This work compared TBS and rTMS regarding their safety and therapeutic effect on MDD, mainly, including response rates, adverse events rates, remission rates and changes in depression scores reported by all the RCTs. Irrespective of whether the RE or QE model was used, eligible RCTs suggested that both TBS and rTMS groups exhibited comparable remission and response rates after treatment, thus, indicating similar antidepressant effects between the two groups. Regarding safety, the rate of adverse effects, such as headache, nausea, dizziness, fatigue, insomnia, anxiety/agitation, back/neck pain, tinnitus, migraine aura, and abnormal sensations, was also similar between the TBS and rTMS groups.
In 2018, as reported by a large-scale, and multi-cohort study involving 414 TRD cases, iTBS demonstrated similar acceptability and therapeutic effect as the FDA-approved standard 10 Hz rTMS on DLPFC (20 daily sessions), along with the comparable rate of side-effects.17 Similarly, in 2022, Blumberger et al. [41] reported that bilateral TBS (cTBS in the right DLPFC and iTBS in the left DLPFC) achieved a considerable reduction in depressive symptoms among older adults with TRD, compared to standard bilateral rTMS (1 Hz in the right DLPFC and 10 Hz in the left DLPFC). TBS was more time-efficient than standard rTMS during each session [48], which improved its clinical treatment potential, flexibility, and adherence [49]. Therefore, a meta-analysis that compared TBS with rTMS from the perspective of antidepressant therapy was urgently required. As revealed by previous two meta-analyses [21, 27], the efficacy of TBS in treating depression was related to increased remission and response rates, compared with sham stimulation in the treatment of depression. However, due to the time of publication, one meta-analysis included only two RCTs comparing TBS and rTMS, while the other included only three RCTs with the same comparative trials [27]. Our meta-analysis comparing TBS to rTMS included nine comparable trials involving 1196 cases, which suggested that both treatment modalities had similar results, which possibly enhances and supports the findings of the previous meta-analyses.
Another benefit of our meta-analysis was the low heterogeneity between each study, be it for response rates, remission rates, or variations in depression scores measured by HRSD-17, MADRS, or QIDS-C16 before and after treatment. Therefore, additional subgroup analysis or regression analysis to identify the cause of heterogeneity was not required. Regarding the response rates, we also compared the efficacy of iTBS with 10 Hz rTMS in treating depression. Likewise, the pooled OR values of six RCTs revealed equivalent antidepressant effects between the two groups. Particularly, Bulteau et al. found that both iTBS and 10 Hz rTMS still showed a similar significant reduction in depression scores and increase in quality of life at 6 months, not just at the acute phase [42].
Clarifying the neurobiological mechanisms behind the effect of TBS treatment in depression will help to determine the optimal forms of TBS, which can result in more effective personalized medicine. At the cellular level in the targeted rat brain, both cTBS and iTBS enhanced GABAergic neurotransmission, although these parameters caused different effects on the cortical expression of calcium-binding proteins such calbidin D-28k (CB) and parvalbumin (PV) [50]. By reducing interneuronal PV expression, iTBS may aim to suppress the output of pyramidal cells, and cTBS affects the inhibitory activity of interneurons producing CB, which controls the synaptic inputs to pyramidal cells [51]. In preclinical studies, there is insufficient data to determine whether the antidepressant effect of iTBS is related to changes in synaptic function in the prefrontal cortex (PFC). According to a recent study, iTBS treatment alleviated both the aberrant long-term depression and the impaired long-term potentiation (LTP) in the PFC of antidepressant-resistant depression model rat brains. Furthermore, downstream molecules of brain-derived neurotrophic factor were engaged in the process of LTP enhancement by iTBS [52]. Baeken et al. took patients with TRD as their study subjects and discovered that active, but not sham, accelerate iTBS, caused acute volumetric alterations in specific regions of the left dentate gyrus in the hippocampus, suggesting a connection with adult neurogenesis [53]. Indeed, because the DLPFC and the hippocampus are synaptically connected via (glutaminergic) pyramidal neurons [54], from an electrophysiological perspective, iTBS applied to the left DLPFC may also directly influence neuronal activity in hippocampal regions and it may be related to the neuroplastic processes.
Both rTMS and TBS show high tolerance. Except for Iwabuchi et al. [46], the dropout rate of remaining eight studies was less than 15%, which was significantly lower than the 25% mean attrition reported by other studies on antidepressant medications [55]. As reported by Lomarev et al. [56], high-frequency rTMS at certain intensity induced seizures, the incidence of which increased further with an increase in high-intensity stimulation. In all the included RCTs, no epilepsy was observed even if the treatment intensity reached 3150 pulses per session [45]. Notably, both rTMS and TBS groups showed a relatively high incidence of headaches, which is consistent with the findings of earlier systematic reviews [57, 58]. Most of the individuals who experienced headache recovered after rest or symptomatic treatment, and finally, accomplish the follow-ups. However, individual heterogeneities must be considered before the results can be generalized.
Our work has a few limitations. First, several included articles enrolled TBS or rTMS as the augmentation treatment plus medications, which obscured our explanation of the therapeutic effect of TBS or rTMS alone. Second, this work compared the acute therapeutic efficacies of TBS and rTMS in depression, although the best maintenance duration for TBS remains unknown. Therefore, further research on TBS is needed to analyze its long-time effect on MDD. Third, although only a mild heterogeneity between studies was observed in this study, several treatment protocols, including iTBS alone, in combination with cTBS, or prolonged TBS, were included in determining the ideal strategy for the treatment of MDD. Heterogeneities of such factors could not be controlled in this systematic review, which must be analyzed in subsequent research.