This is a parallel randomized, double-blinded, sham-controlled clinical trial in which a total of 72 drug-naïve MDD subjects (36 per arm) are randomized to one of two groups: Cognitive-Behavior Therapy (CBT) combined with either active or sham tDCS.

The primary outcome is mood improvement, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). The secondary outcome is to test whether tDCS combined with CBT can engage the proposed mechanistic target, of restoring the prefrontal imbalance and connectivity, by changes over EEG.

Major Depression Disorder (MDD) is widely recognized as a staggering global healthcare challenge, as well as a potentially lethal illness. In Portugal, 7% of the population is diagnosed with depression every year, and suicide is responsible for more than a thousand deaths annually.

The current standard care for MDD involves the use of psychotherapy, antidepressant medication, or a combination of both. However, approximately 30% of people suffering from MDD exhibit depressive symptoms despite the appropriate psychological and pharmacological treatments. One option is to combine several treatments, usually by the use of drug augmentations and/or combinations of different drugs, which often increases the risk of adverse effects. Thus, it is important to study non-pharmacological interventions targeting mechanisms not directly involved with the regulation of neurotransmitters.

Cognitive-behavioral Therapy (CBT) is a well-established, and empirically-supported non-pharmacological treatment for depression, including for those that have not responded to antidepressants. However, several patients remain refractory to CBT.

tDCS is a safe, non-invasive, rather inexpensive, easy to administrate, and well-tolerated neuromodulatory technique. Several studies, including studies from our group, already shown that tDCS can be effective in MDD. However, tDCS seems to have a better effect when used as an add-on treatment to other intervention.

What is not known so far are the effects of using tDCS as add-on intervention to CBT on MDD symptoms.

Therefore, this is a parallel randomized, double-blinded, sham-controlled clinical trial in which a total of 72 first-episode MDD subjects (36 per arm) will be randomized to one of two groups: CBT combined with either active or sham tDCS. The design and the tDCS parameters will be similar to the SELECT trial by Brunoni et al. (2013).

The primary outcome is mood improvement, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). The secondary outcome is to test whether tDCS combined with CBT can engage the proposed mechanistic target, of restoring the prefrontal imbalance and connectivity, by changes over resting-state EEG and fMRI.

Inclusion Criteria:

• 1)Aged 18-75 years;
• 2)Unipolar, nonpsychotic MDD;
• 3)Score in the MADRS between 7 and 34(mild to moderate depression);
• 4)Low risk of suicide;
• 5)Able to sign informed consent

Exclusion Criteria:

• 1)Any contraindication to receive tDCS(such as metal in the head, implanted brain medical devices);
• 2)any significant or unstable neurologic or psychiatric disorder other than MDD;2) history of substance abuse within the past 6-months;
• 3)Any personality disorders; and
• 5)any severe life-threatening Axis III disorders or concurrent medical condition likely to worsen patient's functional status in next 6-months such as; cancer, terminal heart, kidney, or liver disease.

Both the Participant, the outcome assessor and the Psychologist providing the CBT will be blinded to the type of the stimulation that the subject is receiving. Unblinding will occur at the end of the participation in the study and subjects that received sham tDCS will have the chance to receive the active tDCS.