Magnitude and Moderators of Depressive Symptom Improvement in Digital Placebo Arms: Systematic Review and Meta-Analysis.

BACKGROUND

Depressive disorders are one of the most prevalent psychiatric disorders globally and impose considerable individual and societal burdens. Psychotherapy, including cognitive behavioral therapy, is recommended as a first-line treatment especially for mild to moderate depressive disorders. However, face-to-face psychotherapy is often limited by issues of accessibility and cost. Digital therapeutics (DTx)-defined as health software intended to treat or alleviate a disease, disorder, condition, or injury by generating and delivering a medical intervention that has a demonstrable positive therapeutic impact on a patient by the International Organization for Standardization-have gained increasing attention as alternatives for overcoming these hurdles. With advances in digital technology, digital placebos have begun to be used as comparators in the clinical trials of DTx to assess the effects of active interventions accurately. However, the characteristics of clinical trials, the magnitude of digital placebos effects, and their moderators remain poorly understood.

OBJECTIVE

This study aimed to characterize clinical trials using digital placebos in control arms and to assess the magnitude and moderators of Patient Health Questionnaire-9 (PHQ-9) improvement in digital placebo arms.

METHODS

The blinded randomized controlled trials (RCTs) evaluating PHQ-9 by setting digital placebos as comparators were identified by searching MEDLINE, Scopus, Web of Science, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and ISRCTN in November 2025. The characteristics of the RCTs and of the digital placebos were reviewed systematically. The meta-analysis including subgroup analyses and meta-regressions were conducted to investigate the magnitude and the moderators of the PHQ-9 improvement in digital placebo arms.

RESULTS

A total of 29 papers and 30 trials with 5680 participants were included in this systematic review and meta-analysis. The most common trial design was 2-arm, parallel-group RCTs conducted in a single country, adopting "Replaced" and "Mobile" as the placebo approach and delivery type, respectively. The pooled effect size for all the included trials, representing PHQ-9 changes within control arms, was Hedges g=0.44 (95% CI 0.29-0.59) with high heterogeneity (I2=93.2%, τ²=0.14). Subgroup analyses and univariable regression showed that "Primary psychiatric disorder" group (P=.008) and baseline PHQ-9 score (P<.001) were the independent moderators of the improvement in digital placebo arms. Multivariable regression indicated that these 2 variables are the major contributing factors of the high heterogeneity (I2=82.1%, τ²=0.07, R2=51.5%).

CONCLUSIONS

Our findings indicate that improvement in digital placebo arms is not negligible and should be incorporated into trial design. The factors identified in this study will be useful when estimating expected improvement in control arms and planning adequately powered future DTx clinical trials, alongside other relevant conceptual and methodological factors that may influence digital placebo effects.

TRIAL REGISTRATION: PROSPERO CRD420251118826; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251118826.