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

Importance: Antidepressant 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. Objective: To evaluate the efficacy of open-label placebo (OLP) in reducing antidepressant discontinuation symptoms. Design, Setting, And Participants: A 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. Interventions: The 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 Measures: The 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. Results: A 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 Relevance: This 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.