Translation of preclinical findings: The effect of low intensity repetitive Transcranial Magnetic Stimulation (rTMS) on depression score and biomarkers in patients with major depression

Abstract Background: Major depressive disorder is one of the most prevalent and costly medical conditions, with approximately 280 million people affected worldwide. It is estimated that 30-60% of individuals suffering from this disorder are treatment-resistant, not responding to psychotherapy or antidepressants. Non-invasive brain stimulation in the form of repetitive transcranial magnetic stimulation (rTMS) is often considered an alternative treatment with response rates of up to 60% in this population. However, outcomes are variable suggesting that treatment protocols remain suboptimal. Current clinical guidelines are poorly defined due to a lack of systematic evaluation when techniques were first developed. Our lab has compared a range of brain stimulation protocols in a preclinical model of treatment-resistant depression and has shown that rTMS delivered at a low intensity matches the behavioural effects obtained from the much higher intensities that are currently approved for the treatment of depression in the clinic. Structural brain changes were also observed at the lower intensity, which may lead to longer lasting beneficial effects as in seen in previous animal studies. It is hypothesised that the same outcomes will translate to patients in a clinical setting. Methods: Participants will be recruited from patients diagnosed with Major Depressive Disorder. The study will consist of 4 to 6 weeks of treatment comprising 20-30 sessions (weekdays-only) of rTMS to the left dorsolateral prefrontal cortex. A “head-to-head trial” has been established due to ethical considerations and the need to retain the current clinical protocol. Patients will be randomly assigned to the FDA-approved standard protocol or standard protocol plus an additional low intensity stimulation group. In addition, patients will undergo psychological testing and a blood test at baseline, post-treatment and again at a 6-month follow up appointment Discussion: This study will prospectively evaluate the antidepressant efficacy of a new rTMS parameter. Specifically, we will translate a novel low intensity rTMS protocol and compare its long-term effects to the current FDA-accredited standard protocol. We will also test the validity of blood biomarkers, including those identified in our previous animal studies, to objectively monitor individual’s response to rTMS treatment. Trial registration: Registered with Australian New Zealand Clinical Trials Registry, prospectively registered 20/11/2018, Registration ACTRN12618001889246.