Late-life depression (LLD), often conceptualized as a clinically meaningful depressive syndrome in adults 60 years of age or older (Brender et al., 2021), has become an increasingly severe global mental health problem because of high morbidity and comorbidity associated with increasing age. In China, the lifetime prevalence of depressive disorders is approximately 7.3 % in people over 65 years of age, which is more common than that in the younger population (Lu et al., 2021). Patients with LLD have a higher rate of failure to respond to first-line antidepressant medication and are more likely to experience relapses and recurrences (Knöchel et al., 2015). One of the reasons may be the age-related changes that affect pharmacokinetics, pharmacodynamics and drug interactions, making LLD patients less likely to tolerate appropriate treatment dosages and more susceptible to side effects (Lotrich and Pollock, 2005). In addition, many older adults do not adhere to regular psychosocial or pharmacologic interventions due to frailty, physical comorbidities, or cognitive impairment. As a result of these multiple biological factors, LLD is often inadequately treated. Considering the challenges with pharmacotherapy and the high rates of treatment resistance in LLD, newer noninvasive brain stimulation treatments have gradually emerged as promising alternatives for LLD treatment in clinical practice.

Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment strategy for patients with major depressive disorder (MDD) that induces a magnetic field that creates an electrical field a few centimeters below the scalp and induces action potentials that stimulate cortical pathways critical in depression, such as the dorsolateral prefrontal cortex (DLPFC). Theta burst stimulation (TBS) is a newer form of rTMS that mimics endogenous hippocampal theta patterns (Huang et al., 2005) and may have comparable efficacy to standard rTMS in treating depression (Blumberger et al., 2018). Compared to electroconvulsive therapy (ECT), which is the “gold standard” in the treatment of LLD patients, rTMS stimuli are subconvulsive and more focused. It also does not require anesthesia, thus significantly reducing the risk of cognitive side effects, making it a potentially safe alternative to ECT in LLD patients. The efficacy of rTMS for MDD has been verified by many randomized controlled trials (RCTs) (Fitzgerald et al., 2009; O Reardon et al., 2007) and has also been concluded by some meta-analyses (Voigt et al., 2021; Lam et al., 2008). In a systematic review and meta-analysis of twenty-four studies that included 1092 subjects, the pooled response and remission rates were 25 % and 17 % for active rTMS and 9 % and 6 % for sham conditions, respectively (Lam et al., 2008). Although moderate, a significant anti-depression effect was observed and verified. However, rTMS outcomes among LLD patients remain unclear.

The effectiveness of rTMS in older adults has been debated for a long time. Some earlier RCTs found no benefit of using active stimulation with an intensity equal to or lower than the resting motor threshold (RMT) when compared to sham stimulation (Mosimann et al., 2004; Manes et al., 2001). A number of possible age-related reasons accounting for the poor efficacy of rTMS in LLD have been proposed, including atrophy of cortical gray matter, reduced synaptic connectivity, declining axon conduction velocities, changes in cerebrovascular function and immune-inflammatory control (Conelea et al., 2017). Each of these factors could alter the effect of TMS-induced currents by altering the anatomic and electromagnetic properties of cortical tissue underneath the TMS coil and thus influence treatment efficacy. However, recently, other studies have also reported that active rTMS stimulation was associated with higher odds of response than sham rTMS in LLD patients (Dai et al., 2020; Kaster et al., 2018). This raises the important question of whether rTMS is useful when treating depression in older populations.

Determining whether older age is a poor predictive factor will help clinicians prescribe antidepressant strategies. A systematic review of both randomized and uncontrolled trials tried to answer this question and concluded that there was no reliable evidence negating the utility of rTMS in LLD patients, largely because most early trials excluded older adults (Sabesan et al., 2015). Additionally, newer RCTs have been published since 2015, so a comprehensive study of the currently available published data is needed. The current study performed an updated systematic review and meta-analysis of RCTs that evaluated rTMS efficacy in LLD patients. The primary purpose was to evaluate all published, peer-reviewed RCTs comparing active rTMS (unilateral or bilateral) to sham therapy. We examined the widely accepted clinical outcomes of response rates and remission rates for treating LLD with rTMS. We also tried to determine the parameters associated with improved antidepressant effects, aiming to provide up-to-date guidance for the clinical practice of rTMS in LLD treatment.