Determinants of sham response in tDCS depression trials : a systematic review and meta-analysis

Background: Randomised clinical trials (RCTs) investigating transcranial direct current stimulation (tDCS) efficacy for depression show significant heterogeneity in outcomes. Objective: To investigate the magnitude of the sham tDCS response and its potential moderators in the treatment of depression. Methodology: A systematic review and aggregate meta-analysis (PROSPERO ID CRD42020161254). The systematic review was conducted in the PubMed, Scopus (EMBASE) and Cochrane Library databases. Only RCTs enrolling adult subjects with an acute depressive episode with a sham tDCS group were included. Results: Twenty-three studies (twenty-five datasets, 501 participants) were included. Sham tDCS response was large (Hedges & rsquo; g = 1.09; 95% CI: 0.8;1.38). Secondary and subgroup analyses showed that sham protocols employing a ramp-up/ramp-down at the beginning and end of stimulation presented a significantly lower sham response compared to other protocols. Univariate meta-regression analyses found that sham response was associated with higher risk of blinding bias, and with thetreatment effect size of the active tDCS group. Subgroup analyses also showed that placement of the cathode over the lateral right frontal area (F8) presented a significantly lower sham response. Other moderators, including treatment resistance, baseline severity of depressive symptoms, and total charge delivered were not associated with the magnitude of the sham response. Conclusion: The sham tDCS response was large. Our findings demonstrate the need for standardization of sham tDCS protocols and bring attention to important considerations that can guide future RCTs employing tDCS for the treatment of MDD