Depressive SymptomsPHEANCT05191277
Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation
A study testing Treatment 'discontinuation of antidepressant medication', Treatment 'continuation of antidepressant medication' and Expectation 'high' in people with Depressive Symptoms and Expectations, run by Universitätsklinikum Hamburg-Eppendorf at 1 site in Germany.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Depressive Symptoms, Expectations, Antidepressants
- What is being tested?
- Treatment 'discontinuation of antidepressant medication', Treatment 'continuation of antidepressant medication' and Expectation 'high'
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 56 participants
- Where
- 1 siteGermany
- Study dates
- 1 Aug 2022to 26 Nov 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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.)
Trial locations and contacts
1 site in 1 country.
Germany1 site
University Medical Center Hamburg-Eppendorf
Hamburg, Free and Hanseatic City of Hamburg, 20251
About this study
Official title: Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation - a Randomized, Balanced Open-hidden Trial
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.
Read more
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).
Read the 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.
- Conditions
- Depressive Symptoms, Expectations, Antidepressants
- Being tested
- Treatment 'discontinuation of antidepressant medication', Treatment 'continuation of antidepressant medication', Expectation 'high', Expectation 'moderate'
- Keywords
- Antidepressant medication, Discontinuation symptoms, Pharmacological effects, Expectation effects, Nocebo, Open-hidden trial
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Treatment 'discontinuation of antidepressant medication'Drug
Pharmacological intervention: Participants will discontinue their antidepressant medication.
Treatment 'continuation of antidepressant medication'Drug
Pharmacological intervention: Participants will remain on their antidepressant medication.
Expectation 'high'Behavioural
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).
Expectation 'moderate'Behavioural
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).
| Study group | Role | What they receive |
|---|---|---|
| Open discontinuation (OD) | Experimental | Participants will discontinue their antidepressant medication and will be fully informed about treatment (i.e., high expectation). Receives: 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). Receives: 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). Receives: 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). Receives: Drug: Treatment 'continuation of antidepressant medication'; Behavioral: Expectation 'moderate' |
What is being measured
The primary outcome is the main question the study is designed to answer.
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: 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'
The Posner Task manipulates attentional resources, provokes emotional responses and robustly activates limbic, prefrontal, and visuo-spatial brain circuits. In short, participants respond as fast as possible to a dot target by button pressing while neutral, happy, sad or fearful face distractors are presented. Targets are preceded by either spatially-directing cues leading to covert shifts in the attentional focus (i.e., low attentional resources to process distractors) or non-spatial cues leaving the attentional focus on the distractors. Reaction times will be measured in milliseconds (ms) for each condition, difference scores will be calculated under high attention to faces for happy and neutral faces, sad and neutral faces, as well as fearful and neutral faces.
Measured: 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)
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: 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
Appearance of a new, depressive episode after full remission of depressive symptoms and a period of recovery. Potential recurrence will be monitored weekly during run-in and (dis-) continuation phase, biweekly during monitoring phase, and 6, 9 and 12 months post-baseline based on BDI-II and MADRS scores. If recurrence is suspected (as indicated by BDI-II scores >19 OR MADRS scores >21 over two weeks/study visits), corresponding SCID-5-CV sections will be conducted to (dis-)confirm recurrence.
Measured: 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)
Self-reported measure of subjective stress, including 10 items with 5 rating categories (0-4), total scores range between 0-40 with higher scores indicating more pronounced stress.
Measured: At baseline (T0) and 13 weeks post baseline at primary endpoint (T9)
Anxiety vs. depression - 'State-Trait-Anxiety-Depression-Inventory' (STADI)
Self-report questionnaire as indicator of state and trait anxiety and depression, divided in 2 sections (state vs. trait) consisting of 20 statements with 4 response options (1-4), respectively. Total scores per scale range between 20 and 80 with higher sum scores indicating higher state/trait anxiety or depression.
Measured: At baseline (T0) and 13 weeks post baseline at primary endpoint (T9); Trait scale measured at baseline only
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2022
- Study start1 Aug 2022
- Primary completion26 Feb 2025
- Study completion26 Nov 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Depressive SymptomsStudies of the same condition, open and under way.
- More trials run by Universitätsklinikum Hamburg-EppendorfThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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).
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 56 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitätsklinikum Hamburg-Eppendorf
- Sponsor type
- University, hospital or other
- Collaborators
- Philipps University Marburg, Helmut Schmidt University, University Hospital, Essen
- Responsible party
- Sponsor
- Investigators
- Yvonne Nestoriuc, Prof. Dr., Principal investigator, Universitätsklinikum Hamburg-EppendorfTilo Kircher, Prof. Dr., Principal investigator, Philipps University Marburg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05191277
- Sponsor's protocol ID
- PV7151
- Other IDs
- CRC 289 Project A15, U1111-1271-7231
- Acronym
- PHEA
- Status last verified
- May 2026
- First submitted
- 17 Sep 2021
- Last updated
- 18 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The PHEA-study is a project within a special research area funded by the DFG, namely the TRR-SFB 289 Treatment Expectation. Individual participant data will be shared with the study team of the TRR-SFB 289 after deidentification and will be available in this form for other researchers upon reasonable request. Only anonymized data in agglomerated form is used for publications. No personal data will be shared.
Publications
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.
PubMed 37344789
Study at a glance
From the registry record, last updated by the sponsor on 18 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Disentangling Pharmacological and Expectation Effects in Antidepressant Discontinuation - a Randomized, Balanced Open-hidden Trial
- ClinicalTrials.gov ID
- NCT05191277
- Acronym / sponsor ID
- PHEA / PV7151
- Conditions
- Depressive Symptoms, Expectations, Antidepressants
- Keywords
- Antidepressant medication, Discontinuation symptoms, Pharmacological effects, Expectation effects, Nocebo, Open-hidden trial
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 56 participants (actual)
- Lead sponsor
- Universitätsklinikum Hamburg-EppendorfUniversity, hospital or other
- Collaborators
- Philipps University Marburg, Helmut Schmidt University, University Hospital, Essen
- Study start
- 1 Aug 2022 (actual)
- Primary completion
- 26 Feb 2025 (actual)
- Study completion
- 26 Nov 2025 (actual)
- First posted
- 13 Jan 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 4
- 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).
| Arm | Type | Receives |
|---|---|---|
| Open discontinuation (OD) | Experimental | Drug: Treatment 'discontinuation of antidepressant medication', Behavioral: Expectation 'high'Participants will discontinue their antidepressant medication and will be fully informed about treatment (i.e., high expectation). |
| Hidden discontinuation (HD) | Experimental | Drug: Treatment 'discontinuation of antidepressant medication', Behavioral: Expectation 'moderate'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). |
| Open continuation (OC) | Experimental | Drug: Treatment 'continuation of antidepressant medication', Behavioral: Expectation 'high'Participants will remain on their initial antidepressant medication and will be fully informed about treatment (i.e., high expectation). |
| Hidden continuation (HC) | Experimental | Drug: Treatment 'continuation of antidepressant medication', Behavioral: Expectation 'moderate'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). |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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)
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Treatment 'discontinuation of antidepressant medication'Pharmacological intervention: Participants will discontinue their antidepressant medication. | Drug | Hidden discontinuation (HD), Open discontinuation (OD) |
| Treatment 'continuation of antidepressant medication'Pharmacological intervention: Participants will remain on their antidepressant medication. | Drug | Hidden continuation (HC), Open continuation (OC) |
| Expectation 'high'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). | Behavioural | Open continuation (OC), Open discontinuation (OD) |
| Expectation 'moderate'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). | Behavioural | Hidden continuation (HC), Hidden discontinuation (HD) |
Primary outcome
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.
5 secondary outcomes
Attentional and emotional processing - 'Posner task'
Time frame: 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)
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]; follow-up [9 months]
Recurrence
Time frame: 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)
Time frame: At baseline (T0) and 13 weeks post baseline at primary endpoint (T9)
Anxiety vs. depression - 'State-Trait-Anxiety-Depression-Inventory' (STADI)
Time frame: At baseline (T0) and 13 weeks post baseline at primary endpoint (T9); Trait scale measured at baseline only
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 May 2026.
- Derived from this study: PubMed 37344789Meissner 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.
- Individual participant dataSharing planned: Yes. The PHEA-study is a project within a special research area funded by the DFG, namely the TRR-SFB 289 Treatment Expectation. Individual participant data will be shared with the study team of the TRR-SFB 289 after deidentification and will be available in this form for other researchers upon reasonable request. Only anonymized data in agglomerated form is used for publications. No personal data will be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yvonne Nestoriuc, Prof. Dr. principal investigator
Universitätsklinikum Hamburg-Eppendorf
Tilo Kircher, Prof. Dr. principal investigator
Philipps University Marburg
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Treatment 'discontinuation of antidepressant medication', Treatment 'continuation of antidepressant medication' and Expectation 'high' in people with Depressive Symptoms and Expectations, run by Universitätsklinikum Hamburg-Eppendorf at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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) (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]). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05191277, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 May 2026.