This trial compares intermittent theta-burst stimulation (iTBS) to low frequency repetitive transcranial magnetic stimulation (LFR) in regards to depression and anxiety outcomes in 100 patients with treatment resistant depression (TRD).

The overarching goal of this trial is to evaluate whether a definite adaptive pragmatic trial would be feasible and establish clear go/no-go criteria as to whether proceeding to such definite trial is feasible. Specific aims include 1) testing the feasibility of recruiting a sample of TRD patients with less strict inclusion and exclusion criteria; 2) comparing different depression and anxiety scales (both clinician-rated and self-rated) and seek input from patients regarding their preferences; 3) seek input from patients with regards to the use of digital phenotyping as a tool to investigate biomarkers as well as engaging in the design of a potential implementation of such biomarker in a future definite trial.

Aim 1. To evaluate the feasibility of a future definite adaptive pragmatic RCT comparing left vs right DLPFC repetitive transcranial magnetic stimulation (rTMS) in TRD.

Hypothesis 1a: Enrollment will be 70% of the planned target over the 1-year recruitment period.

Hypothesis 1b: Retention rate of randomized participants will be ≥70% at the end of the intervention in both groups.

Aim 2. To evaluate patients' preferences regarding information about treatment options when there is no response to allocated treatment.

Hypothesis 2: Patients will prefer to modify treatment when there is no response.

Aim 3. To assess the feasibility of digital phenotyping as an tool to investigate biomarkers in TRD.

Hypothesis 3a: Survey uptake and participation in the study regarding the use of digital phenotyping will be 80% of randomized participants. Hypothesis 3b: Of those survey responders, 75% will indicate they would consent to digital phenotyping in a future definite RCT.

Aim 4. To develop a Bayesian statistical model that continuously updates personalized treatment effect estimates as the trial progresses, and identify the circumstances under which use of the model in a full-scale trial could inform treatment choice as the trial progresses.

Hypothesis 4: The modeling results will identify at least one subgroup for whom early stopping of the definitive trial in that subgroup may be warranted.

Inclusion Criteria:

1. are outpatients;
2. are voluntary and competent to consent to treatment;
3. are ≥ 18 years;
4. have a score ≥ 26 on the IDS-30-SR;
5. have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening;
6. able to adhere to the treatment schedule;
7. pass the TMS adult safety screening (TASS) questionnaire

Exclusion Criteria:

1. have active suicidal intent;
2. are pregnant;
3. have a lifetime diagnosis of schizophrenia, bipolar disorder type I, schizophreniform, schizoaffective disorder or presence of psychotic symptoms within last 3 months;
4. have a concomitant major unstable medical illness;
5. have any significant form of dementia or any history of epilepsy;
6. have any intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed;
7. If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study;
8. If they are taking psychotropic medication, be on a stable dose for 4 weeks before starting treatment, and no initiation of new regular psychotropic medication;
9. have a clinically significant laboratory abnormality, in the opinion of the one of the principal investigators;
10. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).

Single-masked (i.e. raters)