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Invited Commentary
September 24, 2021

Treatment-Resistant Depression—Resistant to Placebos as Well?

Author Affiliations
  • 1Depression Clinical and Research Program, Massachusetts General Hospital, Boston
  • 2Department of Pain and Translational Science Symptoms, School of Nursing, University of Maryland, Baltimore
JAMA Netw Open. 2021;4(9):e2127952. doi:10.1001/jamanetworkopen.2021.27952

The article by Jones et al1 applies meta-analysis to examine placebo responses across different treatment modalities in clinical trials conducted in patients with treatment-resistant depression (TRD). While high rates of placebo responses are a well-established challenge in studying depression treatments, it has generally been assumed that placebo response rates should be lower in TRD studies.

The authors examined 50 studies including 3228 participants, and the resulting effect size for placebo would be considered large (Hedges g = 1.05), albeit smaller than that typically observed in major depressive disorder (MDD) trials in individuals without TRD. The pooled response rate for placebo/sham treatment across all treatment modalities (placebo, pharmacology, brain stimulation, or psychotherapy) in TRD was 23.5%, and the remission rate was 15.5%, substantially lower than the average response rate to placebo in MDD trials (35-40%). Still, the reported overall placebo or sham response rate in TRD may be greater than what many clinicians would expect based on their own practices, which may reflect differences between clinical trials and real-world outcomes.

The meta-analysis also considered study characteristics associated with differential placebo effect sizes. Some of these were to be expected, such as lower number of prior treatments indicating less treatment resistance; the varying definitions of TRD contribute substantially to heterogeneity across studies.2 Others may be more surprising, including industry sponsorship and inclusion of an open-label prospective treatment phase. Over the past 2 decades, pharmaceutical companies have invested tremendous effort in minimizing the placebo response rate in clinical trials, including adopting novel or more complex study designs.3 Colloca and Barsky4 suggested other strategies to minimize unwanted placebo responses in the context of clinical trials, such as including measurements of patients’ expectations of individual improvements, measurements of patients’ beliefs about the efficacy of an active treatment, and adoption of standardized language for benefit/risk profile(s) of the treatment, duration of the visits, and checklists for assessing adverse effects.

With lower placebo response rates, it should be easier to design and implement informative clinical trials, yet the number of treatments approved for TRD remains quite low. There are many reasons clinical trials may fail to demonstrate benefit even for potentially efficacious interventions, including nonadherence to protocol, enrollment of inappropriate participants or secondary gains, measurement errors, and high dropout rates. Among the greatest challenges is a high placebo response rate. The placebo phenomenon per se encompasses expectations (possibly higher in a novel treatment, or with a more invasive procedure), relationship between clinician and patient, and other contextual or environmental factors. One placebo researcher has noted that, “When a treatment is given to a patient, be it sham or real, it is not administered in a vacuum, but in a complex set of psychological states that vary from patient to patient and from situation to situation. Novel interventions may be administered along with a complex set of psychosocial stimuli which tell the patient that a clinical improvement should be occurring shortly.”5 Complex or invasive procedures in TRD interventions might contribute to increase the placebo response. While this meta-analysis showed that placebo responses are similar across treatment modalities in TRD (placebo, pharmacotherapy, brain stimulation, or psychotherapy), this is not the case for other disorders; for example, a meta-analysis in migraine prophylaxis pointed out that sham acupuncture and sham surgery resulted in higher placebo responses than oral placebos.6 The fact that placebo response ratios vary across disorders and treatments outlines the need for more mechanistic research to be translated into clinical trial methodology and development.

More generally, the placebo mechanisms in depression and in particular in TRD remain minimally understood, mostly because of the difficulty of creating a model for understanding short-term and long-term changes reliably associated with placebo manipulation.

The article by Jones et al1 sets a benchmark for future clinical trials in TRD regarding the expected placebo response rate, and calls attention to the need for translational efforts to understand the neurobiological basis of placebo effects.

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Article Information

Published: September 24, 2021. doi:10.1001/jamanetworkopen.2021.27952

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Cusin C et al. JAMA Network Open.

Corresponding Author: Cristina Cusin, MD, Depression Clinical and Research Program, Massachusetts General Hospital, One Bowdoin Square, Ste 634, Boston, MA 02114 (ccusin@mgh.harvard.edu).

Conflict of Interest Disclosures: Dr Cusin reported personal fees from Janssen, Perception, and Takeda; and grants from Clexio, Livanova, AFSP, and the National Institute of Mental Health outside the submitted work. No other disclosures were reported.

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Meissner  K, Fässler  M, Rücker  G,  et al.  Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis.   JAMA Intern Med. 2013;173(21):1941-1951. doi:10.1001/jamainternmed.2013.10391PubMedGoogle ScholarCrossref