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Journal of Integrative Medicine ›› 2024, Vol. 22 ›› Issue (1): 46-53.doi: 10.1016/j.joim.2024.01.007

• Original Chinical Research • Previous Articles     Next Articles

Predictors of the placebo response in a nutraceutical randomized controlled trial for depression

Rosemary Arnold a, Jenifer Murphy-Smith a, Chee H. Ng a, David Mischoulon b, Gerard J. Byrne c, Chad A. Bousman d,e, Con Stough f, Michael Berk e,g,h,i, Jerome Sarris i,j   

  1. a Professorial Unit, the Melbourne Clinic, Department of Psychiatry, University of Melbourne, Richmond 3121, Australia
    b Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
    c Faculty of Medicine, Discipline of Psychiatry, Centre for Clinical Research, Royal Brisbane & Women’s Hospital, Herston, the University of Queensland, Brisbane 4006, Australia
    d Departments of Medical Genetics, Psychiatry, Physiology & Pharmacology and Community Health Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada
    e Department of Psychiatry, the University of Melbourne, Melbourne 3052, Australia
    f Centre for Human Psychopharmacology, Swinburne University, Melbourne 3122, Australia
    g The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong 3220, Australia
    h The Centre of Excellence in Youth Mental Health, the University of Melbourne, Parkville 3052, Australia
    i Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville 3052, Australia
    j NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia
  • Received:2021-12-10 Accepted:2023-08-10 Online:2024-01-31 Published:2024-01-24
  • Contact: Jerome Sarris

The placebo response in depression studies is the change in symptoms amongst those who receive an inactive treatment. Many well-designed randomized controlled trials (RCTs) of depression have a high proportion of placebo responders, with little understanding as to why. The present study assesses characteristics associated with the placebo response in a nutraceutical trial with a large proportion of placebo responders.

This is a secondary analysis of a nutraceutical depression RCT which identified no overall treatment benefit relative to placebo (n = 69 in placebo group). We investigated participant characteristics such as socio-demographics, clinical features, and recruitment methods, and their association with the placebo response. Monoaminergic genetic polymorphisms were also assessed. Placebo response was measured based on change in Montgomery-Asberg Depression Rating Scale score. The association of these hypothesis-driven variables of interest and the placebo response was examined using linear mixed effects models.

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 failed antidepressant therapies in the current depressive episode were associated with greater placebo response. An increased placebo response was not found in those recruited via social media nor in those with concomitant antidepressant therapy. Single nucleotide polymorphisms from the tryptophan hydroxylase 1 (TPH1) gene (A779C and A218C) were weakly associated with greater placebo response, although the evidence was attenuated after accounting for multiple comparisons.

This is, to our knowledge, the first study within nutraceutical research for depression to assess the association between participant characteristics and variation in the placebo response. Several variables appeared to predict the placebo response. Such findings may encourage future trial designs which could dampen placebo response, improve assay sensitivity, and allow for treatment effects to be potentially more detectable.

Key words: Randomized controlled trial, Placebo, Depression, Nutraceutical, Psychiatry

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