"Safe Discontinuation of Antidepressants in Individuals with Clinically Remitted Depressive Disorders"

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universita Degli Studi Di Verona

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

13 Feb 2026 → ongoing

Decision date (initial)

2024-10-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

The DISCARD study will compare hyperbolic with linear tapering in adults with currently remitted depression. The primary outcome will be the proportion of participants who fail to discontinue the AD by the end of the pre-defined schedule (with a tolerance period of no more than 15% of the total duration of the tapering phase) or re-initiate the AD during the 16 weeks after its discontinuation.

Secondary objectives 1

1. The DISCARD study aims at comparing hyperbolic and linear tapering to detect possible differences in terms of the proportion of individuals who are not able to discontinue the AD by the end of the predefined tapering schedule and the proportion of participants re-starting the AD in the 16 weeks after its discontinuation. Additionally, we will assess the proportion of participants who cannot fully adhere to the tapering schedule: the proportion of those experiencing clinically relevant withdrawal symptoms; the mean of DESS overall score throughout the tapering and the follow-up; the proportion of those experiencing clinical relapse; and the proportion of those leaving the study early due to any reason.

Conditions and MedDRA coding

Patients with currently remitted depressive disorders.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 18 years old or above;
2. diagnosed with a depressive disorder, single episode (ICD-11, 6A70) or recurrent (ICD-11, 6A71);
3. currently taking a selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), or vortioxetine for the treatment of depression;
4. the current AD has been taken for at least 6 months;
5. the current AD has been on a stable dose over the last 2 months;
6. a score ≤9 on the PHQ-9 and ≤5 on the GAD-7 at study enrolment;
7. DSM-5-TR criteria for a depressive episode are not met at the time of recruitment;
8. no clinical evidence of moderate-to-severe symptoms in the last 6 months, as assessed by the recruiting clinician;
9. discontinuing the AD is clinically indicated by the recruiting clinician, and agreed to by the participant in a shared decision-making process;
10. uncertainty about which discontinuation strategy would be best for the participant;
11. the participant is willing to sign the informed consent to participate to the study.

Exclusion criteria 6

1. comorbid schizophrenia-spectrum disorders, bipolar disorder, or dementia, as formally diagnosed by a psychiatrist, neurologist, geriatrician, or other specialists;
2. current treatment with more than one AD at therapeutic doses;
3. ccurrent treatment with ADs of other classes (e.g., mirtazapine, agomelatine, bupropion, for which the evidence on the risk of withdrawal is unclear) (Taylor, 2021), alone or in combination with other ADs;
4. 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);
5. 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);
6. pregnancy or willingness to become pregnant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of participants who fail to discontinue the AD or re-start an AD during the 16 weeks after its discontinuation. Failure to discontinue the AD is defined as continued use of the medication beyond the predefined tapering schedule, allowing for a tolerance period of no more than 15% of the total tapering duration. This failure may occur for any reason, such as the onset of withdrawal symptoms or the recurrence of depressive or anxiety symptoms.

Secondary endpoints 17

1. Proportion of participants who fail to discontinue the AD by the end of the pre-defined schedule (with a tolerance period of no more than 15% of the total duration of the tapering phase)
2. Proportion of participants who re-start an AD for any reason during the 16 weeks after its discontinuation. No pre-defined criteria for re-starting the AD will be employed. As occurs in realworld practice, the decision to re-start the AD can be taken by the recruiting psychiatrist, another practitioner not involved in the study, or independently by the participant;
3. Proportion of participants failing to adhere to the pre-defined tapering schedule for any reason, including: new medical condition or treatment no longer compatible with the discontinuation strategy; new psychiatric condition or treatment no longer compatible with the discontinuation strategy; the participant discontinues the AD more quickly than the schedule; the participant resumes the previous AD dose and abandon the tapering schedule for reasons other than withdrawal symptoms or relapse.
4. Proportion of participants experiencing “clinically relevant withdrawal symptoms” throughout the discontinuation and the 16-weeks follow-up period, defined as having at least one severe/extremely severe symptom or at least two moderately severe symptoms on the Discontinuation-Emergent Signs and Symptoms Scale (DESS) (Lewis et al., 2021), modified in order to assess the severity of each symptom as follows: 0=not present, 1=minimal, 2=mild, 3=moderate, 4=severe, 5=extremely severe;
5. Mean of DESS highest overall scores during the tapering phase and the 16-weeks follow-up period;
6. Proportion of participants experiencing clinical relapse throughout the discontinuation and the 16- weeks follow-up period, defined as having at least moderately severe depression or anxiety symptoms, namely a score ≥15 on the PHQ-9 or ≥10 on the GAD-7 (Kroenke et al., 2016);
7. Proportion of participants leaving the study early due to any reason without meeting criteria for the primary outcome. This includes people who do not attend follow-up visits and cannot be contacted, people who refuse to be involved in follow-up assessments, or people who die during the tapering or the follow-up for reasons unrelated to withdrawal symptoms or relapse.
8. Exploratory end point: Proportion of participants requiring one or more “rescue strategies” to address withdrawal symptoms during the tapering phase and the 16-weeks follow-up period;
9. Exploratory end point: Time to clinical relapse (defined as having at least moderately severe depression or anxiety symptoms, namely a score ≥15 on the PHQ-9 or ≥10 on the GAD-7) at the end of the 16-weeks follow-up period;
10. Exploratory end point: Time to clinical relapse (defined as having at least moderately severe depression or anxiety symptoms, namely a score ≥15 on the PHQ-9 or ≥10 on the GAD-7) at the end of the follow-up period (36 weeks from randomization);
11. Exploratory end point: Proportion of participants experiencing “withdrawal-associated relapse”, defined as having a score ≥15 on the PHQ-9 or ≥10 on the GAD-7 within 4 weeks after the participant experienced “clinically relevant” withdrawal symptoms during the tapering phase and the 16-weeks follow-up period;
12. Exploratory end point: PHQ-9 mean overall score at the end of 16-weeks follow-up period;
13. Exploratory end point: GAD-7 mean overall score at the end of 16-weeks follow-up period;
14. Exploratory end point: Proportion of participants with suicidal behaviours (including suicidal ideation, as reported by the participant, or according to a score ≥2 on the item 9 of the PHQ-9, suicide attempt, and deaths by suicide) at the end of 16-weeks follow-up period;
15. Exploraotry end point: Short Form 12 Health Survey (SF-12) (Gandek et al., 1998) mean score on the Mental Component Summary at the end of the 16-weeks follow-up period;
16. Exploratory end point: Social Adaptation Self-evaluation Scale (SASS) (Bosc et al., 1997) mean score at the end of the 16-weeks follow-up period;
17. Exploratory end point: Cost-effectiveness, based on an adapted version of the Client Sociodemographic and Service Receipt Inventory (CSSRI-EU) (Chisholm et al., 2000);

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universita Degli Studi Di Verona

Sponsor organisation

Universita Degli Studi Di Verona

Address

Piazzale Ludovico Antonio Scuro 10

City

Verona

Postcode

37134

Country

Italy

Scientific contact point

Organisation

Universita Degli Studi Di Verona

Contact name

Giovanni Ostuzzi

Public contact point

Organisation

Universita Degli Studi Di Verona

Contact name

Giovanni Ostuzzi

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 25 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications