Heart Rate Modulation and Clinical Improvement in Major Depression: A Randomized Clinical Trial with Accelerated Intermittent Theta Burst Stimulation

Intermittent theta burst stimulation (iTBS) is a promising non-invasive treatment for major depressive disorder (MDD), though significant variability exists in patient responses. This quadruple-blind, sham-controlled crossover randomized clinical trial investigated whether clinical improvement was influenced by the spatial selection of stimulation sites or early cardiac rhythm modulations. Seventy-five MDD patients (33 women) were randomized to either personalized stimulation sites— identified via the strongest negative functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and the default mode network (DMN)—or fixed stimulation at the F3 position of the 10-20 EEG system. Electrocardiograms throughout stimulation monitored heart rate and its variability, focusing on heartbeat deceleration (RR slope) and changes in the root mean square of successive differences between heartbeats (RMSSD). Findings demonstrated that a higher RR slope within the first 45 seconds of stimulation predicted greater clinical improvement at six weeks, while a lower RMSSD change during the first 270 seconds correlated with improvement at one week. However, no significant differences in outcomes were observed between personalized and fixed stimulation sites. This study identified a significant relationship between early heart rhythm modulations and the antidepressant effects of accelerated iTBS in MDD. Although the spatial determination of stimulation sites did not enhance clinical improvement, iTBS-induced changes in cardiac rhythm during early sessions may develop into valuable biomarkers for stratifying patients, enabling more personalized and effective treatment strategies in the future.