The Placebo Effect Is Real in Depression Studies

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A team of investigators sought to determine the extent of the placebo effect in the management of treatment-resistant depression, as well as factors contributing to it.

Clinical trials for treatment-resistant depression have been found to show a large placebo effect in a recent meta-analysis published in JAMA Psychiatry. The findings serve as a placebo effect size benchmark that researchers can use to interpret findings from future studies.

As people with treatment-resistant depression often experience lower rates of response and remission, it is important to quantify the magnitude of the placebo effect in clinical trials.

Researchers therefore conducted a search of MEDLINE, Web of Science, and PsychInfo databases that ranged from inception to June 21, 2021. They looked for parallel-arm, double-blind, placebo-controlled, randomized clinical trials (RCTs) or the first phase of randomized crossover trials that exclusively recruited patients with treatment-resistant depression and included at least 1 placebo arm with an inert pill placebo, parenteral placebo, sham device, or sham therapy. After applying inclusion and exclusion criteria, the researchers included 50 studies in the analysis.

The researchers identified a large (g=1.05) combined placebo effect size for all interventions, but the placebo effect sizes for each treatment modality did not significantly differ. This finding is similar to those from prior analyses with RCTs involving antidepressants that showed a large placebo effect size in major depressive disorder (not treatment resistant). They also found that the effect size in RCTs involving patients with treatment-resistant depression is numerically smaller for pill placebo and numerically larger for sham stimulation than the effect sizes reported in RCTs that involved patients without treatment-resistant depression. Response and remission rates did not differ significantly across treatment modalities.

The analysis did not include studies assessing psychotherapy, electroconvulsive therapy, or magnetic seizure therapy, which is a limitation of the current research. The researchers did not include 2 large studies because of conflicting definitions of treatment-resistant depression.

The researchers concluded, “to better understand the placebo effect, the following improvements are needed: more consistent reporting of data, an agreement on a standard definition of [treatment-resistant depression] and its possible subgroups, and further assessment and reporting of participants’ expectations and experiences within a clinical trial.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Jones BDM, Razza LB, Weissman CR, 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;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531