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6th October 2021
Treatment-resistant depression (TRD) can be defined as a major depressive disorder (MDD) in adults who failed to respond to at least two different antidepressant treatments in their current moderate-to-severe depressive episode. It is a common problem with a prevalence estimated from one analysis to affect 30.9% of patients. Although the efficacy of an antidepressant in clinical trials is assessed by comparison against placebo, a common problem is the large and positive placebo response often observed. The magnitude of average placebo response in studies of major depression has been found to be 29.7%, but ranged between 12.5 and 51.8%. Moreover, in an analysis of 252 antidepressant controlled trials with 26,324 patients assigned to placebo, a placebo response was seen in 35 to 40% of patients, although the analysis did not specifically examine treatment-resistant depression.
However, what remains uncertain, is the magnitude of the placebo response in patients with TRD who are exposed to a range of different modalities. This prompted a team from the Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada, to not only assess the size of the placebo response in patients with TRD, but to also identify relevant factors associated with the placebo response. The team undertook a comprehensive literature search and included studies that were parallel-arm, double-blind and placebo-controlled, specifically recruiting patients with treatment-resistant depression. They set the primary outcome as the Hedges g value, which is a measure of the effect size, for the placebo response. The value of Hedges g indicates the extent to which two groups differ, based on the size of the standard deviation, e.g., a value of 1 indicates that groups differ by one standard deviations, 2 denotes two standard deviations and so on. As a secondary outcome, the team used meta-regression to explore potential moderators of the placebo effect.
A total of 50 clinical trials with 3228 patients, with a mean age of 45.8 years (20.7% women), where included in the final analysis. The placebos included pills, liquids, parenteral injections and several sham procedures such as sham transcranial magnetic stimulation, transcranial direct current stimulation or invasive brain stimulation. The pooled placebo effect size for all treatment modalities was large (Hedges g = 1.05, 95% CI 0.91 – 1.1) although this did vary with the type of placebo intervention. For example, with pill placebos, g = 1.14, parenteral placebo, g = 1.33. The pooled placebo response rate in all trials was 21.2% with a pooled remission rate of 13%.
In the TRD trials, meta-regression revealed that industry-sponsored trials, year of publication and studies with an open-label prospective phase before randomisation, all had a significantly higher placebo effect.
Discussing these findings, the authors felt that their results offered future researchers a benchmark for expected placebo responses in TRD trials. They concluded by calling for more consistent reporting of data, an agreement on the definition of TRD, and an assessment and reporting of participant’s expectations and experiences within a clinical trial.
Jones BDM et al. Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis. JAMA Netw Open 2021
9th October 2020
Consequently, researchers often use a combination of objective and subjective measures when assessing the response to treatment. For instance, it is known that subjective measures, for example, pain scores can be high, hence the need for independent, objective measures. However, in a new analysis of the placebo response among patients in trials for rheumatoid arthritis therapies, a team from the Brigham and Women’s Hospital, Boston, USA, found significant improvements in both measures. The team examined the placebo arm responses for five double-blind trials conducted internationally of at least 24 weeks duration between 2005 and 2009 among patients with rheumatoid arthritis. They extracted the individual level patient data from trials and focused on pain scores (subjective) and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values, both of which are objective measures. Pain scores were assessed using a standardised measure, namely a 0 to 100 mm visual analogue scale (VAS) and CPR and ESR were measured by blood testing. As some patients in the trials crossed-over to the active treatment, the researchers pre-selected 12 weeks from baseline to assess responses. Study medications included methotrexate and other disease-modifying antirheumatics.
The data set included 788 patients (82% women) with a mean age of 51 years. There was a statistically significant reduction in pain intensity (-14mm, 95% CI – 12 to 16 mm), CRP levels (-0.51mg/dl 95% CI -0.47 to -0.56) and ESR (-11mm/h, 95% CI -10 to -12), all with p values less than 0.001. Commenting on their findings, the authors were surprised by the clinically meaningful reductions in subjective and objective measures observed in placebo participants, indicating that it was more than a psychological placebo effect.
Furthermore, the cautioned that simply using objective rather than subjective measures in future trials would not necessarily lead to clearer results and that there was a need to further understand the effect of confounding factors and baseline covariates in placebo responders.
Vollett J et al. Assessment of placebo response in objective and subjective outcome measures in rheumatoid arthritis clinical trials. JAMA Netw Open 2020;3(9):e2013196. doi:10.1001/jamanetworkopen.2020.13196