Open-Label Placebos for Antidepressant Discontinuation Symptoms: A Series of N-of-1 Trials

Key pointsQuestion Can open-label placebos (OLP) reduce antidepressant discontinuation symptoms in patients with remitted major depression? Findings This series of N-of-1 trials in 25 patients, over 8 weeks following antidepressant discontinuation, found small effects of OLP vs no treatment in reducing discontinuation symptoms. While the overall treatment effect did not reach the threshold of clinical meaningfulness, 38% of patients experienced a small benefit. Discontinuation symptoms were mostly mild, with few exceptions, and diminished over time. Meaning These findings support the use of personalized approaches and suggest that open-label placebos may be beneficial for antidepressant discontinuation symptoms in some patients. ImportanceAntidepressant discontinuation symptoms are highly prevalent and can be severe. Interventions leveraging the placebo effect have the potential to alleviate symptoms and facilitate the discontinuation process. ObjectiveTo evaluate the efficacy of open-label placebo (OLP) in reducing antidepressant discontinuation symptoms. Design, Setting, And ParticipantsA series of randomized, single-blinded, N-of-1 trials of OLP vs no treatment in an alternating order (ABAB, BABA). Patients with remitted major depressive disorder, reporting moderate to severe discontinuation symptoms after successful antidepressant discontinuation with state-of-the-art clinical supervision were enrolled between December 2021 to December 2023. InterventionsThe OLP treatment consisted of a standardized verbal and written rationale and twice-daily placebo intake for two-week periods alternating with no treatment during the eight-week N-of-1 trial. Main Outcomes and MeasuresThe primary outcome was discontinuation symptoms assessed twice daily by the Generic Rating Scale of Treatment Effects (0-10, with higher scores indicating greater discontinuation symptoms). Secondary outcomes were symptom expectations and depressive symptoms. Bayesian mixed models of individual and aggregated N-of-1 trial data were used to estimate posterior probabilities of treatment effect differences across different thresholds (>0 superior; [≥]0.2 small effect; [≥]0.8 clinically meaningful effect). Analyses were conducted as intention-to-treat. ResultsA total of 25 patients (mean [SD] age, 43.2 [16.0] years; 80% females) with moderate to severe discontinuation symptom scores at baseline (mean [SD], 5.8 [1.4] severity) were enrolled. Among 21 patients analyzed at individual level, 13 showed improvements in discontinuation symptoms during OLP vs no treatment, 8 indicated small and none clinically meaningful effects. Aggregated Bayesian mixed models estimated a 76% posterior probability for a superior treatment effect, with a 53% for a small and 4% for a clinically meaningful effect. Overall discontinuation symptom burden was low and decreased over time. Adverse events did not differ significantly between OLP and no treatment; there were no serious adverse events. Conclusion and RelevanceThis series of N-of-1 trials found OLP may improve discontinuation symptoms following clinician-supervised antidepressant discontinuation, but effects did not reach the threshold for clinical meaningfulness. Small effects in over one-third of patients indicate OLP may be a low-risk intervention for certain individuals after discontinuation. Trial registrationClinicalTrials.gov Identifier: NCT05051995 - including a priori published SAP dated December 21, 2023.