Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation - a Randomized, Balanced Open-hidden Trial
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 56
- Locations
- 2
- Primary Endpoint
- Discontinuation symptom load over the course of the experimental phase from baseline T0 to primary endpoint T9 - 'Discontinuation Related Signs and Symptoms Scale' (DESS)
Study Overview
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).
Detailed Description
Antidepressant medication is established as an evidence-based, guideline-recommended treatment for Major Depressive Disorders. Following initial response to antidepressant medication and full remission of depressive symptoms, treatment guidelines generally recommend maintenance therapy for several months in order to prevent relapse and subsequent discontinuation of antidepressant medication. German national S3 guidelines for treating Major Depressive Disorders recommend that patients with a single episode remain on maintenance therapy for at least 4 months, while those with recurring episodes and significant functional impairment persist for at least 24 months. In the past decades, prescriptions of antidepressant medication have markedly increased, with a specific upsurge in maintenance prescriptions and consequential long-term intake, despite guideline recommendations to discontinue antidepressant medication.
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. Additionally, discontinuation of antidepressant medication is associated with elevated risks of deterioration of depressive symptoms and recurrence. While S3 guidelines recommend dose-tapering over at least four weeks when stopping antidepressant medication, precise recommendations on how to minimize the risk of recurrence and the potential burden associated with depressive and discontinuation symptoms are lacking. Discontinuation symptoms, deterioration of depressive symptoms, and recurrence can result from pharmacological effects of antidepressant discontinuation and patients' expectations towards discontinuation are likely to play an essential role in occurrence, too.
The present study aims 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.
The trial will consist of a 13-week experimental phase (1 week run-in, 4 weeks of either discontinuation following a pre-specified tapered dose-reduction scheme or continuation of initially prescribed antidepressant medication, 8 weeks monitoring either off antidepressant medication or on initially prescribed antidepressant medication) and a 39-week clinical observation phase. During run-in, all participants will remain on their prescribed antidepressant medication and initial dose, though newly encapsulated to control for tablet appearance effects. All pills for all participants will look identical throughout the whole trial.
During the subsequent 4 weeks, participants within the hidden arms (HD and HC) will be blinded as to whether they are receiving tapered dose-reduction or their initial antidepressant medication. During the following 8-week monitoring phase, participants within the hidden arms will receive double-blind placebo pills (HD) or double-blind antidepressant medication (HC).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Masking Description
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.
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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)
Exclusion Criteria
- •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
- •Upon optional participation: MRI-specific exclusion criteria (phobic anxiety, claustrophobia, ferromagnetic implants, etc.)
Arms & Interventions
Hidden continuation (HC)
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).
Intervention: Treatment 'continuation of antidepressant medication' (Drug)
Hidden continuation (HC)
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).
Intervention: Expectation 'moderate' (Behavioral)
Open discontinuation (OD)
Participants will discontinue their antidepressant medication and will be fully informed about treatment (i.e., high expectation).
Intervention: Treatment 'discontinuation of antidepressant medication' (Drug)
Open discontinuation (OD)
Participants will discontinue their antidepressant medication and will be fully informed about treatment (i.e., high expectation).
Intervention: Expectation 'high' (Behavioral)
Hidden discontinuation (HD)
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).
Intervention: Treatment 'discontinuation of antidepressant medication' (Drug)
Hidden discontinuation (HD)
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).
Intervention: Expectation 'moderate' (Behavioral)
Open continuation (OC)
Participants will remain on their initial antidepressant medication and will be fully informed about treatment (i.e., high expectation).
Intervention: Treatment 'continuation of antidepressant medication' (Drug)
Open continuation (OC)
Participants will remain on their initial antidepressant medication and will be fully informed about treatment (i.e., high expectation).
Intervention: Expectation 'high' (Behavioral)
Outcomes
Primary Outcomes
Discontinuation symptom load over the course of the experimental phase from baseline T0 to primary endpoint T9 - 'Discontinuation Related Signs and Symptoms Scale' (DESS)
Time Frame: 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]
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.
Secondary Outcomes
- 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))
- 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])
- 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)