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Trial record 6 of 11 for:    nestoriuc

Combined N-of-1 Trials to Assess Open-Label Placebo Treatment for Antidepressant Discontinuation Symptoms (FAB)

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ClinicalTrials.gov Identifier: NCT05051995
Recruitment Status : Recruiting
First Posted : September 21, 2021
Last Update Posted : April 19, 2022
Sponsor:
Collaborators:
Philipps University Marburg Medical Center
Helmut Schmidt University
University Hospital, Essen
Information provided by (Responsible Party):
Universitätsklinikum Hamburg-Eppendorf

Brief Summary:

It has been widely recognized that the placebo effect has a profound impact on treatment outcome in many different conditions. Recent studies imply that this effect appears even if placebos are openly administered; so called "open-label placebos" (OLP). Compelling evidence suggests the efficacy of OLP in the treatment of pain disorders, neuropsychological syndromes, menopausal hot flushes, depression and allergic rhinitis. Research on the underlying mechanisms of OLP is scarce, yet studies indicate that psychological mechanisms as well as neurobiological processes related to expectation- and prediction mechanisms may play a role. While these effects have been linked to OLP as additional treatment, to date, it has not been examined whether OLP could support discontinuation of drug treatments.

Antidepressant discontinuation has been frequently associated with negative side effects, interfering with the discontinuation process and generally discouraging discontinuation. Patients frequently report negative expectations towards the discontinuation process, such as fear of experiencing a relapse and negative side effects. Interestingly, OLP may support antidepressant discontinuation, not only through the generation of (positive) expectations, but also mechanisms related to habituation (i.e. taking pills). The objective of this study is to investigate whether OLP is efficacious in reducing negative side effects caused by discontinuation of 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).


Condition or disease Intervention/treatment Phase
Depressive Symptoms Expectations Antidepressants Drug: Open-label placebo Other: No-treatment Not Applicable

Detailed Description:

Rationale: A current issue in the frame of antidepressant medication is the rise of long-term antidepressant use associated with noticeable adverse effects such as withdrawal effects, sexual difficulties, weight gain and emotional numbness. A key factor hindering patients in the discontinuation of antidepressant medication is the emergence of discontinuation symptoms, reported by over half of fully remitted patients discontinuing antidepressants. To date, there is no study examining open-label placebo responses on antidepressant discontinuation symptoms. However, several findings imply that open-label placebos may support the discontinuation process in remitted depressed patients. The susceptibility to placebo responses is encouraged by findings indicating substantial placebo effects in antidepressant trials (67-82%). Additionally, evidence suggests the central role of expectation effects influencing the course of antidepressant discontinuation. Open-label placebos have been found to work through the generation of positive expectations, induced by a positive framing (e.g. verbal instructions). A recent meta-analysis suggests a medium to large effect size of open-label placebos. Regarding the treatment of antidepressant discontinuation symptoms, open-label placebos have the potential to reduce symptoms not only by inducing positive expectations, but also by triggering automatic (positive) responses to the intake of a pill (i.e. conditioning).The aim of this study is to investigate the effect of open-label placebos on antidepressant discontinuation symptoms in fully remitted depressed patients.

Methods: In the proposed study, a pilot sample will discontinue their antidepressant intake under extensive medical and psychological supervision, according to the national and international guidelines over a 13-week course. After a run-in week and the baseline assessment, antidepressant medication will be gradually reduced with individualized discontinuation plans over a period of 4 weeks. Weekly measurements serve to monitor the condition of the participants. After discontinuation, patients will be monitored (with biweekly study visits) for another 8 weeks (experimental phase). Finally, a follow-up measurement 6 months after the study start constitutes long-term monitoring and the assessment of relapse after antidepressant discontinuation. During the experimental phase, patients experiencing moderate discontinuation symptoms are allocated to the intervention group, aimed to examine the effect of open-label placebo on antidepressant discontinuation symptoms. For this purpose, N-of-1 trials comprising multiple crossovers (A: open-label placebo; B: no treatment) within each individual, and varying in a biweekly rhythm, are applied. Patients are randomized to different treatment orders (ABAB; BABA). Twice daily smartphone-measurements are implemented to assess discontinuation symptoms, expectations and mood. Additionally, study visits consist of extensive measurements related to discontinuation symptoms, depressive symptomatology, psychological well-being and treatment expectations. These serve as observational measurement of different effects related to antidepressant discontinuation. During the experimental phase, outcome assessors will be blind to the randomization (i.e. treatment order) of the patients.

Objectives: At the end of the study, the investigators will determine whether open-label placebo reduces negative side effects caused by antidepressant discontinuation by aggregating the N-of-1 trials. Underlying mechanisms such as treatment expectations, as well as the relation to depressed mood, will be under explorative investigation. Additionally, the course of discontinuation symptoms, depressive symptoms (self-report and expert-rated) and treatment adherence during the entire study will be explored. Therefore, potential modulators such as psychopathology, demographics, adverse events, expectations, prior experience, subjective stress, side effects of antidepressants and anxiety vs. depression (trait/state) will be taken into account in data analyses.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

To investigate the efficacy of open-label placebo in the reduction of antidepressant discontinuation symptoms, patients experiencing moderate discontinuation symptoms after successful discontinuation (4 weeks) receive open-label placebo treatment or no treatment during the experimental phase (8 weeks).

For this purpose, a series of N-of-1 trials is implemented, consisting of multiple crossover trials within each participant. The factor treatment (open-label placebo vs. no treatment) varies intra-individually with a biweekly rhythm, to assess the treatment effect on discontinuation symptoms. A block-randomization is applied, with patients either receiving (A) open-label placebo or (B) no treatment in a biweekly rhythm (group 1: ABAB; group 2: BABA).

Masking: Single (Outcomes Assessor)
Masking Description: The person performing the data collection (assessor) will be blind to the randomization of the participant for the entire duration of the experimental phase.
Primary Purpose: Supportive Care
Official Title: Combined N-of-1 Trials to Assess Open-Label Placebo Treatment for Antidepressant Discontinuation Symptoms
Actual Study Start Date : February 17, 2022
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : August 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Placebo Comparator: Open-label placebo ABAB Sequence
The N-of-1 trial will, on the level of the individual patient, test whether open-label placebo reduces negative side effects caused by discontinuation of antidepressants compared to no treatment. After antidepressant discontinuation, subjects will be randomized to 2 arms differing in the treatment order (ABAB; BABA). Subjects in this arm (ABAB) will start with open-label placebo (A) for 2 weeks; they will then crossover to no treatment (B) for 2 weeks and repeat this sequence once again.
Drug: Open-label placebo
Prior to the open-label placebo administration, an explanation why placebos without concealment might be effective is offered. Participants receive placebo pills with the instruction to take 2 pills daily for 2 weeks.

Other: No-treatment
During the no-treatment phase, participants receive no treatment for 2 weeks.

Placebo Comparator: Open-label placebo BABA Sequence
The N-of-1 trial will, on the level of the individual patient, test whether open-label placebo reduces negative side effects caused by discontinuation of antidepressants compared to no treatment. After antidepressant discontinuation, subjects will be randomized to 2 arms differing in the treatment order (ABAB; BABA). Subjects in this arm (BABA) will start with no treatment (B) for 2 weeks; they will then crossover to open-label placebo (A) for 2 weeks and repeat this sequence once again.
Drug: Open-label placebo
Prior to the open-label placebo administration, an explanation why placebos without concealment might be effective is offered. Participants receive placebo pills with the instruction to take 2 pills daily for 2 weeks.

Other: No-treatment
During the no-treatment phase, participants receive no treatment for 2 weeks.




Primary Outcome Measures :
  1. Change in antidepressant discontinuation symptoms assessed by the 'Generic rating scale for treatment effects' (GEEE_ACT) [ Time Frame: Continuous measurement (2xdaily) for 8 weeks ]
    The generic rating scale for treatment effects item 3 assesses the current treatment effect concerning side effects (i.e. antidepressant discontinuation side-effects) on a numeric analogue scale, ranging from 0-10; higher scores indicating higher antidepressant discontinuation symptoms.


Secondary Outcome Measures :
  1. Change in treatment expectations assessed by 'Generic rating scale for treatment expectations' (GEEE_EXP) [ Time Frame: Continuous measurement (2xdaily) for 8 weeks ]
    The generic rating scale for treatment expectations item 3 assesses treatment expectations regarding side effects (i.e. antidepressant discontinuation side-effects) on a numeric rating scale, ranging from 0-10; higher scores indicating higher treatment expectations.

  2. Change in (depressed) mood assessed by the 'Patient-Healthcare-Questionnaire' (PHQ-2) [ Time Frame: Continuous measurement (2xdaily) for 8 weeks ]
    Self-report comprising 2 items, inquiring the degree to which an individual experiences the core symptoms of depression (i.e. anhedonia and depressed mood); items are scored on a four level Likert scale ranging from 0 (not at all) - 3 (almost constant); total score range from 0-6 (higher scores indicate a higher degree of depressed mood).


Other Outcome Measures:
  1. Discontinuation symptoms - 'Discontinuation Related Signs and Symptoms Scale' (DESS) [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    The discontinuation related signs and symptoms scale is a self-report questionnaire to assess discontinuation symptoms, incorporating 43 discontinuation symptoms of antidepressant with intensity ratings ranging from 0 (not present) - 3 (severe); total score range from 0-129 with higher scores indicating more severe discontinuation symptoms.

  2. Current treatment effects - 'Generic rating scale for treatment effects' (GEEE_ACT) [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    The generic rating scale for treatment effects assesses the current treatment effects (i.e. antidepressant discontinuation) regarding side effects as well as positive and negative aspects on 3 numeric rating scales with eleven response options (0-10); total score range from 0-30 with higher scores indicating higher antidepressant discontinuation effects.

  3. Subjective depressive symptomatology - 'Beck Depression Inventory' (BDI-II) [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    Self-report measure to assess depressive symptoms, including 21 items with 4 response options (0-3); total scores range from 0 - 63 (higher scores indicating higher depression severity).

  4. Expert-rated depression severity scores - 'Montgomery-Åsberg Depression Scale' (MADRS) [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    Expert-rated interview to assess the severity of depression by 10 items with up to 7 rating categories (0-6) for each item; total scores range between 0-60 with higher scores indicating more severe depression severity.

  5. Recurrence [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    New-onset depressive episode following a period of recovery. Recurrence will be determined by BDI-II sumscore (>19) or MADRS sumscore (>21) over a period of two weeks, confirmed by SCID-5-CV section for MDD.

  6. Mental well-being - 'Short Warwick-Edinburgh Mental Wellbeing Scale' (SWEMWBS) [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    Self-report questionnaire to assess mental well-being by 7 statements about thoughts and feelings using 5 response options; total score range from 7-35 with higher sum scores reflecting a higher level of mental well-being.

  7. Adherence - single item [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks) ]
    Treatment adherence assessed by a single item in the clinical interview about adherence to medication or placebo (i.e. experimental phase) intake.

  8. Treatment expectations - 'Treatment Expectation Questionnaire' (TEX-Q) [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    Self-reported measure to assess patients' treatment expectations, consisting of 15 items with 11 response options, total score range from 0-150 (higher scores implying more positive treatment expectations).

  9. Current treatment expectations - 'Generic rating scale for treatment expectations' (GEEE_EXP) [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    The generic rating scale for treatment expectations assesses treatment expectations (i.e. antidepressant discontinuation expectations) regarding positive and negative aspects as well as side effects on 3 numeric rating scales (ranging from 0-10); total score range from 0-30 with higher scores indicating higher treatment expectations.

  10. Pre-experiences with antidepressant discontinuation - 'Generic rating scale for previous treatment experiences' (GEEE_PRE) [ Time Frame: Baseline ]
    Self-reported previous experiences with antidepressant discontinuation. If experience with antidepressant discontinuation is indicated, the following 3 items rate the experiences regarding side effects as well as positive and negative aspects on 3 numeric analogue scales (ranging from 0-10); total score range from 0-30; higher scores indicate more pre-experiences with antidepressant discontinuation effects.

  11. Subjective Stress - 'Perceived Stress Scale' (PSS-10) [ Time Frame: Baseline ]
    Self-reported measure of subjective stress, including 10 items with 5 rating categories, total scores range between 0-40; higher scores are suggestive of more subjective stress.

  12. Anxiety vs Depression - 'State-Trait-Anxiety-Depression-Inventory' (STADI) [ Time Frame: Baseline ]
    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, respectively. Total scores per scale range between 20 and 80 with higher sum scores indicating higher state/trait anxiety or depression.

  13. Side effects of SSRIs - 'Generic Assessment of Side Effects' (GASE) [ Time Frame: Baseline, post-antidepressant discontinuation (8 weeks after baseline) ]
    Self-report measure to assess side effects of antidepressant medication, including 36 items (symptom descriptions) with 4 response options. Items are additionally evaluated on their relation to antidepressant medication (Yes/ No questions). Total scores range from 0-108 (higher scores are reflective of stronger experiences of side effects).

  14. Adverse events - single safety items [ Time Frame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later) ]
    Interview-based measure assessing adverse events by 3 questions (Yes/ No questions), followed by an expert-rating of the intensity of the adverse events (1-5) and relation to treatment (1-5). Higher scores indicate more and/or a higher intensity of adverse events.

  15. Psychopathology - 'Structured Clinical Interview for DSM-5, Clinician Version' (SCID-5-CV) [ Time Frame: Screening ]
    Expert-rated semi-structured interview to assess DSM-5 diagnoses.

  16. SSRI/SNRI blood serum level [ Time Frame: Pre-antidepressant discontinuation (1 week after baseline); post-antidepressant discontinuation (5 weeks after baseline) ]
    Blood analysis assessing the blood serum level.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult participants (18+years) with a former diagnoses of major depressive disorder (MDD), single or recurrent as main diagnosis confirmed by prescribing physician and currently remitted
  • Intake of selective serotonin reuptake inhibitors (SSRI)/ serotonin-norepinephrine reuptake inhibitors (SNRI) (citalopram 20-40mg, duloxetine 60-100mg, escitalopram 10-20mg, paroxetine 20-40mg, sertraline 50-150mg, venlafaxine 75-150mg) or noradrenergic and specific serotonergic antidepressants (NaSSA) (mirtazapine 30-45mg)
  • Discontinuation wish by patient supported by prescribing physician
  • Fulfils the criteria of the S3 national guideline recommendations "Depression" to discontinue antidepressant medication: a) response to antidepressant; b) symptom remission for at least 4 months (first episode) or for 2 years (2 or more episodes with significant functional impairment), constant intake of antidepressant medication (at least 4 weeks on a steady dose)
  • Informed consent

Exclusion Criteria:

  • Current moderate or severe psychopathological symptoms or psycho-social impairments
  • Acute or chronic somatic illness which might interfere with depressive disorder, antidepressant or proposed study
  • Acute suicidality, psychotic symptoms, substance abuse, or addiction, current mania, or hypomania confirmed by SCID-5 or other psychopathology which might interfere with depressive disorder, antidepressant or proposed study
  • Any history of bipolar disorder or psychosis confirmed by SCID-5
  • Severe stressful life events (e.g., death of a family member) within six months prior to study participation
  • Current pregnancy
  • Insufficient German language proficiency.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05051995


Contacts
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Contact: Amke Müller, M.Sc. +49(0)40 6541-3918 muellera@hsu-hh.de
Contact: Tahmine Fadai, Dr. +49(0)40 741053217 t.fadai@uke.de

Locations
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Germany
Philipps University Marburg Medical Center Recruiting
Marburg, Hessen, Germany, 35037
Contact: Christoph Vogelbacher, Dr.       vogelbac@staff.uni-marburg.de   
Principal Investigator: Tilo Kircher, Prof. Dr.         
University Medical Center Hamburg-Eppendorf Recruiting
Hamburg, Germany, 20251
Contact: Amke Müller, M.Sc.    +49(0)40 65413918    muellera@hsu-hh.de   
Contact: Tahmine Fadai, Dr.    +49(0)40 741053217    t.fadai@uke.de   
Principal Investigator: Yvonne Nestoriuc, Prof. Dr.         
Sponsors and Collaborators
Universitätsklinikum Hamburg-Eppendorf
Philipps University Marburg Medical Center
Helmut Schmidt University
University Hospital, Essen
Investigators
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Principal Investigator: Yvonne Nestoriuc, Prof. Dr. Universitätsklinikum Hamburg-Eppendorf
Principal Investigator: Tilo Kircher, Prof. Dr. Philipps University Marburg Medical Center
Publications:
Rief, W., Nestoriuc, Y., Mueller, E. M., Hermann, C., Schmidt, K., & Bingel, U. Generic rating scale for previous treatment experiences, treatment expectations, and treatment effects (GEEE). PsychArchives. 2021 https://doi.org/10.23668/PSYCHARCHIVES.4717
Shedden-Mora, M. C., Pan, Y., Heisig, S. R., von Blanckenburg, P., Rief, W., Witzel, I., Albert, U.-S., & Nestoriuc, Y. Optimizing expectations about endocrine treatment for breast cancer: Results of the randomized controlled psy-breast trial. Clinical Psychology in Europe. 2020; 2(1), e2695.

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Responsible Party: Universitätsklinikum Hamburg-Eppendorf
ClinicalTrials.gov Identifier: NCT05051995    
Other Study ID Numbers: 0721-20
CRC 289 Project A15 ( Other Grant/Funding Number: DFG Deutsche Forschungsgemeinschaft )
U1111-1274-2336 ( Registry Identifier: Universal Trial Number (UTN) )
First Posted: September 21, 2021    Key Record Dates
Last Update Posted: April 19, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The FAB-study is a pilotproject within a special research area funded by the DFG: TRR-SFB 289 Treatment Expectation. After deidentification, individual participant data will be shared with the TRR-SFB 289 study team and will be available for other researchers upon reasonable request. Only anonymized data in agglomerated form is used for publications. No personal data of participants will be shared.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Analytic Code
Time Frame: upon reasonable request following publication
Access Criteria: upon reasonable request following publication

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Universitätsklinikum Hamburg-Eppendorf:
N-of-1 trials
open-label placebo
discontinuation symptoms
antidepressant medication
expectation effects
Additional relevant MeSH terms:
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Depression
Behavioral Symptoms