Investigating Biomarkers in Inpatients With Depression Receiving Accelerated Repetitive Transcranial Magnetic Stimulation (rTMS)

Major Depressive Disorder (MDD) is a highly prevalent and disabling disorder with substantial societal cost; furthermore, the costs associated to MDD increase substantially when it requires hospital admission. Among Neurological, Mental and Substance Use (NMS) disorders, depression is the number one cause of disability worldwide. Considering this high increase in prevalence, in addition to the limited efficacy of current treatments, with only 30-40% of patients achieving remission after an initial treatment, the illness burden attributable to NMS is projected to increase during the next decade. In Ontario alone, $12.5 billion a year is attributed to mood disorder related costs. Unfortunately, research into the treatment and prevention of mental illness is disproportionately low relative to the disease burden. Approved by Health Canada for MDD in 2002, repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for medically refractory major depressive disorder (MDD). rTMS involves direct stimulation of cortical neurons using externally applied, powerful, focused magnetic field pulses. Dozens of studies and several meta-analyses over the last 15 years have shown that rTMS of the dorsolateral prefrontal cortex (DLPFC) produces statistically significant improvements in MDD, even when medications have failed. In the most recent generation of randomized controlled trials, rTMS consistently achieves response rates of 50-55% and remission rates of 30-35% in medically refractory MDD patients. However, the vast majority of studies have focused on its used in outpatient samples. Furthermore, the few studies that have investigated its used in inpatient samples have demonstrated similar efficacy rates than medications using the conventional 10 Hz rTMS protocol. No study, has addressed the question whether rTMS can speed up the response rate, and shorten length of stay in hospital, nor what are the biomarkers of treatment response to rTMS in inpatient population. Conventional rTMS protocols, as used in the major trials in the USA that secured FDA approval in 2008, applied 3000 pulses of unpatterned, 10 Hz stimulation administered over 37.5 minutes. These protocols limit the number of patients who can be treated with a single machine to approximately 10 per day, thus perpetuating the high cost of treatment. In contrast, iTBS has been shown to have induce neuroplasticity, effective in MDD, and only requires 3 minutes to administer, making it a feasible option for multiple treatments per day, particularly in inpatient populations.

Therefore, addressing the question of biomarkers in inpatient population suffering MDD and whether improvement can be accomplished in only 3 weeks is a critical question with very direct impact and translation to clinical care.

HYPOTHESES:

1. Response to an index course of accelerated Left-iTBS 3 treatments per day will be associated with associated with increased activation of frontal regions in functional Near Infrared Spectroscopy (fNIRS) and electroencephalogram (EEG) (increase cerebral blood flow to left DLPFC, and decrease in alpha power in left DLPFC), and decrease of inflammatory biomarkers.
2. Depression scores on Hamilton Depression Ration Scale (HDRS)-17 will decrease by at the end of second week of treatment, in 50% of the sample.

OBJECTIVES: