Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation

NCT05191277 | Active Not Recruiting DMC

• 3 other identifiers: PV7151CRC 289 Project A15U1111-1271-7231
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

Antidepressant medication is established as an evidence-based, guideline-recommended treatment for Major Depressive Disorders. In the past decades, prescriptions of antidepressant medication have markedly increased, with a specific surge in maintenance prescriptions and therefore, long-term intake, despite guideline recommendations to discontinue antidepressant medication after maintenance therapy has been completed. Over half of fully remitted patients who attempt to discontinue their antidepressant medication report adverse discontinuation symptoms. For many patients, discontinuation symptoms are so severe, that they do not manage to complete their discontinuation attempt. While discontinuation symptoms, deterioration of depressive symptoms, and recurrence can result from pharmacological effects of antidepressant discontinuation, patients' expectations towards discontinuation are likely to play an essential role in occurrence, too. The aim of the present study is to explore the interplay of expectations and pharmacological effects in antidepressant discontinuation. Participants who fulfill German national S3 guideline recommendations will receive a 1:1 chance to either discontinue their antidepressant medication or remain on their antidepressant medication. In addition, participants' expectations are intended to be manipulated by varying verbal instructions using the open-hidden paradigm. Within the open trial arms, participants will receive full information about their treatment (i.e., high expectation). Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant medication (i.e., moderate expectation). Participants will have a 1:1:1:1 chance of being allocated to 1 of the 4 experimental groups: open discontinuation (OD), hidden discontinuation (HD), open continuation (OC), or hidden continuation (HC) of their antidepressant medication. This preregistration is part of the collaborative research center (CRC) SFB/TRR289 which aims to characterize the psychological and neurobiological effects of treatment expectations on health outcome (https://treatment-expectation.de) and is funded by the Deutsche Forschungsgemeinschaft (DFG).

Conditions

Depressive Symptoms; Expectations; Antidepressants

Keywords

Antidepressant medication; Discontinuation symptoms; Pharmacological effects; Expectation effects; Nocebo; Open-hidden trial

Outcome Measures

Primary Outcomes (1)

• Discontinuation symptom load over the course of the experimental phase from baseline T0 to primary endpoint T9 - 'Discontinuation Related Signs and Symptoms Scale' (DESS)

  The Discontinuation Related Signs and Symptoms Scale is a self-report questionnaire to assess discontinuation symptoms, incorporating 43 discontinuation symptoms of antidepressants with intensity ratings ranging from 0 (not present) - 3 (severe) each. Total sum score ranges from 0-129 with higher scores indicating more pronounced discontinuation symptoms.

  Measured as area under the curve (AUC) over the following time points: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]

Secondary Outcomes (5)

• Attentional and emotional processing - 'Posner task'

  13 weeks post baseline at primary endpoint (T9)

• Discontinuation symptom load over the course of the trial from baseline T0 to study completion FU3 - 'Discontinuation Related Signs and Symptoms Scale' (DESS)

  Measured as area under the curve (AUC) over the following time points: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]

• Recurrence

  Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]

• Psychophysiological Stress - 'Perceived Stress Scale' (PSS-10)

  At baseline (T0) and 13 weeks post baseline at primary endpoint (T9)

• Anxiety vs. depression - 'State-Trait-Anxiety-Depression-Inventory' (STADI)

  At baseline (T0) and 13 weeks post baseline at primary endpoint (T9); Trait scale measured at baseline only

Other Outcomes (26)

• Treatment expectations - 'Treatment Expectation Questionnaire' (TEX-Q)

  Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]

• Treatment expectations - 'Generic rating scale for treatment expectations' (GEEEexp)

  Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]

• Side effects of antidepressant medication - 'Generic Assessment of Side Effects' (GASE)

  At baseline (T0) and 13 weeks post baseline at primary endpoint (T9)

Study Arms (4)

Open discontinuation (OD)

EXPERIMENTAL

Participants will discontinue their antidepressant medication and will be fully informed about treatment (i.e., high expectation).

Drug: Treatment 'discontinuation of antidepressant medication'; Behavioral: Expectation 'high'

Hidden discontinuation (HD)

EXPERIMENTAL

Participants will discontinue their antidepressant medication, but will be informed about a 50% chance of discontinuing versus remaining on their antidepressant medication (i.e., moderate expectation).

Drug: Treatment 'discontinuation of antidepressant medication'; Behavioral: Expectation 'moderate'

Open continuation (OC)

EXPERIMENTAL

Participants will remain on their initial antidepressant medication and will be fully informed about treatment (i.e., high expectation).

Drug: Treatment 'continuation of antidepressant medication'; Behavioral: Expectation 'high'

Hidden continuation (HC)

EXPERIMENTAL

Participants will remain on their initial antidepressant medication, but will be informed about a 50% chance of discontinuing versus remaining on their antidepressant medication (i.e., moderate expectation).

Drug: Treatment 'continuation of antidepressant medication'; Behavioral: Expectation 'moderate'

Interventions

Treatment 'discontinuation of antidepressant medication' DRUG

Pharmacological intervention: Participants will discontinue their antidepressant medication.

Hidden discontinuation (HD); Open discontinuation (OD)

Treatment 'continuation of antidepressant medication' DRUG

Pharmacological intervention: Participants will remain on their antidepressant medication.

Hidden continuation (HC); Open continuation (OC)

Expectation 'high' BEHAVIORAL

Psychological intervention: Participants' expectations will be manipulated by varying verbal instructions using the open-hidden paradigm. Within the open trial arms, participants will receive full information about their treatment (i.e., high expectation). expectation).

Open continuation (OC); Open discontinuation (OD)

Expectation 'moderate' BEHAVIORAL

Psychological intervention: Participants' expectations will be manipulated by varying verbal instructions using the open-hidden paradigm. Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant medication (i.e., moderate expectation).

Hidden continuation (HC); Hidden discontinuation (HD)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (18 to 75 years) with fully remitted Major Depressive Disorder, single or recurrent, as main diagnosis confirmed by prescribing physician and SCID-5 (American Psychiatric Association, 2013)
• Intake of SSRI/SNRI (citalopram: 20-40mg, escitalopram: 10-20mg, sertraline: 50-150mg, venlafaxine: 75-150mg, duloxetine: 60-100mg, paroxetine: 20-40mg) or NaSSA (mirtazapine: 30-45mg)
• Discontinuation wish by patient supported by prescribing physician
• Fulfils criteria of the German S3 national guideline recommendations for treatment of Major Depressive Disorders to discontinue antidepressant medication: a) response to antidepressant medication, b) symptom remission for at least four months (for a single episode) or two years (for two or more episodes with significant functional impairment) and c) concurrent intake of antidepressant medication (at least 4 weeks on a steady dose)

You may not qualify if:

• Acute or chronic somatic illness and/or intake of medication which might interfere with depressive disorder, antidepressant medication or proposed study
• Acute suicidality, psychotic symptoms, substance abuse or addiction, current mania, or hypomania confirmed by SCID-5 (American Psychiatric Association, 2013) or other psychopathology which might interfere with depressive disorder, antidepressant medication or proposed study
• Any history of bipolar disorder or psychosis confirmed by SCID-5 (American Psychiatric Association, 2013)
• Severe stressful life events (e.g., death of a family member) within six months prior to study participation
• Insufficient German language proficiency
• No informed consent

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead
• Philipps University Marburg: collaborator
• Helmut Schmidt University: collaborator
• University Hospital, Essen: collaborator

Study Sites (1)

University Medical Center Hamburg-Eppendorf

Hamburg, 20251, Germany

Location

Related Publications (1)

• Meissner C, Warren C, Fadai T, Muller A, Zapf A, Lezius S, Ozga AK, Falkenberg I, Kircher T, Nestoriuc Y. Disentangling pharmacological and expectation effects in antidepressant discontinuation among patients with fully remitted major depressive disorder: study protocol of a randomized, open-hidden discontinuation trial. BMC Psychiatry. 2023 Jun 21;23(1):457. doi: 10.1186/s12888-023-04941-3.

  PMID: 37344789 DERIVED

MeSH Terms

Conditions

Depression

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Study Officials

• Yvonne Nestoriuc, Prof. Dr.

  Universitätsklinikum Hamburg-Eppendorf

  PRINCIPAL INVESTIGATOR

• Tilo Kircher, Prof. Dr.

  Philipps University Marburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: In case of assignment to one of the hidden arms, both participants and investigators (i.e. physicians, psychologists, and research assistants) will be blinded to group assignment. Accordingly, in case of assignment to one of the open trial arms, participants and investigators will be aware of group assignment. The primary outcome is a self-report measure assessed via an online-survey by the participants; the outcome assessor (= participant) will therefore only be blinded to group assignment in the hidden arms. The person responsible for randomization and preparation of the medication is not blinded, but has no contact with the study participants.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The PHEA-study is a randomized, balanced open-hidden discontinuation trial with a 2x2-factorial design (treatment: continuation versus discontinuation; expectation: high versus moderate). A stratified block-randomization will be applied, with participants receiving either open discontinuation (OD), hidden discontinuation (HD), open continuation (OC), or hidden continuation (HC) of their antidepressant medication. Participants will have a 1:1:1:1 chance of being allocated to one of the four experimental groups. With an anticipated dropout rate of 20 % our recruitment target is N=196 (n=49 per group). Randomization will be stratified by i) intake duration of antidepressant medication with 24 months as a marker for long-term intake (\<24 months intake vs. ≥ 24 months intake, 3:7); and ii) risk of developing discontinuation symptoms associated with the antidepressant medication (moderate vs. higher or unknown risk, 1:1).

Study Record Dates

• First Submitted: September 17, 2021
• First Posted: January 13, 2022
• Study Start: August 1, 2022
• Primary Completion: February 26, 2025
• Study Completion: November 26, 2025
• Last Updated: April 23, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: upon reasonable request following publication
• Access Criteria: upon reasonable request following publication

Locations

DE (1)