Discontination of Antidepressants in Remitted Depression

ConditionDepression - Major Depressive Disorder

Trial statusNot yet recruiting

Trial phasePhase 4

Trial typeInterventional

Biological sexAll

Age18+

SponsorUniversita di Verona

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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;

Disqualifiers

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);

Trial design

Design model

Parallel

Treatments tested in this trial

Hyperbolic tapering
Drug
The dose will be reduced by 20-25% every 2 weeks.
Linear tapering
Drug
Dose will be reduced by fixed amounts (generally 50% of the minimum effective dose) every 2 weeks.

Treatment groups

150 Participants

are divided into 2 treatment groups

Group A: Linear taperingActive comparator 1 intervention

Group B: Hyperbolic taperingActive comparator 1 intervention

Trial outcomes

Primary outcomes

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).

Time frame

16 weeks

Secondary outcomes

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

Proportion of participants who do not complete antidepressant discontinuation by the end of the predefined tapering schedule, regardless of reason

Time frame

Up to the end of the predefined tapering period

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

Proportion of participants who restart any antidepressant medication for any reason after successful completion of the tapering schedule.

Time frame

Up to 16 weeks after complete antidepressant discontinuation

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

Proportion of participants who deviate from the predefined tapering schedule for any reason.

Time frame

Up to the end of the predefined tapering period

Mean of DESS highest overall scores

A mean of the highest scores reached by each patient on the modified Discontinuation-Emergent Signs and Symptoms Scale (DESS)

Time frame