The aim of this study is to test the hypothesis that low-frequency rTMS (LFR) works as well as the established intermittent thetaburst rTMS (iTBS) treatment for treatment resistant depression (TRD).

In this multi-centre, triple-blinded, non-inferiority trial 420 patients with TRD will be recruited at two academic centres (UBC, CAMH). Patients will be randomised to receive either iTBS or LFR for 30 sessions. The primary outcome will be the improvement on a depression scale. Secondary outcome will be improvement of suicidal ideation. A secondary aim is to test the predictive capacity of a novel, easy to implement heart rate based biomarkers (i.e. heart rate variability).

Inclusion Criteria:

1. are female or male;
2. are outpatients;
3. are voluntary and competent to consent to treatment;
4. have a DSM 5 diagnosis of MDD,55 single or recurrent confirmed by Mini-International Neuropsychiatric Interview (MINI) version 7.0;
5. are 18yo to 65yo;
6. have failed to achieve a clinical response to an adequate dose of an antidepressant based on an Antidepressant Treatment History Form (ATHF) score of > 3 in the current episode OR have been unable to tolerate at least two separate trials of antidepressants at less than the minimum adequate dose and/or duration (ATHF 1 or 2);
7. have a score ≥ 18 on the Hamilton Depression Rating Scale (HDRS-17 item);
8. have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening;
9. are able to adhere to the treatment schedule;
10. pass the TMS and MRI adult safety screening questionnaires.

Exclusion Criteria:

1. have a history of substance use within the last 3 months;
2. have a concomitant major unstable medical illness;
3. have active suicidal intent;
4. are pregnant;
5. have a lifetime (MINI) diagnosis of any psychotic or bipolar disorder;
6. have a MINI anxiety disorder or personality disorder assessed by a study investigator to be primary and causing greater impairment than MDD;
7. have failed a course of ECT in the current episode;
8. have any significant neurological disorder, any history of seizure (except those therapeutically induced by ECT), significant head trauma with loss of consciousness for > 5 min;
9. have any intracranial implant (e.g., aneurysm clips) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed;
10. are participating in psychotherapy, must have been in stable treatment for at least 3 months prior to study entry, with no anticipated change in the frequency of therapeutic sessions, or focus of therapeutic sessions over the duration of the study;
11. have a clinically significant laboratory abnormality, in the opinion of the one of the principal investigators;
12. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview);

Study doctors and raters obtaining outcome measures will be blind to treatment assignment.