Background Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique, which has yielded promising results in treating major depressive disorder. However, its effect on treatment-resistant depression remains to be determined. Meanwhile, as an emerging treatment option, patients’ acceptability of tDCS is worthy of attention. Methods This pilot study enrolled 18 patients (wome n = 13) with treatment-resistant unipolar ( n = 13) or bipolar ( n = 5) depression. Twelve sessions of tDCS were administered with anode over F3 and cathode over F4. Each session delivered a current of 2 mA for 30 min per ten working days, and at the 4th and 6th week. Severity of depression was determined by Montgomery–Åsberg Depression Rating Scale (MADRS); cognitive performance was assessed by a computerized battery. Results Scores of MADRS at baseline (29.6, SD = 9.7) decreased significantly to 22.9 (11.7) ( p = 0.03) at 6 weeks and 21.5 (10.3) ( p = 0.01) at 8 weeks. Six (33.3%) participants were therapeutically responsive to tDCS. MADRS scores of responders were significantly lower than those of non-responders at the 6th and 8th week. Regarding change of cognitive performance, improved accuracy of paired association ( p = 0.017) and social cognition ( p = 0.047) was observed at the 8th week. Overall, tDCS was perceived as safe and tolerable. For the majority of patients, it is preferred than pharmacotherapy and psychotherapy. Conclusions TDCS can be a desirable option for treatment-resistant depression, however, its efficacy may be delayed; identifying predictors of therapeutic response may achieve a more targeted application. Larger controlled studies with optimized montages and sufficient periods of observation are warranted. Trial registration This trial has been registered at the Chinese Clinical Trial Registry ( ChiCTR-INR-16008179 ).

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