Depression is a leading cause of disability (World Health Organization, 2017), and occurs in 7% of the elderly population worldwide (World Health Organization, 2016). A diagnosis of depression in old age is often associated with poorer long-term prognoses, higher recurrence rates, lower quality of life, and a greater likelihood of morbidity and early mortality (Mitchell and Subramaniam, 2005; Aziz and Steffens, 2013). Up to 1/3 of individuals experiencing major depressive disorder (MDD), particularly in the elderly population, fail to achieve clinical remission after acute pharmacological treatment (Rush et al., 2006). Because comorbid physical diseases are common, elderly patients with depression are highly likely to experience side effects of medication (Kok and Reynolds, 2017). Thus, non-pharmacological treatments, such as electroconvulsive therapy (ECT) (Dong et al., 2018; Jiang et al., 2020), transcranial magnetic stimulation (TMS) (Blumberger et al., 2015; Conelea et al., 2017), transcranial direct current stimulation (tDCS) (Kumar et al., 2020; Brooks et al., 2021), vagus nerve stimulation (VNS) (van Rooij et al., 2020), deep brain stimulation (DBS) (McDonald, 2016) and theta-burst stimulation (TBS) (Cristancho et al., 2020), may be reasonable alternatives for older patients with depression.

A type of non-invasive brain stimulation, repetitive transcranial magnetic stimulation (rTMS), was approved by the FDA as a treatment for MDD in 2008 (Holtzheimer et al., 2010). A network meta-analysis of 81 randomized clinical trials (RCTs) found that active rTMS showed a significantly higher clinical response and remission rates than non-active rTMS (Brunoni et al., 2017). A typical course for rTMS involves five days of treatment/week over a period of 3–6 weeks (Holtzheimer et al., 2010). However, this schedule may be inconvenient for patients and can hinder compliance (Frey et al., 2020). Thus, consolidating the treatment (e.g., over 2–3 days) may make it more accessible and could potentially increase compliance.

Accelerated rTMS (aTMS) protocols have been studied as a potential solution for this problem (Sonmez et al., 2019). Recent meta-analyses have found that aTMS protocols may be effective for individuals suffering from depression (Sonmez et al., 2019) and post-stroke depression (PSD) (Frey et al., 2020). A randomized controlled study (RCT) of twice-daily rTMS for the treatment of MDD found that rTMS given twice daily was effective and safe (Loo et al., 2007). Two open-label studies have also reported positive findings for adjunctive aTMS as a therapy in addition to antidepressants for older patients with depression (Dardenne et al., 2018; Desbeaumes Jodoin et al., 2019). For example, Dardenne et al. reported that aTMS was safe and well-tolerated in older patients with MDD (≥65 years old) (Dardenne et al., 2018). Similarly, a recent study reported that aTMS protocol (two sessions per day) is a safe and effective treatment for older patients (≥60 years old) suffering from treatment-resistant depression (TRD) (Desbeaumes Jodoin et al., 2019).

To date, no systematic review examining the therapeutic role and safety of adjunctive aTMS for older patients with depression has been published. In view of this important gap, we conducted this review to systematically investigate the efficacy and safety of adjunctive aTMS for older patients with depression.

This article is the first systematic review to examine the potential therapeutic role and safety of adjunctive aTMS for older patients (≥60 years old) suffering from depression. Only two observational studies (Dardenne et al., 2018; Desbeaumes Jodoin et al., 2019) involving 29 older patients with depression were included in this systematic review. The two studies (Dardenne et al., 2018; Desbeaumes Jodoin et al., 2019) were published within the last three years, indicating that this is a novel and clinically important topic. This systematic review provides preliminary support for the utility of aTMS for reducing depressive symptoms in older patients with depression. Furthermore, adjunctive rTMS was safe and well-tolerated in elderly depressed patients. However, aTMS may have resulted in higher discomfort rates than standard daily rTMS (Fitzgerald et al., 2018).

According to this systematic review, adjunctive aTMS appears to be effective in treating older patients suffering from depression, although the long-term efficacy was not reported. The rationale for an accelerated approach comes from the idea that repeated application of stimulation within short time intervals could be associated with greater antidepressant effects (Sonmez et al., 2019). A recent review reported that high-frequency (HF) rTMS delivered over the left dorsolateral prefrontal cortex (DLPFC) could reduce suicidal behavior in individuals with the treatment-resistant depression (Godi et al., 2021).

The response rates of HF rTMS tended to range from 20 to 30% (O'Reardon et al., 2007; Avery et al., 2008; George et al., 2010), which was far lower than the response rate to aTMS (73.7%) (Desbeaumes Jodoin et al., 2019). However, a recent RCT, involving 115 outpatients with MDD who randomly received either aTMS or standard daily rTMS, found that aTMS and rTMS had comparable efficacy for treating depression (Fitzgerald et al., 2018). Although this systematic review found that aTMS may be an effective therapy in elderly patients with depression, a variety of parameters have been applied to the two included studies (Dardenne et al., 2018; Desbeaumes Jodoin et al., 2019). For example, the total stimuli of aTMS ranged between 31,200 and 90,000, and the optimal parameters for aTMS remain unclear.

The following limitations must be considered. First, only two open-label self-controlled studies (single-group, before-after design) examining the efficacy and safety of adjunctive aTMS for older patients with depression were included (Dardenne et al., 2018; Desbeaumes Jodoin et al., 2019). Second, the relatively small sample sizes in both studies potentially reduced their power and increased the possibility of type II error. Third, this systematic review on adjunctive aTMS for older patients with depression has not been registered. Fourth, given that the heterogeneity between the studies, a quantitative analysis could not be performed in this study. Finally, some important outcome measures, such as cognitive functioning, were not reported in the included studies.

The current evidence from open-label self-controlled studies, while limited, indicates that adjunctive aTMS is a safe and effective therapy for older patients with depression. Further RCTs with rigorous methodology need to be performed in order to confirm and extend these findings.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

X-YZ and RX selected studies and extracted the data. WZ reviewed all the data, helped mediate disagreements, and wrote the first draft. All authors contributed to the interpretation of data and approved the final manuscript.

This study was funded by the the Science and Technology Planning Project of Liwan District of Guangzhou (202004034), National Natural Science Foundation of China (82101609), Scientific Research Project of Guangzhou Bureau of Education (202032762), Science and Technology Program Project of Guangzhou (202102020658), Guangzhou Health Science and Technology Project (20211A011045), Guangzhou science and Technology Project of traditional Chinese Medicine and integrated traditional Chinese and Western medicine (20212A011018), China International Medical Exchange Foundation (Z-2018-35-2002), Guangzhou Clinical Characteristic Technology Project (2019TS67), science and Technology Program Project of Guangzhou (202102020658), and Guangdong Hospital Association (2019ZD06). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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