Intermittent Theta Burst Stimulation for Major Depressive Disorder with Comorbid Anxiety: A Systematic Review of Clinical Efficacy and Predictors of Response

<b>Background:</b> Intermittent theta burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS), has gained increasing attention as a time-efficient neuromodulation protocol for major depressive disorder (MDD). However, its clinical effectiveness in individuals with co-occurring depression and anxiety remains insufficiently characterized. This systematic review aimed to evaluate clinical outcomes, including depressive and anxiety symptom severity, response, and remission, following rTMS in individuals with major depressive disorder and elevated anxiety symptoms. The primary outcome was the reduction of depressive and anxiety symptoms, while secondary outcomes included response and remission rates, adverse events, and potential predictors of treatment response. <b>Methods:</b> A systematic search was performed following the PRISMA guidelines in the following databases: PubMed, Scopus, Embase, PsycInfo, Web of Science, Elsevier, Google Scholar. The protocol was registered in PROSPERO (CRD420251117784). Six studies that met the inclusion criteria were selected as eligible; these included one randomized controlled trial, one controlled clinical trial, three open-label studies, and one retrospective study on iTBS alone or compared to conventional 10 Hz rTMS or pharmacotherapy. iTBS has demonstrated safety and efficacy in reducing depressive and anxiety symptoms. The response rate ranged between 30 and 60%, and the remission rate between 10 and 40%. Regarding comparative findings, the results are mixed, with some studies showing superior or comparable improvements to 10 Hz rTMS and others reporting no significant differences. Reported treatment outcomes were largely influenced by age, baseline severity, medication status, and comorbid anxiety. Antipsychotics, anticonvulsants, and benzodiazepines were associated with attenuated clinical benefit, and bupropion use was associated with increased response. <b>Conclusions:</b> Current evidence supports iTBS as an effective, well-tolerated, and time-efficient intervention for adults with depression and comorbid anxiety. However, variability in treatment outcomes and limited mechanistic data highlight the need for larger, harmonized, and mechanistically informed randomized trials to refine stimulation parameters, improve patient stratification, and clarify the neurobiological substrates of treatment response.