Discontination of Antidepressants in Remitted Depression

NCT07393919 | Not Yet Recruiting Phase 4

• 2 other identifiers: OSTUZZI_PRIN_PNRR2022_M4C2_INV2023-509377-23
• Study Type: interventional
• Target: 150
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Depression - Major Depressive Disorder

Keywords

depression; antidepressants; clinically remitted depressive disorder; discontinuation of the antidepressant

Outcome Measures

Primary Outcomes (1)

• Proportion of Participants Who Do Not Successfully Discontinue Antidepressant Treatment Within 16 Weeks

  Proportion of participants who fail to successfully discontinue the antidepressant treatment, defined as either: 1. continued use of the antidepressant beyond the predefined tapering schedule (allowing a tolerance period of up to 15% of the total tapering duration), or 2. re-initiation of any antidepressant medication for any reason (e.g., withdrawal symptoms, recurrence of depressive or anxiety symptoms).

  16 weeks

Secondary Outcomes (5)

• Proportion of Participants Who Fail to Discontinue Antidepressant Treatment by the End of the Predefined Tapering Schedule

  Up to the end of the predefined tapering period

• Proportion of Participants Who Re-initiate Antidepressant Treatment Within 16 Weeks After Discontinuation

  Up to 16 weeks after complete antidepressant discontinuation

• Proportion of Participants Non-adherent to the Predefined Antidepressant Tapering Schedule

  Up to the end of the predefined tapering period

• Mean of DESS highest overall scores

  Up to the end of the 16-weeks follow-up period

• Proportion of participants leaving the study early due to any reason without meeting criteria for the primary outcome

  Up to the end of the 16-weeks follow-up period

Other Outcomes (8)

• Proportion of participants requiring "rescue strategies" to address withdrawal symptoms

  Up to the end of the 16-weeks follow-up period

• Time to clinical relapse

  Up to the end of the 16-weeks follow-up period

• Proportion of participants with "withdrawal-associated relapse"

  Up to the end of the 16-weeks follow-up period

Study Arms (2)

Linear tapering

ACTIVE COMPARATOR

Antidepressant (AD) dose will be reduced by fixed amounts (generally 50% of the minimum effective dose) every 2 weeks, according to pre-defined schedules, with the aim of reaching 50% of the minimum effective dose (as defined in the AIFA Summary of Product Characteristics), and finally discontinuing the AD after 4 to 10 weeks (depending on the initial dose). This approach is similar to the tapering schedules commonly used in current clinical practice. Any SSRI, SNRI, tricyclic antidepressant, and vortioxetine will be allowed.

Drug: Linear tapering

Hyperbolic tapering

ACTIVE COMPARATOR

Antidepressant (AD) dose will be reduced by 20-25% every 2 weeks, according to pre-defined schedules adapted from the Maudsley Hospital Guidelines (Taylor, 2021), with the aim of reaching at least 20% of the minimum effective dose (as defined in the AIFA Summary of Product Characteristics), and finally discontinuing the AD after 12 to 20 weeks (depending on the initial dose). Any SSRI, SNRI, tricyclic antidepressant, and vortioxetine will be allowed.

Drug: Hyperbolic tapering

Interventions

Hyperbolic tapering DRUG

The dose will be reduced by 20-25% every 2 weeks.

Hyperbolic tapering

Linear tapering DRUG

Dose will be reduced by fixed amounts (generally 50% of the minimum effective dose) every 2 weeks.

Linear tapering

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

Sponsors & Collaborators

• Universita di Verona: lead
• Azienda Ospedaliera Universitaria Integrata Verona: collaborator
• Centro Ricerche Cliniche di Verona: collaborator

MeSH Terms

Conditions

Depression

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The outcome assessor and the statistician will be blinded to treatment allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator; Assistant Professor; MD; PhD

Model Details: Individuals will be randomized 1:1 to linear or hyperbolic tapering, The sequence of treatments will be randomly permuted in blocks of constant size. The allocation will be stratified by (a) recruiting centre; (b) individuals at high- vs. low-risk of withdrawal symptoms,

Study Record Dates

• First Submitted: January 21, 2026
• First Posted: February 6, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: February 6, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF