The goal of this randomized controlled trial is to he effectiveness of two different TMS techniques in TRD, repetitive TMS (rTMS) and deep TMS (dTMS). The main questions it aims to answer are:

type of study: clinical trial participant population/health conditions : Major Depressive Disorder To assess the superiority of dTMS over rTMS in TRD To evaluate the predictive capacity of scalable candidate biomarkers Participants will be randomly allocated to one of the two intervention groups (rTMS or dTMS).

The primary aim of this trial is to compare the effectiveness of two different TMS techniques in TRD, repetitive TMS (rTMS) and deep TMS (dTMS). Compared to rTMS, dTMS delivers a broader magnetic field, which in turn reduces coil positioning error and maximizes the probability of optimal cortical stimulation. A past RCT comparing both approaches found a greater depression score decrease and response/remission rates for dTMS, but was short of reaching significance for remission rates (primary outcome). Critical components of this RCT were suboptimal, including too few treatment sessions and insufficient statistical power, both of which could have obscured an actual difference between modalities. Proof of a more effective type of TMS over another would translate into increased odds of improvement for TRD patients who live with a chronic and disabling illness.

Inclusion Criteria:

• Diagnosis of Major Depressive Disorder, at least moderate intensity, single or recurrent episode
• HRSD-17 score of at least 18
• No improvement to at least two adequate courses of antidepressants (based on the ATHF) or were unable to tolerate at least two separate trials of antidepressants of inadequate dose and duration
• On a stable antidepressant regimen for the past four weeks before screening
• Patients with a chronic depressive episode >2 years and who have previously received ECT or ketamine will be eligible to participate

Exclusion Criteria:

• Having previously received TMS;
• Substance use disorder within the last three months
• Diagnosis of bipolar or psychosis spectrum disorder
• Anxiety or personality disorder that is assessed by a study investigator to be the primary cause and causing greater impairment than MDD
• Concomitant major unstable medical or neurological illness
• Intracranial implant, cardiac pacemaker or implanted medication pump
• Significant laboratory abnormality;
• Active suicidal intent
• Pregnancy
• If participating in psychotherapy, must have been in stable treatment for at least three months before entry into the study, with no anticipation of change
• Currently taking more than the equivalent of 2 mg of lorazepam of a benzodiazepine daily or any dose of an anticonvulsant due to the potential to limit TMS effectiveness

Given the study's design, blinding participants and TMS operators will not be possible. Still, staff responsible for participant assessments and data analysis will be blinded to treatment conditions and external to the clinic staff. Patients will be instructed not to reveal their group assignment to the raters. Patients will not be given the specifics of the treatment parameters and will be instructed not to talk to each other during the study period. Both treatments will be presented as effective to them. Lastly, the data management center will strictly control access to the randomization code.