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

Study Overview
=================
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.

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

Conditions
-----------------
Depressive Symptoms, Expectations, Antidepressants

Intervention / Treatment
-----------------
* Drug: Open-label placebo
* Other: No-treatment


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Open-label placebo ABAB Sequence<br>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<br>* 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.<br>Other: No-treatment<br>* During the no-treatment phase, participants receive no treatment for 2 weeks.<br>|
| Placebo Comparator: Open-label placebo BABA Sequence<br>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<br>* 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.<br>Other: No-treatment<br>* During the no-treatment phase, participants receive no treatment for 2 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in treatment expectations assessed by 'Generic rating scale for treatment expectations' (GEEE_EXP) | 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. | Continuous measurement (2xdaily) for 8 weeks | 
| Change in (depressed) mood assessed by the 'Patient-Healthcare-Questionnaire' (PHQ-2) | 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). | Continuous measurement (2xdaily) for 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
N-of-1 trials, open-label placebo, discontinuation symptoms, antidepressant medication, expectation effects