The Safety and Efficacy of Repetitive Transcranial Magnetic Stimulation in the Treatment of Major Depression Among Children and Adolescents: A Systematic Review

Major depression is a chronic debilitating condition affecting people of all ages and is rising over the past decade. Major depression among children and adolescents is often resistant to traditional treatments, thus necessitating the exploration of novel strategies. Repetitive transcranial magnetic stimulation (rTMS) is gaining increasing attention as a useful tool in treating various conditions and has received the US Food and Drug Administration (FDA) approval to treat depression and obsessive-compulsive disorder among adults. Favorable outcomes among adults generated interest in using it among children. Until recently, the existing literature lacked randomized sham-controlled trials on this topic among children and adolescents. The newest additions in the literature necessitated another in-depth look at the data to explore the safety and efficacy of rTMS in the context of depression among children and adolescents. We searched the Medline and Cochrane databases and included 18 articles for our systematic review. Our systematic review indicates level 1 evidence that rTMS is safe but failed to show its superiority to placebo as a stand-alone treatment for resistant depression among children and adolescents. However, there is level 2 evidence favoring add-on rTMS to treat major depression among children and adolescents. The study subjects appear to tolerate the rTMS treatment well with some minor and mostly self-limited side effects. Risks of treatment-emergent hypomanic symptoms and seizure appear to be very low. There is no evidence of worsening of suicidal ideation or cognitive decline during rTMS treatment.


Introduction And Background
The rate of major depression has increased from 8.7% in 2005 to 11.3% in 2014 in adolescents [1]. Major depression in childhood is often associated with school dropout, unemployment, and unwanted pregnancy [2]. The Treatment for Adolescents with Depression Study showed that a combination of fluoxetine and cognitive-behavioral therapy was associated with a higher remission rate in adolescent depression than either treatment alone [3]. Nevertheless, almost 30-40% of depressed adolescents fail to respond to traditional treatment [4,5]. There are also concerns about treatment-emergent side effects, such as suicidality with the use of antidepressants [6,7]. The practice parameter of the American Association of Child and Adolescent Psychiatry recommends electroconvulsive therapy (ECT) for adolescents in resistant cases of major depression [8]. However, ECT is less frequently used [4,9] due to cognitive side effects, prolonged seizure, and anesthetic complications [4,10]. As a result, there is an increasing interest in novel treatment approaches for major depression.
Repetitive transcranial magnetic stimulation (rTMS) is a relatively new treatment modality that is gaining attention in the treatment of various conditions afflicting adults [11][12][13]. Three large, multi-site, randomized, sham-controlled trials amongst medication-free depressed adults who failed to respond to antidepressant trials have demonstrated its efficacy in major depression [14][15][16]. A recent systematic review indicates a better response rate among adults with fewer previous failed antidepressant trials [17]. The response rate can be as high as 95.5% and a remission rate of 68.2% in the first episode [18].
The US FDA approved the use of rTMS for major depression and obsessive-compulsive disorder among adults who failed to respond to medications [13,19]. Adult literature indicates that the most common side-effects of rTMS are scalp tenderness and headache [11,20]. Serious side-effects such as seizure and treatmentemergent mania or hypomania are rare [20,21]. The adult literature generated a growing interest in investigating its role in depression among children and adolescents. The current systematic review explores the safety and efficacy of rTMS in the case of major depression among children and adolescents.

Review Methods
The systematic review aimed to collate various open-label studies, randomized controlled trials (RCTs), case reports, case series investigating the safety and efficacy of rTMS in treating major depression among children and adolescents (age≤18). Studies that included children and adults but focused on adults or did not present data of children and adolescents separately were not included. We searched the Medline and Cochrane databases and kept various MeSH keywords such as "pediatric," "adolescent," "depression," "rTMS" in varying combinations. Additionally, we searched the reference lists of various articles and reviews using the same search engine and contacted other researchers to gather additional information about their published papers. We included literature in the English language published until November 2020. We excluded studies whose primary diagnosis was not major depression and those who used other variety of TMS. We have utilized the Joanna Briggs Institute quality appraisal tool to assess the quality of the included studies [22]. One of the authors (PM), in consultation with two other authors (SB and TP), selected the articles for the systematic review and followed the PRISMA guideline ( Figure 1). We did not attempt a quantitative synthesis with the data due to the heterogeneity of studies and outcome parameters/assessment methods.

FIGURE 1: PRISMA 2009 Flow Diagram
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The image was obtained from Moher et al. [23].

Results
Using the various combinations of keywords, we retrieved 457 articles. Removal of duplicates resulted in 300 publications. All these 300 articles were screened based upon the titles and abstracts. We excluded 186 articles due to various reasons (as shown in Figure 1). We retrieved 114 full texts for eligibility amongst which, 96 were excluded based on relevance (N 10), involving adults (N 60), reviews (N 17), different diagnosis (N 4), unable to access (N 1), secondary analysis (N 3), and could not differentiate pediatric data from adult data (N 1). Finally, 18 articles, including 13 multi-subject trials and 5 case reports, were incorporated in this systematic review. We identified another three studies [24][25][26] that incorporated data from previous studies already included in this systematic review. We have discussed their findings.

Characteristics of the Studies
Tables 1 and 2 summarized the characteristics of the studies. The studies include open-label trials [27][28][29][30][31][32], case reports [33][34][35][36][37], case series [38][39][40][41], naturalistic studies [42], and randomized sham-controlled trial [43]. One study used emailed questionnaires to a Worldwide pool of rTMS centers [44]. The majority of the studies are from the USA [28][29][30][31][33][34][35]40,43]. The rest of the studies were from China [37,38,42], Israel [32], Finland [36], Canada [27,39], Australia [41], and across multiple nations [44]. The lowest age of the recipient of rTMS was ten [40,42,43], but most of the patients were above 12.   The sample size ranged from 1 (case reports) to 103 [43]. The case series by Croarkin et al. presented three cases [40]. However, one of the three cases was a healthy control. So, we have included two out of these three cases in this systematic review. Similarly, the case series by Walter et al. presented seven cases. However, we included three of them as the other four subjects had other primary diagnoses such as bipolar disorder and schizophrenia [44]. All the multi-subject trials allowed comorbid anxiety disorder, dysthymia, attention deficit hyperactivity disorder (ADHD) but excluded schizophrenia, bipolar disorder, substance use disorder, post-traumatic stress disorder (PTSD), intellectual disability, pervasive developmental disorders, and eating disorders. One study included comorbid substance abuse [32], and another one allowed the inclusion of bipolar type II [42]. Zhang et al. included "mood or anxiety disorder" and thus, incorporated other diagnoses such as bipolar type II, dysthymia, generalized anxiety disorder [42]. No change in psychotherapy was allowed a few weeks before and during the trial [30][31][32]. Some studies have excluded patients with suicide attempts in the previous six months [28,31] or with "suicidal propensity" [42].

Efficacy/Effectiveness
The majority of the studies found that rTMS is a safe and effective add-on treatment for child and adolescent depression [27][28][29][30][31][32]34,38,39,42]. The improvement started as early as one [32,38] to two weeks [28,42]. Treatment benefits were noted at six months [28][29][30][31] [42]. The older group had a less impressive improvement, higher baseline depression and anxiety scores, and shorter follow-up. A secondary analysis by Zhang et al. indicated that add-on rTMS improved depression and somatic and psychic anxiety among adolescents [24]. Sonmez et al. pooled data from three previous studies [28,30,31] and found that rTMS may improve hypersomnia in addition to its antidepressant action [26].

Suicidal Ideation
Several studies have assessed suicidal behavior and found no worsening of symptoms during rTMS. Croarkin et al. reported that 4 out of 103 patients developed suicidal ideation, but none were related to rTMS treatment [43]. Wall et al. reported 8 out of 10 subjects had suicidal ideation before the study, two subjects experienced worsening suicidal thoughts during the trial [28]. One subject had self-injurious behavior at six months follow up. In another study, subjects with suicidal thoughts at baseline reported improvement with treatment [31]. At the end of six months, one patient had self-mutilating behavior, and another patient needed hospitalization, which was unrelated to rTMS. In a pooled data analysis of the above studies [28,31], the suicidal ideation at baseline and at the end of the study period was 63.16% and 16.67%, respectively [25]. In another case series by Pan et al., one out of three subjects experienced remission of suicidal ideation during rTMS [38]. Segev et al. reported a case where suicidality was transiently improved, followed by deterioration, and finally plateaued [35]. Bloch et al. also found out that suicidal ideation was not affected by the stage of rTMS treatment [32].

Discussion
To the best of our knowledge, our systematic review is the only one that has incorporated the data of more than 250 patients. Our findings support the results of the previous systematic reviews on the topic [45,46]. Previous systematic reviews on this topic have been criticized for lacking a controlled group in the included studies and the relatively smaller number of total subjects in the included studies [45,46]. In our systematic review, the addition of the only available RCT with a sham-control group improved the quality of the evidence of efficacy by utilizing a comparison group that approximates a placebo group [47]. Our systematic review included the three recent studies with larger sample sizes than previous articles [27,42,43]. Although better quality studies are still needed, there is a strong indication that rTMS is a safe and useful add-on, but not a stand-alone treatment for child and adolescent depression that has not responded to at least one antidepressant treatment. Twelve out of 18 included studies found out that rTMS could be an effective treatment for major depression among children and adolescents.
Studies showing reduced depressive symptoms have most commonly delivered rTMS in 10 Hz frequency, 120% MT, four seconds train, and 3000 stimuli per session for 30 sessions. One of the significant advantages of rTMS is that the patient can be monitored multiple times a week. Moreover, the side-effects are mild and self-limiting. Suicidality and treatment-emergent manic or hypomanic symptoms appear to be rare with rTMS in this age group. The side effects reported in the majority of the studies are mild and selflimiting. Out of the three case reports demonstrating the development of seizure spells in the context of rTMS, one delivered rTMS in a somewhat different protocol from the other studies, such as they used twosecond trains (instead of the usual four-second trains used by other authors), used 18 Hz frequency instead of 10 Hz frequency, and delivered a total of 1980 pulses per session [33]. The other case report of seizure spell involved the use of 75 mg olanzapine (which was later corrected by the author as 7.5 mg) and a blood alcohol concentration of 0.20% at the time of the seizure episode [36]. The only one case report of the emergence of hypomanic symptoms has used 6000 pulses per session [38]. Such a low occurrence of significant side effects has also been reported in other non-invasive brain stimulation studies involving children and adolescents [48][49][50].
According to the University of Oxford Centre for Evidence-Based Medicine published criteria to determine the evidence levels, the sham-controlled RCT demonstrated level 1 evidence that rTMS is safe but is not better than placebo as a stand-alone treatment for resistant depression among children and adolescents [23]. Nevertheless, 41.7% responded, and 29.2% achieved remission with rTMS [43]. Seven open-label studies showed level 2 evidence for efficacy [27][28][29][30][31][32]42]. Multiple case series and case reports showed a level 4 degree of evidence of efficacy [34][35][36][37][38][39][40][41]44]. The study's treatment response rate by Zhang et al. seems to be an outlier. It could be because of the naturalistic study design or having a somewhat different inclusion and exclusion criteria [42]. Further, the study's comparison groups were different from each other in significant parameters such as the course of illness, baseline HAM-D score [42]. The studies that did not find rTMS as a useful tool for the treatment of depression have either used it as a stand-alone treatment [43] or comprise of only case reports demonstrating side-effects that led to premature termination of treatment [36,37,40].
We have used Joanna Briggs Institute Critical Appraisal Tools to assess the quality of the included studies (see Appendix) [22]. The overall quality of the studies is average except for Croarkin et al. which seems to have high [43]. rTMS can still be considered a relatively novel treatment option for minors and could have contributed to the included studies' relatively small sample sizes. Moreover, almost all the studies have used well-validated diagnostic tools and rating scales to provide objective data of the treatment response. All the studies attempted to use rTMS only in the context of previous treatment failures. Still, the existing database's main drawbacks are the studies' limited sample size and mostly open-label study designs. The overall quality of the existing studies is low. The other limitations are heterogeneity in the inclusion criteria, the number of previously failed antidepressant trials, various parameters, and the number of rTMS sessions. The heterogeneity mentioned above could explain some varied treatment responses in the reported studies. There is a strong need to conduct RCTs involving large study subjects to explore the efficacy of rTMS as an add-on treatment in child and adolescent major depression. There is a need to explore the stage of treatment of Major Depression when the addition of rTMS to antidepressant treatment could lead to the best possible treatment outcome in terms of its utility as an add-on agent for treatment. This is especially true given the favorable side effects reported in the previously published studies. Although it is challenging to draw a sweeping conclusion at this time, rTMS has a strong potential in treating depression among children and adolescents, particularly among adolescents.

Conclusions
Major depression among children and adolescents is associated with a high non-response rate with traditional treatment. rTMS can be a useful add-on treatment for child and adolescent major depression, not responding to at least one antidepressant. The existing database is limited by the limited number of RCTs. Despite limitations, most of the studies indicate that rTMS is generally safe among children and adolescents and carries a minimal risk of seizure and treatment-emergent hypomanic symptoms. rTMS is not more effective than placebo as a stand-alone treatment of resistant major depression among children and adolescents.    Q1. Was true randomization used for the assignment of participants to treatment groups? Q2. Was allocation to treatment groups concealed? Q3. Were treatment groups similar at the baseline? Q4. Were participants blind to treatment assignment? Q5. Were those delivering treatment blind to treatment assignment? Q6. Were outcomes assessors blind to treatment assignment? Q7. Were treatment groups treated identically other than the intervention of interest? Q8. Was follow-up complete and if not, were differences between groups in terms of their follow-up adequately described and analyzed? Q9. Were participants analyzed in the groups to which they were randomized? Q10. Were outcomes measured in the same way for treatment groups? Q11. Were outcomes measured in a reliable way? Q12. Was appropriate statistical analysis used? Q13. Was the trial design appropriate, and any deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: Dr. Pradipta Majumder is an rTMS provider. However, this has not have influenced the outcome ot the systematic review. Dr. Perera is an rTMS provider. However, this has not have influenced the outcome of the systematic review. No conflict of interest relevant for other authors.