‘Participant characterisations’ could affect placebo response in trials that assess the impact of nutraceuticals on depression

Researchers analysed participant characteristics in a randomised controlled trial (RCT) that assessed the effectiveness of a nutraceutical treatment for depression.

They found that socio-demographic and clinical features could affect placebo response. Participants of the RCT were outpatients from clinics in Melbourne and Brisbane, Australia.

“Within antidepressant trials, the ‘placebo response’ is the reduction in depressive symptoms seen in individuals taking the placebo treatment,” explained the researchers in Journal of Integrative Medicine​.

“The present study presents several novel findings regarding the placebo response in a nutraceutical antidepressant trial. We found that marriage/de facto, more severe baseline depression, a greater number of prior failed antidepressant therapies, and greater mood improvement in the first trial week were associated with greater placebo response. By contrast, lower levels of education, poorer general health, and more severe pain were associated with less placebo response,” said the researchers.

There is little understanding on why many well-designed RCTs on depression have a high proportion of placebo responders. Some studies reported that there has been a sharp increase in placebo response in antidepressant RCTs since 1980, but other studies found that the placebo response proportion has generally remained consistent since 1991. Additionally, there is little research into the placebo response in depression trials using nutraceuticals.

Therefore, to further understand what makes people respond to placebos, researchers analysed participant characteristics in a nutraceutical trial with a large proportion of placebo responders.

The eight-week RCT assessed the effects of nutraceuticals in the treatment of depression in patients aged 18–70 years, who were divided into three groups. Group A was prescribed S-adenosylmethionine (SAMe), group B was assigned SAMe plus a combination nutraceutical capsule containing omega-3 fatty acids, zinc and tryptophan (combination nutraceutical group), and group C received a placebo that contained 1% fish oil.

For this analysis, researchers investigated participant characteristics and their association with the placebo response. The characteristics included socio-demographics, clinical features, recruitment methods, and monoaminergic genetic polymorphisms (genetic variations that can affect brain response).

Apart from the findings listed earlier, the researchers found that genetic variations in the TPH1 gene may be weakly linked to placebo response, but this connection became less clear during the course of their analysis: “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.”

The following observations could be considered in future antidepressant trial designs to minimise placebo response, therefore enabling a more accurate assessment of the treatment being tested: (1) Rapid treatment response in the first trial week was associated with greater subsequent placebo response. This indicated that placebos may influence the treatment effect in depression trials. (2) Participants with more unsuccessful antidepressant trials in their current episode had greater placebo response. (3) The use of concomitant antidepressant therapy alongside the placebo did not alter the placebo response. (4) Recruitment methods for participants, such as through social media or via general recruitment strategies, do not appear to affect placebo response. (5) Education level should be considered given its close relationship with social and psychological factors.

“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,” concluded the researchers.

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Source: Journal of Integrative Medicine​

DOI: https://doi.org/10.1016/j.joim.2024.01.007​

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

Authors: Rosemary Arnold, Jenifer Murphy-Smith et al​.