Equivalent efficacy of left versus right hemisphere accelerated intermittent theta burst stimulation for major depressive disorder

Davin Kenneth Quinn^1*Joel Upston¹Thomas Ryall Jones¹Tessa A. Olmstead¹Justine H. Yang¹Samuel Enrique Reyes Sanchez¹Samuel MacDonald¹Adam Littleton²Alexander Win¹Dorothy H. Bowers-Wu¹Jordan G. Lee³Pearl M. Huynh³Robert T. DeBurlo¹Ali Nakip¹Elizabeth R. Richardson¹Justin R. Davis³Shawn Hazlewood¹Crystal A Garcia¹Cesar J. Ojeda¹Karen Luo²Julian David²Benjamin C. Gibson⁴Gregory M. Nikogosyan¹Brant W. Hager¹Danielle Farrar¹Orrin Myers⁵Andrei A Vakhtin⁶Christopher C. Abbott¹

• ¹Department of Psychiatry and Behavioral Sciences, University of New Mexico, Albuquerque, United States
• ²Department of Neurosciences, University of New Mexico, Albuquerque, United States
• ³School of Medicine, University of New Mexico, Albuquerque, United States
• ⁴Department of Psychology, University of New Mexico, Albuquerque, United States
• ⁵Department of Family and Community Medicine, University of New Mexico, Albuquerque, United States
• ⁶Mind Research Network, Albuquerque, United States

Background: Intermittent theta burst stimulation (iTBS) to the dorsolateral prefrontal cortex (DLPFC) for major depression has been FDA-approved in the United States since 2018. Accelerated iTBS (aiTBS) protocols of multiple treatments per day have shown promising response and remission rates for major depression, especially when combined with connectivity-guided targeting. Brain networks associated with emotion regulation demonstrate significant changes in connectivity after effective iTBS. However, these findings have been confined to treatment of the left DLPFC, despite literature suggesting equivalent outcomes with right side stimulation. To date there has not been a direct comparison of clinical outcomes and connectivity changes between left and right DLPFC aiTBS for depression. Methods: Forty-four patients aged 50-79 with chronic major depressive disorder underwent open-label accelerated fMRI-guided aiTBS (45 sessions, 9 days) to the DLPFC (18 left, 26 right). Depression, anxiety, and anhedonia symptoms were assessed, and resting-state fMRI was obtained at baseline (Visit 1), after 15 sessions (Visit 2), and end of treatment (Visit 3). Patients who were not demonstrating at least 10% improvement in depression at Visit 2 were switched to contralateral stimulation for the remaining 30 sessions. Results: For the entire cohort (N = 44), mean depression (IDS-C30) scores decreased significantly over the course of treatment. Mean change in IDS-C30, GAD-7, TEPS, SHAPS, and BISBAS between participants with right-sided stimulation (N = 26) and those with left-sided stimulation (N = 18) were not statistically different. Functional connectivity analysis demonstrated significant decreases in connectivity from Visit 1 to Visit 3 between default mode network and limbic networks in patients receiving right DLPFC iTBS, whereas patients receiving left DLPFC iTBS demonstrated limited changes in connectivity. Conclusion: Accelerated iTBS to the right DLPFC appears to have equivalent efficacy as aiTBS to the left DLPFC in terms of magnitude of reduction of depressive, anxious, and anhedonic symptoms in a late-life population. However, connectivity changes associated with treatment were asymmetric, and may reflect hemispheric lateralization of functional network responses to iTBS. Further work is needed to confirm the comparative efficacy and network dynamics of left versus right hemisphere aiTBS for depression.