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

NCT05051995 | Completed DMC

• 3 other identifiers: 0721-20CRC 289 Project A15U1111-1274-2336
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

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).

Conditions

Depressive Symptoms; Expectations; Antidepressants

Keywords

N-of-1 trials; open-label placebo; discontinuation symptoms; antidepressant medication; expectation effects

Outcome Measures

Primary Outcomes (1)

• Change in antidepressant discontinuation symptoms assessed by the 'Generic rating scale for treatment effects' (GEEE_ACT)

  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.

  Continuous measurement (2xdaily) for 8 weeks

Secondary Outcomes (2)

• Change in treatment expectations assessed by 'Generic rating scale for treatment expectations' (GEEE_EXP)

  Continuous measurement (2xdaily) for 8 weeks

• Change in (depressed) mood assessed by the 'Patient-Healthcare-Questionnaire' (PHQ-2)

  Continuous measurement (2xdaily) for 8 weeks

Other Outcomes (16)

• Discontinuation symptoms - 'Discontinuation Related Signs and Symptoms Scale' (DESS)

  Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)

• Current treatment effects - 'Generic rating scale for treatment effects' (GEEE_ACT)

  Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)

• Subjective depressive symptomatology - 'Beck Depression Inventory' (BDI-II)

  Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)

Study Arms (2)

Open-label placebo ABAB Sequence

PLACEBO COMPARATOR

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; Other: No-treatment

Open-label placebo BABA Sequence

PLACEBO COMPARATOR

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; Other: No-treatment

Interventions

Open-label placebo DRUG

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.

Open-label placebo ABAB Sequence; Open-label placebo BABA Sequence

No-treatment OTHER

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

Open-label placebo ABAB Sequence; Open-label placebo BABA Sequence

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (2)

Philipps University Marburg Medical Center

Marburg, Hesse, 35037, Germany

Location

University Medical Center Hamburg-Eppendorf

Hamburg, 20251, Germany

Location

Related Publications (9)

• Nestoriuc Y, Pan Y, Kinitz T, Weik E, Shedden-Mora MC. Informing About the Nocebo Effect Affects Patients' Need for Information About Antidepressants-An Experimental Online Study. Front Psychiatry. 2021 Apr 27;12:587122. doi: 10.3389/fpsyt.2021.587122. eCollection 2021.

  PMID: 33986697 BACKGROUND

• 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

  BACKGROUND

• Pan Y, Meister R, Lowe B, Kaptchuk TJ, Buhling KJ, Nestoriuc Y. Open-label placebos for menopausal hot flushes: a randomized controlled trial. Sci Rep. 2020 Nov 18;10(1):20090. doi: 10.1038/s41598-020-77255-z.

  PMID: 33208855 BACKGROUND

• Bowers HM, Kendrick T, Glowacka M, Williams S, Leydon G, May C, Dowrick C, Moncrieff J, Laine R, Nestoriuc Y, Andersson G, Geraghty AWA. Supporting antidepressant discontinuation: the development and optimisation of a digital intervention for patients in UK primary care using a theory, evidence and person-based approach. BMJ Open. 2020 Mar 8;10(3):e032312. doi: 10.1136/bmjopen-2019-032312.

  PMID: 32152159 BACKGROUND

• Meister R, Lanio J, Fangmeier T, Harter M, Schramm E, Zobel I, Hautzinger M, Nestoriuc Y, Kriston L. Adverse events during a disorder-specific psychotherapy compared to a nonspecific psychotherapy in patients with chronic depression. J Clin Psychol. 2020 Jan;76(1):7-19. doi: 10.1002/jclp.22869. Epub 2019 Oct 1.

  PMID: 31576565 BACKGROUND

• Shedden-Mora MC, Pan Y, Heisig SR, von Blanckenburg P, Rief W, Witzel I, Albert US, Nestoriuc Y. Optimizing Expectations About Endocrine Treatment for Breast Cancer: Results of the Randomized Controlled PSY-BREAST Trial. Clin Psychol Eur. 2020 Mar 31;2(1):e2695. doi: 10.32872/cpe.v2i1.2695. eCollection 2020 Mar.

  PMID: 36397978 BACKGROUND

• Pan Y, Meister R, Lowe B, Winkelmann A, Kaptchuk TJ, Buhling KJ, Nestoriuc Y. Non-concealed placebo treatment for menopausal hot flushes: Study protocol of a randomized-controlled trial. Trials. 2019 Aug 16;20(1):508. doi: 10.1186/s13063-019-3575-1.

  PMID: 31420050 BACKGROUND

• Pan Y, Kinitz T, Stapic M, Nestoriuc Y. Minimizing Drug Adverse Events by Informing About the Nocebo Effect-An Experimental Study. Front Psychiatry. 2019 Jul 25;10:504. doi: 10.3389/fpsyt.2019.00504. eCollection 2019.

  PMID: 31427995 BACKGROUND

• Muller A, Konigorski S, Meissner C, Fadai T, Warren CV, Falkenberg I, Kircher T, Nestoriuc Y. Study protocol: combined N-of-1 trials to assess open-label placebo treatment for antidepressant discontinuation symptoms [FAB-study]. BMC Psychiatry. 2023 Oct 13;23(1):749. doi: 10.1186/s12888-023-05184-y.

  PMID: 37833651 DERIVED

MeSH Terms

Conditions

Depression

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Study Officials

• Yvonne Nestoriuc, Prof. Dr.

  Universitätsklinikum Hamburg-Eppendorf

  PRINCIPAL INVESTIGATOR

• Tilo Kircher, Prof. Dr.

  Philipps University Marburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The person performing the data collection (assessor) will be blind to the randomization of the participant for the entire duration of the experimental phase.
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: August 23, 2021
• First Posted: September 21, 2021
• Study Start: February 17, 2022
• Primary Completion: February 21, 2024
• Study Completion: May 15, 2024
• Last Updated: June 12, 2024

Record last verified: 2024-05

Data Sharing

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

Locations

DE (2)