Importance While the effects of internet- and mobile-based interventions (IMIs) for depression have been extensively studied, no systematic evidence is available regarding the heterogeneity of treatment effects (HTEs), indicating to what extent patient-by-treatment interactions exist and personalized treatment models might be necessary.

Objective:

To investigate the HTEs in IMIs for depression as well as their efficacy and effectiveness. Data Sources A systematic search in Embase, MEDLINE, Central, and PsycINFO for randomized clinical trials and supplementary reference searches was conducted on October 13, 2019, and updated March 25, 2022. The search string included various terms related to digital psychotherapy, depression, and randomized clinical trials. Study Selection Titles, abstracts, and full texts were reviewed by 2 independent researchers. Studies of all populations with at least 1 intervention group receiving an IMI for depression and at least 1 control group were eligible, if they assessed depression severity as a primary outcome and followed a randomized clinical trial (RCT) design. Data Extraction and

Synthesis:

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Risk of bias was evaluated using the Cochrane Risk of Bias Tool. HTE was investigated using logarithmic variance ratios (lnVR) and effect sizes using Hedges g. Three-level bayesian meta-regressions were conducted. Main Outcomes and

Measures:

Heterogeneity of treatment effects was the primary outcome of this study; magnitudes of treatment effect sizes were the secondary outcome. Depression severity was measured by different self-report and clinician-rated scales in the included RCTs.

Results:

The systematic review of 102 trials included 19 758 participants (mean [SD] age, 39.9 [10.58] years) with moderate depression severity (mean [SD] in Patient Health Questionnaire-9 score, 12.81 [2.93]). No evidence for HTE in IMIs was found (lnVR = -0.02; 95% credible interval [CrI], -0.07 to 0.03). However, HTE was higher in more severe depression levels (ß̂ = 0.04; 95% CrI, 0.01 to 0.07). The effect size of IMI was medium (g = -0.56; 95% CrI, -0.46 to -0.66). An interaction effect between guidance and baseline severity was found (ß̂ = -0.24, 95% CrI, -0.03 to -0.46). Conclusions and Relevance In this systematic review and meta-analysis of RCTs, no evidence for increased patient-by-treatment interaction in IMIs among patients with subthreshold to mild depression was found. Guidance did not increase effect sizes in this subgroup. However, the association of baseline severity with HTE and its interaction with guidance indicates a more sensitive, guided, digital precision approach would benefit individuals with more severe symptoms. Future research in this population is needed to explore personalization strategies and fully exploit the potential of IMI.