soon · Phase 4

Conditions studied: Depression - Major Depressive Disorder

In brief

Overprescribing and long-term use of antidepressants (ADs) are common and may increase the risk of adverse effects and withdrawal symptoms when discontinuation is attempted. Although several discontinuation strategies have been proposed, empirical evidence comparing different tapering approaches is limited. In particular, hyperbolic tapering has been suggested as a potentially safer and more effective alternative to standard linear tapering, but no randomized trials have directly compared these strategies. This study is a pragmatic, multicentre, open-label, parallel-group, superiority randomized trial designed to compare two antidepressant discontinuation strategies-linear tapering and hyperbolic tapering-in adults with remitted depressive disorders. Eligible participants are adults aged 18 years or older with currently remitted depressive disorders who have been taking antidepressants for at least six months and are considered clinically appropriate candidates for discontinuation. Participants will be recruited in outpatient psychiatric settings, with the involvement of general practitioners and other medical specialists. After baseline assessment, participants will be randomized to either a linear tapering strategy, consisting of dose reductions of 50% of the minimal effective dose every two weeks until discontinuation, or a hyperbolic tapering strategy, consisting of proportional dose reductions of approximately 20-25% every two weeks until discontinuation. Follow-up assessments will be conducted regularly over a 36-week period. The primary outcome is the proportion of participants who fail to discontinue the antidepressant within the predefined tapering schedule (allowing a limited tolerance period) or who re-initiate antidepressant treatment during the 16 weeks following discontinuation. Secondary outcomes include measures of safety, tolerability, acceptability, clinical effectiveness, and cost-effectiveness, as well as withdrawal symptoms, relapse of depressive or anxiety symptoms, and adherence to the tapering schedule. Participants and recruiting clinicians will not be blinded to treatment allocation, while outcome assessors and the biostatistician will remain blinded until completion of the study to minimize detection bias. The study aims to provide pragmatic evidence to inform clinical practice and guideline development regarding optimal strategies for antidepressant discontinuation.

Key facts

Study ID

NCT07393919

Run by

Universita di Verona

People needed

150

Starts

2026-02-01

Expected to finish

2027-09-30

Last updated by the study team

2026-02-06

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• 18 years old or above;
• diagnosed with a depressive disorder, single episode (ICD-11, 6A70) or recurrent (ICD-11, 6A71);
• currently taking a selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), or vortioxetine for the treatment of depression;
• the current AD has been taken for at least 6 months;
• the current AD has been on a stable dose over the last 2 months;
• a score ≤9 on the PHQ-9 and ≤5 on the GAD-7 at study enrolment;
• DSM-5-TR criteria for a depressive episode are not met at the time of recruitment;
• no clinical evidence of moderate-to-severe symptoms in the last 6 months, as assessed by the recruiting clinician;
• discontinuing the AD is clinically indicated by the recruiting clinician, and agreed to by the participant in a shared decision-making process;
• uncertainty about which discontinuation strategy would be best for the participant;
• the participant is willing to sign the informed consent to participate to the study.

You may not qualify if…

• comorbid schizophrenia-spectrum disorders, bipolar disorder, or dementia, as formally diagnosed by a psychiatrist, neurologist, geriatrician, or other specialists;
• current treatment with more than one AD at therapeutic doses;
• current treatment with ADs of other classes (e.g., mirtazapine, agomelatine, bupropion, for which the evidence on the risk of withdrawal is unclear), alone or in combination with other ADs;
• conditions or medications that contraindicate the use of any AD according to the Summary of Product Characteristics of included ADs (synthetically reported in Table 1) (e.g., current symptoms of mania);
• current treatment with benzodiazepines above the dose of 2.5 mg equivalents of lorazepam per day (corresponding to clonazepam 1.2 mg/day; alprazolam 1.2 mg/day; diazepam 19 mg/day);
• pregnancy or willingness to become pregnant.

Full record on ClinicalTrials.gov

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