The CogniTReaD study is a pilot clinical trial that will compare the effects of active accelerated bilateral sequential theta burst stimulation (absTBS) and sham or inactive treatment. The goal is to see if absTBS can help older adults with treatment-resistant depression (TRD) by looking at dual-task cost and mood, as well as other cognitive functions, anxiety levels, quality of life, and physical performance, while also checking for any treatment side effects. The study will recruit participants who will receive different study treatments in a specific order. The study will be double-blinded, meaning neither the participants nor the researchers will know who is receiving which treatment. The study will include people who are 50 years old or older and diagnosed with treatment-resistant depression with at least a moderate severity of depression. This study seeks to discover if absTBS can modify a dementia risk marker (i.e., dual-task cost and depression) in older patients with TRD, and to determine the effect size for larger investigations in the future.

The CogniTReaD study is a two-arm, sham-controlled, double-blinded, treatment-sequenced, randomized clinical trial that will evaluate and explore the effects and safety of accelerated bilateral sequential theta burst stimulation (absTBS) compared to sham control in terms of improving dual-task cost, cognitive functions, depression, other outcomes (anxiety, health-related quality of life, activities of daily living, global impression, and other gait performance), and occurrence of adverse events (AE) measured at Week 2 (i.e., posttreatment acute effects) in older adults with treatment-resistant depression (TRD). We shall also evaluate the effects and safety of absTBS on improving dual-task cost, cognitive functions, depression and occurrence of AE in terms of AE occurrences measured at Week 6, Week 8, and Week 10 (i.e., posttreatment delayed effects) in older adults with TRD.

Inclusion Criteria

1. Aged 50 years or older;
2. Mini International Neuropsychiatric Interview (MINI)-confirmed diagnosis of a non-psychotic major depressive disorder;
3. Currently in a major depressive episode with a score on HAMD-17 of 17 or more;
4. Insufficient response (i.e., failure to achieve remission) to at least two appropriate courses of antidepressant medications during the current depressive episode (i.e., meeting the criteria for TRD);
5. Participants taking or not taking any psychotropic medication/s. If the eligible participant is on any psychotropic medications, the participant should have taken the medication/s at a stable dose for at least 1 week before the start of study intervention treatment and be willing to remain on a stable dose throughout the study follow-up;
6. Passing the TMS safety screen; and
7. Those who have the capacity to provide consent and who voluntary consent to participate in the study.

Exclusion Criteria

1. Those with MINI-confirmed active substance use disorder within the last 3 months;
2. Those with lifetime MINI-confirmed diagnosis of bipolar I disorder, delusional disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder;
3. Those with major unstable medical comorbidities (i.e., rapidly deteriorating medical/neurological conditions that poses a significant risk to a person's life);
4. Those with a diagnosis of dementia confirmed using the Global Clinical Dementia Rating (CDR) with a score greater than or equal to 1.
5. Those with significant neurological conditions, such as those with any disease process associated with increased intracranial pressure, space-occupying intracranial lesion, history of epilepsy/seizure except those induced by ECT, or febrile seizure of infancy or a single occurrence of seizure associated with a known drug, cerebral aneurysm, or major head trauma resulting to loss of consciousness more than 5 minutes;
6. Those with cardiac pacemaker or implanted mediation pump;
7. Those with intracranial implants/hardwares, including but not limited to aneurysm clips, shunts, stimulators, cochlear implants, electrodes, or any other metal material inside or near the head (excluding the mouth) that cannot be safely removed;
8. Those who are taking more than 2 mg of Lorazepam daily (or equivalent) or taking any dose of an anticonvulsant that may potentially hamper rTMS efficacy;
9. Those who are unable to express and understand using the English language; and
10. Individuals who are pregnant or who are likely pregnant.

Anonymized individual participant data can be made available by request from qualified researchers/investigators.

We shall perform a double-blinding system where the participants, study investigators, transcranial magnetic stimulation (TMS) technicians (those who operate and administer TMS procedures), and research assistants (outcome assessors) are masked to the assignment of the enrolled participants.