Adjuvant Accelerated piTBS for Reducing Suicidal Ideation in TRD Patients

Less than half of patients with major depressive disorder (MDD) remit after first-line therapy (i.e., pharmacotherapy and/or psychotherapy). A progressively smaller proportion of patients remit with each subsequent medication trial, and a remission rate of only 10-15% after a fourth antidepressant trial. Patients with MDD are considered to have a treatment-resistant depression (TRD) whey they do not achieve response to first-line antidepressants. Repetitive Transcranial Magnetic Stimulation (rTMS) applied over the DLPFC for modulating brain activity and network connectivity has well-documented positive effects on major depressive disorder (MDD), especially TRD. rTMS research in treating MDD has shown a dose-response relationship and more recently, studies have shown a trend towards administering more stimuli over a shorter period of time and at higher frequencies leading to accelerated protocols. An optimized rTMS parameter called intermittent theta burst stimulation (iTBS) is a novel protocol that consists of intermittently delivering bursts of 3 TMS pulses at high frequency (50 Hz) every 200 ms for 2 s (5Hz) every 10 s (total 600 pulses), allowing for greater long-lasting effects on cortical excitability and a more important number of rTMS pulses to be delivered in a shorter duration than standardized high frequency (HF) rTMS protocols. iTBS induces a long-term potentiation (LTP)-like effect by increasing the postsynaptic concentration of calcium ions and has been applied to treat MDD. iTBS has been proved to be safe and well tolerated and to have antidepressant properties. Prolonged iTBS (piTBS, total 1800 pulses) has been recently applied to treat MDD with favorable antidepressant properties. An accelerated protocol of piTBS has been recently approved to treat medication-refractory MDD by FDA. MDD is associated with a 2.3 fold increase in prevalence of suicidal ideation as compared to the general population. The lifetime rate of death due to suicide among MDD patients is 15-20%. Research indicates that 30% of TRD patients will attempt suicide during their lifetime, which is a two-to-four times greater proportion than MDD patients who respond to treatment. Research indicates that rTMS improves several preconditions for suicide, including mood, memory, attention, executive functioning. rTMS is thought to have molecular effects similar to those seen with electroconvulsive therapy (ECT), which is effective in treating suicidal patients, such as increased BDNF, increased monoamine turnover and normalization of the hypothalamic-pituitary-adrenal axis. Some research indicates that rTMS may reduce suicidal ideations of patients with MDD. However, powered sham-controlled rTMS clinical trials focusing on the efficacy to improve suicide risks are limited. The study aims to investigate the efficacy of accelerated piTBS over the left DLPFC as an add-on therapy to improve suicide ideations in TRD patients. Moreover, it provides data on other secondary outcomes and neurophysiological data for this intervention condition.