Enhanced Bilateral Accelerated Theta Burst Stimulation for Comorbid Anxiety and Depressive Disorders: The Seville Protocol.

Background: Treatment-resistant depression (TRD) with comorbid anxiety affects up to 30% of patients and frequently fails to respond to conventional therapeutic approaches. The Seville Protocol is a novel, accelerated, high-dose, bilateral theta burst stimulation (TBS) paradigm combining intermittent TBS (iTBS) and continuous TBS (cTBS), specifically designed to address both depressive and anxiety symptoms in TRD. Methods: This retrospective study was conducted at the Andalusian Institute of Brain Health (Seville, Spain). All participants received the Seville Protocol, consisting of neuronavigated iTBS applied to the left and cTBS to the right dorsolateral prefrontal cortex (DLPFC), delivered at high intensity (110-133.5% of the resting motor threshold) over 30 sessions within three weeks. Symptom severity was assessed at baseline and post-treatment using the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). Treatment efficacy was analyzed using the Wilcoxon signed-rank test, and logistic regression models were applied to identify predictors of response and remission. Results: A total of 64 patients diagnosed with TRD and comorbid anxiety were included in the analysis. The Seville Protocol led to significant improvements in both HAM-D and HAM-A scores (p < 0.001). Response rates were 45.3% for depression (95% Confidence Interval (CI) = 33.7-57.4) and 48.4% for anxiety (95% CI = 36.6-60.4), while remission rates were 29.7% for depression (95% CI = 19.9-41.8) and 23.4% for anxiety (95% CI = 14.7-35.1). Logistic regression analysis suggested that a positive family history of mental disorders was associated with a lower likelihood of depression response (β = -1.49, 95% CI = -2.98 to -0.18, p = 0.033); however, this association did not remain significant after false discovery rate (FDR) correction (adjusted p = 0.298). Conclusions: The Seville Protocol appears to be a feasible, practical, and time-efficient neuromodulation approach for patients with TRD and comorbid anxiety. These findings support the potential utility of accelerated bilateral TBS in this population, although further studies are needed to validate the findings and assess their broader applicability.