Clinical trial NCT05191277: Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation
Official title: Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation - a Randomized, Balanced Open-hidden Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Depressive Symptoms
Expectations
Antidepressants
Keywords: Antidepressant medication
Discontinuation symptoms
Pharmacological effects
Expectation effects
Nocebo
Open-hidden trial
Lead sponsor: Universitätsklinikum Hamburg-Eppendorf
Sponsor class: OTHER
Collaborators: name: Philipps University Marburg
name: Helmut Schmidt University
name: University Hospital, Essen
First posted: 2022-01-13
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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).
Primary purpose: BASIC_SCIENCE

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).

Participants within the open trial arms will either be aware of discontinuing their antidepressant medication during the first 4 weeks following run-in, followed by 8 weeks of receiving open-label placebo pills (OD), or will be aware of remaining on their antidepressant medication (OC) during the entire experimental phase, respectively. At 13-weeks post-baseline, the experimental phase will conclude with the primary outcome measure and patients will be debriefed.

Detailed hypotheses are:

Interaction effect of treatment and treatment expectation: Treatment (continuation vs. discontinuation of antidepressant medication) and treatment expectation (high vs. moderate) interact in modulating discontinuation symptom load among remitted MDD patients over the course of the experimental phase.

Post-hoc comparison on the nocebo-determined effect of expectation: Remitted MDD patients who remain on their antidepressant medication will show a higher discontinuation symptom load with moderate than with high expectation.

Post-hoc comparison on the pharmacological effect of treatment: Remitted MDD patients with moderate treatment expectation will show a higher discontinuation symptom load if antidepressant medication is discontinued versus if antidepressant medication is continued.

Post-hoc comparison on the effect of treatment expectation: Remitted MDD patients who discontinue their antidepressant medication will show a higher discontinuation symptom load with high than with moderate treatment expectation.

Modulating effects of further psychological, physiological, and medical factors on the relationship between treatment expectation and discontinuation symptom load: The relationship between treatment expectation and discontinuation symptom load will vary according to stress ratings, prior side effects of antidepressant medication, prior discontinuation experience, personality traits, sensory amplification and illness framwork.

Eligibility criteria: 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.)

Primary outcomes:
measure: Discontinuation symptom load over the course of the experimental phase from baseline T0 to primary endpoint T9 - 'Discontinuation Related Signs and Symptoms Scale' (DESS)
timeFrame: 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:
measure: Attentional and emotional processing - 'Posner task'
timeFrame: 13 weeks post baseline at primary endpoint (T9)
measure: Discontinuation symptom load over the course of the trial from baseline T0 to study completion FU3 - 'Discontinuation Related Signs and Symptoms Scale' (DESS)
timeFrame: 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]
measure: Recurrence
timeFrame: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Psychophysiological Stress - 'Perceived Stress Scale' (PSS-10)
timeFrame: At baseline (T0) and 13 weeks post baseline at primary endpoint (T9)
measure: Anxiety vs. depression - 'State-Trait-Anxiety-Depression-Inventory' (STADI)
timeFrame: At baseline (T0) and 13 weeks post baseline at primary endpoint (T9); Trait scale measured at baseline only
Other outcomes:
measure: Treatment expectations - 'Treatment Expectation Questionnaire' (TEX-Q)
timeFrame: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]
measure: Treatment expectations - 'Generic rating scale for treatment expectations' (GEEEexp)
timeFrame: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Side effects of antidepressant medication - 'Generic Assessment of Side Effects' (GASE)
timeFrame: At baseline (T0) and 13 weeks post baseline at primary endpoint (T9)
measure: Pre-experiences with antidepressant discontinuation - 'Generic rating scale for previous treatment experiences' (GEEEpre)
timeFrame: At baseline (T0)
measure: Blood serum level of antidepressant medication
timeFrame: Exactly 7 days after baseline (T1) and at 13 weeks post baseline at primary endpoint (T9)
measure: Common biological stress markers
timeFrame: 1 week between screening and baseline
measure: Personality traits - 'Brief Big Five Inventory' (BFI 10)
timeFrame: At baseline (T0)
measure: Behavioral Inhibition/Behavioral Approach (motivational systems) - 'Behavioral Inhibition/Behavioral Approach System' Scale (BIS/BAS)
timeFrame: At baseline (T0)
measure: Somatosensory amplification - 'Somatosensory Amplification Scale' (SSAS)
timeFrame: At baseline (T0)
measure: Psychopathology - 'Structured Clinical Interview for DSM-5, Clinician Version' (SCID-5-CV)
timeFrame: At screening
measure: Mental well-being - 'Short Warwick-Edinburgh Mental Wellbeing Scale' (SWEMWBS)
timeFrame: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Depression and anxiety - 'Patient-Healthcare-Questionnaire' (PHQ-4)
timeFrame: During follow-up [9 months]
measure: Subjective impairment - adaptation of 'Pain Disability Index' (PDI)
timeFrame: At baseline (T0), one week post baseline (T1), five weeks post baseline (T5), and 13 weeks post baseline at primary endpoint (T9)
measure: Substance Use
timeFrame: One week post baseline (T1), five weeks post baseline (T5), nine weeks post baseline (T7), and 13 weeks post baseline at primary endpoint (T9)
measure: Warmth & Competence
timeFrame: At baseline (T0), five week post baseline (T5), and 13 weeks post baseline at primary endpoint (T9)
measure: Adverse events
timeFrame: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Suspicions about treatment - 'Generic rating scale for treatment experiences - end' (GEEEend)
timeFrame: 13 weeks post baseline at primary endpoint (T9)
measure: Illness rationale of Major Depressive Disorder:
timeFrame: At baseline (T0)
measure: Current treatment effects - 'Generic rating scale for treatment effects' (GEEEact)
timeFrame: Weekly after run-in and during (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Self-reported depressive symptoms - 'Beck Depression Inventory II' (BDI-II)
timeFrame: Screening; weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Expert-rated depression severity scores - 'Montgomery-Åsberg Depression Rating Scale' (MADRS)
timeFrame: Screening; weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Adherence
timeFrame: Weekly during run-in and (dis-)continuation phase [5 weeks]; biweekly during monitoring phase [8 weeks]; follow-up [9 months]
measure: Magnetic resonance imaging data
timeFrame: Between screening and 1 week post baseline (T1), for OC group up to 4 weeks post baseline (T4).
measure: Psychophysiological Stress - 'Perceived Stress Scale' (PSS-10)
timeFrame: At baseline (T0)
measure: Anxiety vs. depression - 'State-Trait-Anxiety-Depression-Inventory' (STADI)
timeFrame: At baseline (T0)
measure: Discontinuation symptom load during prior discontinuation - 'Discontinuation Related Signs and Symptoms Scale' (DESSpast)
timeFrame: At baseline (T0)
Locations:
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
Study officials:
affiliation: Universitätsklinikum Hamburg-Eppendorf
name: Yvonne Nestoriuc, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Philipps University Marburg
name: Tilo Kircher, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: