Background: Treatment-resistant depression is a burdensome condition. Intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is considered a treatment option in early course of resistance with a proportion of such patients responding to it. Preliminary evidence suggests a role of priming iTBS stimulation with preconditioning using cathodal transcranial direct current stimulation (tDCS). This protocol describes a double-blind randomized sham-controlled study to evaluate the clinical efficacy and tolerability of tDCS-primed iTBS in the treatment of resistant depression. Non-responders to this trial will be offered open-label electroconvulsive therapy. All participants will undergo neurobiological investigations that will enable the identification of potential response predictors and mechanisms. Methods: Three hundred and fifty consenting patients with treatment resistant depression will be randomly assigned to receive 20–30 daily sessions of true-tDCS or sham-tDCS primed iTBS over left dorsolateral prefrontal cortex at three study centers. After this blinded sham-controlled trial, non-responders to the intervention will be offered open-label true ECT. Clinical assessments, neurocognitive assessments and multimodal investigations (magnetic resonance imaging, electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphisms) will be conducted at baseline and repeated after the end of the trial, as well as open-label ECT course. The trial will evaluate the improvement in depressive symptoms (Hamilton depression rating scale) between the two groups as the primary outcome measure.