BACKGROUND: Although add-on transcranial direct current stimulation (tDCS) is a promising intervention for treating unipolar (UD) and bipolar depression (BD), its moderate antidepressant efficacy urges research into biomarkers for predicting therapeutic response and achieving highly targeted applications. METHODS: This open-label trial enrolled UD (N=58) and BD (N=22) patients who had failed 1 or more trials of adequate pharmacologic interventions (ClinicalTrials.gov ID: NCT03287037). Bifrontal tDCS (anode/cathode: F3/F4) was applied using a 2 mA current for 20 min, twice daily, for 5 consecutive weekdays. Depression was measured with Hamilton Depression Rating Scale-17 (HAMD) at baseline, after 10-session stimulation, 1- and 4-week follow-ups. Heart rate (HR) and heart rate variability (HRV) was measured at baseline, during the initial 5 min of the 1(st) session, after 10-session stimulation, 1- and 4-week follow-ups. Cognitive performance and other outcomes were also assessed. RESULTS: Bifrontal tDCS rapidly and equally improved depression in both groups. The effects persisted until the end of the trial. Both groups had similar improvements in cognitive performance, anxiety, and psychosocial functioning. Compared with baseline, increased vagally-mediated HRV was observed one month after tDCS for both groups. A positive correlation was found between HR deceleration within the 1(st) session and treatment response after 10-session tDCS only among UD patients, explaining 20% of the variance. CONCLUSION: tDCS as an adjunct therapy is effective for both UD and BD. Data suggest that the greater the increase in parasympathetic signaling during the 1(st) session, the better the clinical response after 10-session tDCS for UD patients.