Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies

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.

Keywords: Adolescence; Individual patient data; Major depressive disorder; Meta-analysis; Transcranial magnetic stimulation.

Fig. 1

Study selection process according to the PRISMA and PRISMA-IPD flow diagram (Stewart et al. 2015; Page et al. 2020)

Fig. 2

Forest plot of individual observed estimates of standardized mean change (SMCC) including corresponding weights, 95% confidence intervals and the pooled summary model using random-effects, examining the pre- to post-treatment change in depression scores. Studies with high-frequency stimulation applied unilaterally to the left DLPFC are highlighted in gray. CDRS-R Revised version of the Children’s Depression Rating Scale, HDRS-17/24 Hamilton Depression Rating Scale, 17-item/24-item version

Fig. 3

Funnel plots of individual observed effect size estimates of standardized mean change (SMCC) between pre- to post-treatment depression scores against the corresponding standard errors (i.e., the square root of the sampling variances) on the y-axis, and of Transformed Proportion of treatment responders against the corresponding standard errors on the y-axis, to aid assessment of potential small-study bias. A, C: Traditional funnel plots centered at the observed summary effect (SMCC and Transformed Proportion, respectively). B, D: Contour-enhanced funnel plots centered at zero including grey-shaded regions that indicate various levels of statistical significance: the unshaded region in the middle of the funnel corresponds to p values greater than 0.10, the dark grey-shaded region corresponds to p values between 0.10 and 0.05, the light grey-shaded region corresponds to p values between 0.05 and 0.01, and the region outside of the funnel (light blue) corresponds to p values below 0.01 (group comparison and correlational meta-analysis, respectively)

Fig. 4

Forest plot of individual observed estimates of raw and transformed proportion of responders including corresponding weights, 95% confidence intervals and the pooled summary model using random-effects. Studies with high-frequency stimulation applied unilaterally to the left DLPFC are highlighted in gray. CDRS-R Revised version of the Children’s Depression Rating Scale; HDRS-17/24 Hamilton Depression Rating Scale, 17-item/24-item version

Fig. 5

Histograms of standardized individual difference scores plotted separately for each outcome, including Gaussian (normal) curves (black) and individual (smoothed) density curves (blue). BDI-II Beck Depression Inventory-II; CDRS-R Children’s Depression Rating Scale; HDRS Hamilton Depression Rating Scale

Fig. 6

Interaction plots showing significant treatment–covariate interactions with patient- and treatment-level characteristics

Fig. 7

Histograms depicting treatment response vs. non-response by depression scale and trial