Predictors of the placebo response in a nutraceutical randomizedcontrolled trial for depression

Objective:The placebo response in depression studies is the change in symptoms amongst those whoreceive an inactive treatment. Many well-designed randomized controlled trials (RCTs) of depressionhave a high proportion of placebo responders, with little understanding as to why. The present studyassesses characteristics associated with the placebo response in a nutraceutical trial with a large propor-tion of placebo responders. Methods:This is a secondary analysis of a nutraceutical depression RCT which identified no overall treat-ment benefit relative to placebo (n= 69 in placebo group). We investigated participant characteristicssuch as socio-demographics, clinical features, and recruitment methods, and their association with theplacebo response. Monoaminergic genetic polymorphisms were also assessed. Placebo response wasmeasured based on change in Montgomery-Asberg Depression Rating Scale score. The association ofthese hypothesis-driven variables of interest and the placebo response was examined using linear mixedeffects models. Results:Greater levels of education, particularly pursuing post-high school education, better self-reported general health, marriage/de facto, greater improvement in the first trial week, and more failedantidepressant therapies in the current depressive episode were associated with greater placeboresponse. An increased placebo response was not found in those recruited via social media nor in thosewith concomitant antidepressant therapy. Single nucleotide polymorphisms from the tryptophanhydroxylase 1 (TPH1) gene (A779CandA218C) were weakly associated with greater placebo response,although the evidence was attenuated after accounting for multiple comparisons. Conclusion:This is, to our knowledge, the first study within nutraceutical research for depression toassess the association between participant characteristics and variation in the placebo response.Several variables appeared to predict the placebo response. Such findings may encourage future trialdesigns which could dampen placebo response, improve assay sensitivity, and allow for treatment effectsto be potentially more detectable. Please cite this article as: Arnold R, Murphy-Smith J, Ng CH, Mischoulon D, Byrne GJ, Bousman CA, StoughC, Berk M, Sarris J. Predictors of the placebo response in a nutraceutical randomized controlled trial fordepression.J Integr Med. 2024; 22(1): 46-53. & Oacute; 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Thisis an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).https://doi.org/10.1016/j.joim.2024.01.0072095-4964/ & Oacute; 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).