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

NCT ID: NCT05051995

Last Updated: 2024-06-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-02-17
• Study Completion Date: 2024-05-15

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).

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.

Conditions

Depressive Symptoms; Expectations; Antidepressants

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: PLACEBO_COMPARATOR

Open-label placebo

Intervention Type: 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.

No-treatment

Intervention Type: OTHER

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

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.

Group Type: PLACEBO_COMPARATOR

Open-label placebo

Intervention Type: 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.

No-treatment

Intervention Type: OTHER

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

Interventions

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.

Intervention Type: DRUG

No-treatment

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

Intervention Type: OTHER

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Philipps University Marburg

OTHER

Sponsor Role: collaborator

Helmut Schmidt University

OTHER

Sponsor Role: collaborator

University Hospital, Essen

OTHER

Sponsor Role: collaborator

Universitätsklinikum Hamburg-Eppendorf

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Yvonne Nestoriuc, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Universitätsklinikum Hamburg-Eppendorf

Tilo Kircher, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Philipps University Marburg

Locations

Philipps University Marburg Medical Center

Marburg, Hesse, Germany

University Medical Center Hamburg-Eppendorf

Hamburg, , Germany

Countries

Germany

References

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.

Reference Type: BACKGROUND

PMID: 33986697 (View on PubMed)

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

Reference Type: 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.

Reference Type: BACKGROUND

PMID: 33208855 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32152159 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31576565 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 36397978 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31420050 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31427995 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37833651 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

CRC 289 Project A15

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

U1111-1274-2336

Identifier Type: REGISTRY

Identifier Source: secondary_id

0721-20

Identifier Type: -

Identifier Source: org_study_id