Transcranial Magnetic Stimulation in the Treatment of Adolescent Depression: A Systematic Review and Meta-Analysis of Aggregated and Individual-Patient Data From Uncontrolled Studies [Review]

SOURCE: European Child & Adolescent Psychiatry. 31(10):1501-1525, 2022 Oct.

AUTHORS: Sigrist C; Vockel J; MacMaster FP; Farzan F; Croarkin PE; Galletly C; Kaess M; Bender S; Koenig J

ABSTRACT: Transcranial magnetic stimulation (TMS) is a non-invasive treatment for adolescent major depressive disorder (MDD). Existing evidence on the efficacy of TMS in adolescent MDD awaits quantitative synthesis. A systematic literature search was conducted, and data from eligible studies were synthesized using random-effects models. Treatment-covariate interactions were examined in exploratory analyses of individual-patient data (IPD). Systematic search of the literature yielded 1264 hits, of which 10 individual studies (2 randomized trials) were included for quantitative synthesis of mainly uncontrolled studies. Individual patient data (IPD) were available from five trials (all uncontrolled studies). Quantitative synthesis of aggregated data revealed a statistically significant negative overall standardized mean change (pooled SMCC = 2.04, 95% CI [1.46; 2.61], SE = 0.29, p < .001), as well as a significant overall treatment response rate (Transformed Proportion = 41.30%, 95% CI [31.03; 51.57], SE = 0.05; p < 0.001), considering data from baseline to post-treatment. Exploratory IPD analyses suggests TMS might be more effective in younger individuals and individuals with more severe depression, and efficacy might be enhanced with certain treatment modality settings, including higher number of TMS sessions, longer treatment durations, and unilateral and not bilateral stimulation. Existing studies exhibit methodological shortcomings, including small-study effects and lack of control group, blinding, and randomization-compromising the credibility of the present results. To date, two randomized controlled trials on TMS in adolescent depression have been published, and the only large-scale randomized trial suggests TMS is not more effective than sham stimulation. Future large-scale, randomized, and sham-controlled trials are warranted. Future trials should ensure appropriate selection of patients for TMS treatment and guide precision medicine approaches for stimulation protocols.

INTRODUCTION: Adolescent major depressive disorder (MDD) presents a serious and oftentimes life-threatening disorder, with the potential to disrupt normal development, and to impede the quality of life of affected individuals and their families [1, 2]. It has been recognized that MDD is a leading contributor to the burden of disease in young individuals aged 10??4 years [3], yet, currently available options for the treatment of MDD in adolescents remain unsatisfactory. In the past 2 decades, pharmacological and psychological interventions have been widely used in the treatment of MDD in adolescents. Compared to other psychiatric disorders in young individuals, such as anxiety, attention-deficit hyperactivity disorder, or conduct-related problems and disorders, mean effects for the treatment of MDD are, however, modest [4]. Antidepressants, except for fluoxetine, may not offer a clear advantage over placebo for a large percentage of individuals [5, 6]. Of concern, one-third of MDD patients who undergo treatment do not achieve remission after having gone through various treatment options, which can lead to treatment-resistant depression (TRD; [7??]).

Increasingly, transcranial magnetic stimulation (TMS) has been used to both study and treat neuropsychiatric and neurological disorders. TMS is a technique employed for transcranial stimulation of the brain using a magnetic coil positioned on the surface of the head usually tangential to the scalp, and is based on the principle of electromagnetic induction [10]. A brief, high-current pulse is produced in the magnetic coil, resulting in a magnetic field, passing perpendicularly to the plane of the magnetic coil, inducing an electric field perpendicularly to the magnetic field on the surface of the cortex, depolarizing neurons or their axons [11, 12]. Repetitive TMS (rTMS) involves modalities to deliver multiple pulses of stimulation in a short interval of time and at various stimulation frequencies (e.g., 1, 5, or 10 Hz). As compared to single-pulse or paired-pulse TMS protocols, rTMS produces longer-lasting changes in neural activity [13] and is most commonly used in clinical settings. rTMS has been suggested to modulate brain network functioning [14, 15]. Theta burst stimulation (TBS) involves the application of 50 Hz bursts at theta (5 Hz) frequency. This patterned stimulation can deliver a high number of pulses and is thought to confer neurophysiological and therapeutic effects in a shorter time as compared to standard TMS (i.e., in about 40 s to 3 min compared to about 30 min in, e.g., 10 Hz rTMS [16, 17]). The intensity of TMS is generally determined relative to the resting motor threshold (RMT) of the individual patient. RMT is assessed via the primary motor cortex and serves as a proxy for the activation of other cortical regions [18, 19]. Typically, TMS is applied with intensities ranging from 80 to 120% of RMT, and the efficacy of stimulation (besides the state of the receiving brain) generally strongly depends on the stimulation protocol (i.e., dose) [20, 21]. Magnetic stimulators equipped with figure-eight coils have obtained regulatory approval for clinical use in many countries, and are most commonly used in clinical therapeutic settings. Figure-eight coils induce electric fields in the target area with greater focality compared to coil types shaped differently (i.e., concentric coils), also minimizing the potential risk of side effects caused by stimulation of surrounding areas (for a discussion of geometric variations of figure-eight coils and implications for therapeutic use, see, e.g., [22]).

In 2008, the United States Food and Drug Administration (FDA) cleared the first TMS device for therapeutic clinical use in adult MDD [23, 24]. To date, multiple meta-analyses have demonstrated that TMS applied to the dorsolateral prefrontal cortex (DLPFC) is effective, specifically for cases of TRD [25??7]. In a number of existing reviews, TMS has also been ascribed potential as a safe and effective treatment for MDD in adolescents [28??2]. However, findings thus far have been mixed, and quantitative syntheses are currently lacking on TMS in adolescent MDD. Thus, it remains unclear under what conditions and to what extent TMS is effective for the treatment of MDD in youth.

During the neurodevelopmental period of adolescence, aberrations from normative neuro-maturational processes potentially underlie the pathophysiology of depression [33]. Specifically, drastic changes in structural and functional brain architecture may lead to imbalances in excitation and inhibition, changes in cortical plasticity and connectivity, and less effective information exchange between brain regions that are critical to the processing of emotion [34??6]. Of note, it has been suggested previously that neurodevelopmental processes in adolescence might contribute to the currently inconsistent results between studies investigating rTMS in adolescent MDD [37].

A range of further patient-related factors are likely to influence how rTMS is received and processed in the brains of adolescents and adults alike, and in turn, the influence of individual-patient factors on TMS treatment outcome needs to be investigated in adolescent samples. Of note, meta-analytic evidence in adults suggests age to present one of the most important predictors of TMS treatment response, with young age presenting a good prognostic factor [38??0]??hich is also in line with psychotherapeutic and psychopharmacological treatment studies in children and adolescents, suggesting younger patients to be more likely to respond to treatment [41, 42]. Besides patient demographics, stimulation-parameter settings are likely to influence effect size. In a previous meta-analysis of adult patients, stimulation intensity, frequency, and site of stimulation, as well as the course of treatment, were identified as moderators of the treatment outcome [43]. Furthermore, the efficacy of TMS might strongly depend on accurate targeting of the region to be stimulated, while localization of the cortical target region currently lacks standardization. In many, and particularly in earlier studies, the DLPFC as a target site has been approximated from measurements on the scalp, using the so-called ??-cm rule??involving measurement to a location about 5 cm anterior to the Motor Threshold location in the anterior??osterior plane [44, 45]. A further scalp-based targeting method that has found wide application is the Beam F3 method, which additionally accounts for head size and shape [46]. More recently, studies have started to use structural or functional magnetic resonance imaging (MRI) and/or diffusion tensor imaging (DTI) combined with neuro-navigation systems to target specific regions of interest [47??9]. Critically, targeting of specific brain regions by imaging and neuro-navigation seems to result in larger effect sizes as compared to scalp-based approaches [49??1].

Especially in more recent years, consensus has been reached that TMS might be a valuable treatment option for MDD in youth. This same conclusion has been drawn repeatedly from a number of existing systematic literature reviews on the topic ([28??2, 37, 52]), two of which [31, 52] also include a systematic assessment of study quality and risk of bias, respectively. Crucially, among the currently existing studies examining efficacy of TMS treatment in adolescent depression, there are only two randomized, double-blind sham-controlled trials [53, 54]??nd, what is more, the largest and as of yet best-designed study [54] found no additive effect of rTMS compared to sham stimulation considering the reduction of depressive symptoms in adolescents. Most probably based on the current lack of large-scale, high-quality, randomized studies, a quantitative synthesis of the existing evidence on the efficacy of TMS treatment in adolescent MDD is lacking from the literature, and potential moderators of treatment outcome have not yet been meta-analytically examined.

Thus, to tackle these respective gaps, the current systematic review and meta-analysis aims to first summarize the currently existing data on efficacy (defined as pre- to post-treatment change and response rate) of TMS treatment in adolescent MDD on a study level, and second, in exploratory analyses on the level of individual-patient data (IPD), to examine patient- and treatment-related factors which potentially influence the efficacy of TMS in adolescent MDD.

METHODS: The present study protocol was pre-registered through a web-based protocol on the International Prospective Register of Systematic Reviews (PROSPERO; e.g., [55]), available from Updates to the current review will be posted to the protocol. Throughout the meta-analytic process, we followed the current recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements (PRISMA; PRISMA-IPD; [56, 57]), and consulted the Cochrane Handbook for Systematic Reviews of Interventions providing gold-standard advice in conducting systematic reviews on the effects of healthcare interventions [58].

DISCUSSION: The present systematic review and meta-analysis was conducted with the primary aims of quantifying efficacy of TMS in the treatment of adolescent depression and exploring respective patient- and trial-level moderators while considering the data currently available on a study (aggregated data) and patient-level (IPD), respectively. As a secondary aim, we also synthesized available data on rates of treatment response (aggregated data), and explored respective moderators (IPD).

First, meta-analysis of aggregated data suggested TMS to significantly reduce depression severity in adolescent patients, which was further in line with significant response rates. However, analyses of aggregated data also suggested potential biases, such as small-study effects. Indeed, the studies included were characterized by small sample sizes and large standard errors, respectively. Of note, all studies reported a statistically significant mean change in depression severity under active rTMS treatment from baseline to post-treatment, providing strong indications for potential publication bias??hich was also suggested by visual inspection of funnel plots and formal testing of funnel plot asymmetry, respectively. Collectively, the present studies were also very heterogeneous with respect to dosing protocols for TMS. Of note, only two out of 10 studies included in the present synthesis applied a double-blind, randomized, and sham-controlled study design, and there have been considerable concerns about open-label trials to inherently inflate effect sizes and to be prone to several further biases, including regression to the mean, investigator biases, and, critically, confounding of active treatment with placebo effects [37, 83]. Sham stimulation in rTMS trials can be considered in analogy to pill placebo in pharmacological trials [37], and respective trials suggest larger response rates to pill placebo in adolescent as compared to adult depression [84, 85]??ith reported rates of placebo response in adolescents ranging between 22 and 59% [86??3]. Considering rTMS treatment, there is only one large-scale randomized controlled study currently available that would inform on the response rate to sham stimulation in adolescent depression, suggesting a sham response rate of 36.4% [54]??hich falls well within the range of response rates reported for pill placebo. As a comparison, meta-analytic studies suggest response rates to sham rTMS in adult patients with depression to be at around 10 or 11% [25, 94].
Based on IPD from five individual study samples, accounting for repeated measures within individuals clustered within trials, and considering three different depression scales (i.e., HDRS, CDRS-R, and BDI-II), we found treatment efficacy as well as response to be associated with certain patient and trial-level characteristics. Most consistently observed was the influence of patients??age, with younger individuals exhibiting a higher reduction in depression scores as well as a higher likelihood of treatment response compared to individuals of older age. This finding somewhat aligns with existing meta-analytic evidence on TMS in adult patients suggesting young age to present a good prognostic factor [39], as well as with findings from an evidence synthesis of several short-term randomized controlled trials of antidepressants, reporting higher placebo response rates in younger as compared to older adolescents (after the exclusion of one large fluoxetine trial) [93]. Of note, presently, most studies included samples of older-aged adolescents (mean age of 17.45????.99 years), with only one study including relatively younger adolescents between 12 and 14 years. However, based on the present findings as well as growing evidence which points towards a favorable safety profile of TMS for the treatment of adolescent depression [52], future studies should also consider younger individuals with MDD. Furthermore, although only observed when considering HDRS but not CDRS-R or BDI-II scores, depression severity was a significant moderator of pre- to post-treatment change after TMS. This finding also aligns with a considerable amount of evidence in adults, suggesting TMS to be particularly valuable in severe cases of adult MDD, and in patients with TRD [25, 27, 95]. TMS applied to the DLPFC in adolescent MDD might reverse some of the aberrant functional connectivity between prefrontal and subcortical regions, which, during the period of adolescence that is characterized by peak PFC plasticity, might result in long-term clinical improvement, especially in severe cases of depression [37]. Considering the present variability of results based on the outcome measure considered, several potential explanations for this finding exist. First, the present findings based on IPD analyses in general might simply present spurious associations that might have occurred based on a multiple testing situation, and future studies with pre-planned hypotheses testing will be needed to confirm the observed associations. Furthermore, there might be poor concordance between different instruments, i.e., clinician-rated (such as the HDRS or MADRS) and patient-reported (BDI-II) outcome measures of symptoms of depression [96]. Furthermore, specifically considering the CDRS-R, which currently presents the most commonly used scale in adolescent depression research, existing studies on the psychometric properties of this instrument when used in adolescents (but which was originally developed for use in children aged 6??2 years) are of low methodological quality, and thus it currently remains unclear whether the CDRS-R appropriately measures depressive symptom severity in adolescent MDD [97]. Finally, differences in IPD analysis results considering different measures might also go back to underlying sample characteristics, which presently has not been explored further but should be considered in future antidepressant trial. Besides patient factors, several trial-specific, TMS-related factors were identified to significantly moderate treatment efficacy as well as the likelihood of treatment response. These included the laterality of stimulation, the specific TMS modality applied, treatment duration, and the number of stimulation sessions applied, respectively. Concerning the latter, greater efficacy of TMS has also been previously reported for protocols applying a higher number of stimulation sessions, as well as a greater number of pulses per session [98??00]. In the five studies included in IPD meta-analysis, the number of sessions ranged from 10 to 30 sessions, with a treatment duration of 14??2 days. It has been previously suggested that increasing the number of sessions per day from one to multiple might increase efficiency [37]. Yet, as presently observed, a longer treatment duration might also increase efficacy (although potentially confounded by the number of sessions applied). Consequently, future studies should investigate the relative importance of the number of TMS sessions and overall treatment duration considering treatment efficacy to determine a session/duration ratio that optimizes stimulation protocols for both efficacy and efficiency. Concerning laterality of stimulation, the present finding of greater efficacy observed with unilateral compared to bilateral stimulation is in line with results from a double-blind, randomized, and sham-controlled study in adults with TRD [101]. In the respective study, only unilateral stimulation was significantly more effective compared to sham stimulation at treatment termination and was correlated with a higher percentage of patients who showed remission. Further, unilateral but not bilateral TMS showed higher antidepressant efficacy compared to sham stimulation in the respective study. However, these and the present findings are somewhat contradictory to existing meta-analytic evidence, suggesting that bilateral stimulation might not be statistically significantly different from unilateral stimulation in adult MDD [102??04]. Given potential neurodevelopmentally driven differences between the pathophysiology of MDD in adolescents compared to adults, it is important that future studies further investigate whether unilateral compared to bilateral stimulation might be differentially effective in adolescent MDD. Similar, standard rTMS compared to TBS was associated with greater treatment response. Of note, only one of the included studies used TBS. Primary studies addressing the comparative efficacy of rTMS versus TBS are warranted.

The present results must be interpreted within the constraints of considerable limitations inherent to this evidence synthesis. First, given the current lack of randomized controlled trials considering TMS treatment in minors with depression, we failed to conduct a synthesis of results from rigorous randomized controlled trials comparing active rTMS treatment with sham stimulation. Instead, we conducted a quantitative synthesis of results from mainly uncontrolled studies. While non-randomized studies are increasingly recognized as a potential source of insights into real-world performance of novel therapeutics, and thus are certainly of value for healthcare decision making especially in the case of novel and innovative treatments [105], high-quality, randomized controlled trials unequivocally provide the most reliable evidence on the relative efficacy and safety of medical interventions. The present results must therefore be considered highly cautiously. As a further critical limitation, individual-patient data were retrieved only for half (i.e., five out of ten) of the studies that were included in the present meta-analysis, and most critically, we failed to include IPD data from randomized controlled trials??hich certainly would have significantly improved the quality of the data included and allowed us to also consider effects of sham stimulation in IPD meta-analysis. Barriers to obtaining IPD on the one hand were encountered due to a lack of responsiveness of the corresponding authors even to repeated data requests. Furthermore, barriers were also encountered in the form of data sharing policies of study sponsors from the industry. Either problem is strongly impeding on the quality of meta-science, and endeavors to further ameliorate and facilitate practices of data sharing are warranted (for a scoping review and practical guide on the matter, we refer the reader to, e.g., [106]).

CONCLUSION: The present meta-analysis is the first to synthesize existing evidence, consisting of mainly uncontrolled trials, for the use of TMS in adolescents with MDD. We found that TMS might be an efficient treatment for adolescents with MDD, in particular for those of younger age. Several treatment modality settings were identified that significantly influence treatment outcomes. Given the methodological limitations of primary studies included in the present meta-analysis, these should be interpreted with caution but??n the current absence of better evidence??ay inform clinical practice in the application of TMS in youth with MDD.