Clinical trial NCT05051995: Combined N-of-1 Trials to Assess Open-Label Placebo Treatment for Antidepressant Discontinuation Symptoms
Official title: Combined N-of-1 Trials to Assess Open-Label Placebo Treatment for Antidepressant Discontinuation Symptoms
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Depressive Symptoms
Expectations
Antidepressants
Keywords: N-of-1 trials
open-label placebo
discontinuation symptoms
antidepressant medication
expectation effects
Lead sponsor: Universitätsklinikum Hamburg-Eppendorf
Sponsor class: OTHER
Collaborators: name: Philipps University Marburg
name: Helmut Schmidt University
name: University Hospital, Essen
First posted: 2021-09-21
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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).
Primary purpose: SUPPORTIVE_CARE

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.

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.

Primary outcomes:
measure: Change in antidepressant discontinuation symptoms assessed by the 'Generic rating scale for treatment effects' (GEEE_ACT)
timeFrame: Continuous measurement (2xdaily) for 8 weeks
Secondary outcomes:
measure: Change in treatment expectations assessed by 'Generic rating scale for treatment expectations' (GEEE_EXP)
timeFrame: Continuous measurement (2xdaily) for 8 weeks
measure: Change in (depressed) mood assessed by the 'Patient-Healthcare-Questionnaire' (PHQ-2)
timeFrame: Continuous measurement (2xdaily) for 8 weeks
Other outcomes:
measure: Discontinuation symptoms - 'Discontinuation Related Signs and Symptoms Scale' (DESS)
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Current treatment effects - 'Generic rating scale for treatment effects' (GEEE_ACT)
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Subjective depressive symptomatology - 'Beck Depression Inventory' (BDI-II)
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Expert-rated depression severity scores - 'Montgomery-Åsberg Depression Scale' (MADRS)
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Recurrence
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Mental well-being - 'Short Warwick-Edinburgh Mental Wellbeing Scale' (SWEMWBS)
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Adherence - single item
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks)
measure: Treatment expectations - 'Treatment Expectation Questionnaire' (TEX-Q)
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Current treatment expectations - 'Generic rating scale for treatment expectations' (GEEE_EXP)
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Pre-experiences with antidepressant discontinuation - 'Generic rating scale for previous treatment experiences' (GEEE_PRE)
timeFrame: Baseline
measure: Subjective Stress - 'Perceived Stress Scale' (PSS-10)
timeFrame: Baseline
measure: Anxiety vs Depression - 'State-Trait-Anxiety-Depression-Inventory' (STADI)
timeFrame: Baseline
measure: Side effects of SSRIs - 'Generic Assessment of Side Effects' (GASE)
timeFrame: Baseline, post-antidepressant discontinuation (8 weeks after baseline)
measure: Adverse events - single safety items
timeFrame: Weekly during discontinuation phase (4 weeks); biweekly during experimental phase (8 weeks); follow-up (6 months later)
measure: Psychopathology - 'Structured Clinical Interview for DSM-5, Clinician Version' (SCID-5-CV)
timeFrame: Screening
measure: SSRI/SNRI blood serum level
timeFrame: Pre-antidepressant discontinuation (1 week after baseline); post-antidepressant discontinuation (5 weeks after baseline)
Locations:
city: Marburg
country: Germany
facility: Philipps University Marburg Medical Center
state: Hessen
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
Study officials:
affiliation: Universitätsklinikum Hamburg-Eppendorf
name: Yvonne Nestoriuc, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Philipps University Marburg
name: Tilo Kircher, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.