VENLAFAXINE HYDROCHLORIDE for Depressive disorder (in remission)

Inclusion criteria

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

Exclusion criteria

• {"criterion_text":"- comorbid schizophrenia-spectrum disorders, bipolar disorder, or dementia, as formally diagnosed by a psychiatrist, neurologist, geriatrician, or other specialists;\n- current treatment with more than one AD at therapeutic doses;\n- 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;\n- 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);\n- 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);\n- pregnancy or willingness to become pregnant."}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Failure to discontinue defined as continued use beyond the predefined tapering schedule allowing a tolerance period of no more than 15% of total tapering duration; re-starting an AD during the 16 weeks after discontinuation counts as failure."}

Secondary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Defined as continued use beyond the predefined tapering schedule with tolerance ≤15% of taper duration."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Count of participants who resume any antidepressant within 16 weeks post-discontinuation; decision to restart may be by clinician or participant (no pre-defined criteria)."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Proportion not adhering to tapering schedule for any listed reasons (clinical or participant-driven deviations)."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Measured using DESS; clinically relevant withdrawal = ≥1 severe/extremely severe symptom OR ≥2 moderately severe symptoms on modified DESS scale (0–5 scoring)."}
• {"endpoint_text":"- Mean of DESS highest overall scores during the tapering phase and the 16-weeks follow-up period;","definition_or_measurement_approach":"Mean of highest overall DESS scores recorded during tapering and 16-week follow-up."}
• {"endpoint_text":"- 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);","definition_or_measurement_approach":"Clinical relapse defined as PHQ-9 ≥15 or GAD-7 ≥10 during tapering or 16-week follow-up."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Proportion of participants who withdraw or are lost to follow-up for reasons other than primary outcome criteria."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Proportion requiring any predefined rescue strategies for withdrawal (exploratory)."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Time-to-event analysis where event = PHQ-9 ≥15 or GAD-7 ≥10 within 16 weeks."}
• {"endpoint_text":"- 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);","definition_or_measurement_approach":"Time-to-event to relapse up to 36 weeks from randomization using PHQ-9/GAD-7 thresholds."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Proportion meeting relapse thresholds within 4 weeks after a recorded clinically relevant withdrawal episode."}
• {"endpoint_text":"- Exploratory end point: PHQ-9 mean overall score at the end of 16-weeks follow-up period;","definition_or_measurement_approach":"Mean PHQ-9 score at 16-week follow-up."}
• {"endpoint_text":"- Exploratory end point: GAD-7 mean overall score at the end of 16-weeks follow-up period;","definition_or_measurement_approach":"Mean GAD-7 score at 16-week follow-up."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Proportion with suicidal behaviours defined by self-report, PHQ-9 item 9 score ≥2, suicide attempts, or suicide deaths at 16 weeks."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Mean SF-12 Mental Component Summary score at 16 weeks."}
• {"endpoint_text":"- 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;","definition_or_measurement_approach":"Mean SASS score at 16 weeks."}
• {"endpoint_text":"- Exploratory end point: Cost-effectiveness, based on an adapted version of the Client Sociodemographic and Service Receipt Inventory (CSSRI-EU) (Chisholm et al., 2000);","definition_or_measurement_approach":"Cost-effectiveness analysis using adapted CSSRI-EU data."}

Other endpoints

• {"endpoint_text":"- 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;\n- 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;\n- 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);\n- 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;\n- Exploratory end point: PHQ-9 mean overall score at the end of 16-weeks follow-up period;\n- Exploratory end point: GAD-7 mean overall score at the end of 16-weeks follow-up period;\n- 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;\n- 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;\n- 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;\n- Exploratory end point: Cost-effectiveness, based on an adapted version of the Client Sociodemographic and Service Receipt Inventory (CSSRI-EU) (Chisholm et al., 2000);","definition_or_measurement_approach":"Exploratory endpoints measured as described: rescue strategy counts, time-to-relapse using PHQ-9/GAD-7 thresholds, DESS-derived withdrawal measures, PRO instrument scores (PHQ-9, GAD-7, SF-12, SASS), and economic data via CSSRI-EU."}

Methods

• Recruitment at participating clinical sites (psychiatry/mental health departments at listed Italian hospitals and university centres).
• Recruitment materials (leaflet/poster) referenced: K2/K1 recruitment documents (titles: 'K2 Recruitment material leaflet DISCARD_redacted', 'K2 Recruitment material poster DISCARD_09_09_24_redacted').
• Letter to general practitioners (document: 'L2_Lettera MMG DISCARD_redacted') referenced as part of recruitment approach.
• Subject information and informed consent forms available (documents 'L1_SIS and ICF DISCARD_redacted' and related materials) for prospective participants.

Italy

Earliest CTIS Part Ii Submission Date

06-09-2024

Latest Decision Or Authorization Date

20-02-2026

Processing Time Days

532

Number Of Sites

5

Number Of Participants

150

Primary sponsor

Full Name

Universita Degli Studi Di Verona

Organisation Type

Educational Institution

Country Of Registered Address

Italy