Cognitive preservation advantage and efficacy balance of magnetic seizure therapy in adolescent Major Depressive Disorder: a randomized controlled trial revealing efficacy cognition decoupling phenomenon

WEI WANG1*, YI LU1*, GUO-LIN MI1, XIAO-JING LI1, DAN-NING ZHANG1, SU-FANG QI1

1Shandong Mental Health Center, Jinan, China.

*Co-first authors.

Summary. Objective. To compare magnetic seizure therapy (MST) and modified electroconvulsive therapy (MECT) in adolescent major depressive disorder (MDD) regarding cognitive protection (assessed via the Montreal Cognitive Assessment, MoCA) and suicidality improvement (assessed via the Columbia-Suicide Severity Rating Scale, C-SSRS), with a focus on cognitive subdomains and the mediating role of cognitive changes. Methods. This analysis stems from a prospective, assessor-blinded randomized controlled trial (RCT, ChiCTR2500098032) conducted from March 1 to April 30, 2025, at Shandong Mental Health Center, enrolling 120 adolescents aged 13-18 with MDD, randomized 1:1 to MST (n=60) or MECT (n=60). Primary outcome was the Beck Depression Inventory-II (BDI-II) percentage reduction; secondary outcomes included MoCA subdomain scores, C-SSRS suicidality, and adverse events (CTCAE 5.0). Correlation, mediation (Sobel test), and repeated-measures ANOVA (RM-ANOVA) assessed the cognitive-suicidality relationship. Assessments occurred at baseline and 7 days post-treatment. Results. MECT yielded a higher BDI-II reduction rate, with no significant difference in response rate. MST significantly improved MoCA total score, particularly in memory, orientation, and executive function subdomains. MST enhanced suicidality outcomes, with a higher remission rate. The correlation between MoCA change and suicidality improvement was stronger in MST, with mediation analysis indicating a partial mediating role of MoCA improvement in MST. MST showed fewer adverse events and shorter reorientation time. Conclusions. In adolescent MDD, MST offers efficacy comparable to MECT for depression relief, with superior cognitive protection (especially memory, orientation, and executive function) and safety. The association between cognitive improvement and suicidality reduction suggests MST may indirectly mitigate suicide risk via cognitive preservation, providing a novel treatment option. Multicenter, long-term studies are needed to confirm these findings.

Key words. Adolescent Major Depressive Disorder, cognitive protection, magnetic seizure therapy, suicidality.

Vantaggio di preservazione cognitiva ed equilibrio di efficacia della terapia magnetica convulsiva nel DDM adolescenziale: uno studio randomizzato controllato che rivela l’efficacia del fenomeno di disaccoppiamento cognitivo.

Riassunto. Obiettivo. Confrontare la terapia convulsiva magnetica (MST) e la terapia elettroconvulsiva modificata (MECT) nel disturbo depressivo maggiore (DDM) dell’adolescenza per quanto riguarda la protezione cognitiva e il miglioramento della suicidalità, con particolare attenzione ai sottodomini cognitivi e al ruolo di mediazione dei cambiamenti cognitivi. Metodi. Questa analisi deriva da uno studio clinico prospettico, randomizzato e controllato, condotto dal 1° marzo al 30 aprile 2025 presso lo Shandong Mental Health Center, che ha arruolato 120 adolescenti di età compresa tra 13 e 18 anni con DDM, randomizzati 1:1 a MST (n=60) o MECT (n=60). L’esito primario era la riduzione percentuale del Beck Depression Inventory-II (BDI-II); gli esiti secondari includevano i punteggi del sottodominio MoCA, la suicidalità C-SSRS e gli eventi avversi (CTCAE 5.0). La correlazione, la mediazione e l’ANOVA a misure ripetute hanno valutato la relazione tra cognitività e suicidalità. Le valutazioni sono state effettuate al basale e 7 giorni dopo il trattamento. Risultati. La MECT ha prodotto un tasso di riduzione BDI-II più elevato, senza differenze significative nel tasso di risposta. MST ha migliorato significativamente il punteggio totale MoCA, in particolare nei sottodomini della memoria, dell’orientamento e della funzione esecutiva. La MST ha migliorato gli esiti di suicidalità, con un tasso di remissione più elevato. La correlazione tra la variazione del MoCA e il miglioramento della suicidalità è stata più forte nella MST, con un’analisi di mediazione che indica un ruolo di mediazione parziale del miglioramento del MoCA nella MST. MST ha mostrato meno eventi avversi e un tempo di riorientamento più breve. Conclusioni. Nel DDM adolescenziale, la terapia con MST offre un’efficacia paragonabile alla terapia con MECT per il sollievo dalla depressione, con una protezione cognitiva superiore e una maggiore sicurezza. L’associazione tra miglioramento cognitivo e riduzione della tendenza al suicidio suggerisce che la terapia con MST possa mitigare indirettamente il rischio di suicidio attraverso la preservazione cognitiva. Sono necessari studi multicentrici a lungo termine per confermare questi risultati.

Parole chiave. Disturbo depressivo maggiore dell’adolescenza, protezione cognitiva, terapia magnetica delle crisi epilettiche, suicidalità.

Introduction

Adolescent Major Depressive Disorder (MDD) represents a pressing global public health challenge, with a prevalence of approximately 10-15% and a suicide risk up to 20 times higher than the general population1. Treatment-resistant MDD (TR-MDD), characterized by inadequate response to at least two adequate antidepressant trials, further complicates clinical management, with suicide ideation being a critical concern. Modified electroconvulsive therapy (MECT) is a well-established, life-saving intervention for TR-MDD due to its rapid antidepressant effects. However, its cognitive side effects, particularly memory impairment, are significant, especially in adolescents whose brains are still developing. This cognitive burden often leads to patient reluctance and reduced treatment adherence.

Magnetic seizure therapy (MST), a novel convulsive therapy utilizing high-frequency magnetic stimulation to induce therapeutic seizures, offers a promising alternative. Unlike MECT’s diffuse electrical current, MST targets superficial cortical regions, potentially sparing deeper structures like the hippocampus, thus minimizing cognitive adverse effects. Adult studies have demonstrated MST’s comparable efficacy to MECT for depression with reduced cognitive impact2-4. However, evidence in adolescents remains scarce, and the specific impact of MST on suicidality, alongside its cognitive mechanisms, remains underexplored5.

Emerging neurocognitive models suggest that preserving executive function and memory may reduce rumination and enhance problem-solving, thereby lowering suicide risk. Our prior randomized controlled trial (RCT, ChiCTR2500098032) established that MST is slightly less effective than MECT in reducing BDI-II scores but offers superior cognitive preservation and safety in adolescent MD6. This analysis, conducted in accordance with ICMJE guidelines for overlapping publications, delves into unreported aspects: 1) specific MoCA subdomain changes; 2) detailed C-SSRS suicidality outcomes; 3) the mediating role of cognitive improvement in suicidality reduction. We hypothesize that MST’s focal mechanism provides a cognitive advantage that indirectly ameliorates suicidality, offering a balanced treatment option for this vulnerable population.

Materials and methods

Study design and participants

This analysis is derived from a prospective, assessor-blinded RCT (ChiCTR2500098032) conducted from March 1 to April 30, 2025, at Shandong Mental Health Center, China. The study adhered to the Declaration of Helsinki and CONSORT guidelines, receiving ethical approval from the institutional review board (KYSJWLL2024-1-077). We enrolled 120 adolescents aged 13-18 with MDD, randomized 1:1 to MST (n=60) or MECT (n=60) using a block randomization sequence (block size=4) generated by an independent statistician. Assessors were blinded to treatment allocation via shielded devices and exclusion from intervention procedures.

Inclusion criteria

Participants met DSM-5 criteria for MDD, confirmed by two senior psychiatrists (inter-rater reliability Kappa=0.91), were aged 13-18, had TR-MDD (failure of ≥2 adequate SSRI trials [≥8 weeks] or BDI-II item 9 [suicidality] score ≥2), had a baseline BDI-II total score ≥29 (Cronbach’s α=0.89), had no hearing or vision impairments, and provided informed consent from both themselves and their guardians.

Exclusion criteria

Exclusion criteria included comorbid bipolar disorder or schizophrenia spectrum disorders, intracranial metal implants, history of epilepsy or severe physical illness, and prior MST or MECT treatment.

Sample size calculation

The sample size was calculated based on a non-inferiority hypothesis for BDI-II reduction rate (effect size d=0.8, α=0.05, β=0.2, with a 20% dropout adjustment)2. Post-hoc power analysis (G*Power 3.1) confirmed statistical power >0.80.

Interventions

• MST Group: delivered using the NS7000 device (YIRUIDE medical, Wuhan, China), with stimulation at the Cz position, 100 Hz frequency, 100% intensity, and 8-10 seconds per session.

• MECT Group: administered via the Thymatron® System IV, with bilateral stimulation dosed according to the age-based percentage method.

• Anesthesia: propofol (1.5-2.0 mg/kg) and succinylcholine (0.5 mg/kg) were used.

• Adjunctive treatment: all participants continued SSRIs without benzodiazepines or mood stabilizers.

• Treatment schedule: 12-16 sessions, conducted thrice weekly.

Outcome measures

• Cognitive function: MoCA (total score and subdomains: visuospatial/executive function, naming, attention, language, abstraction, memory, orientation; <24 indicates impairment, with a 1-point correction for ≤6 years of education).

• Suicidality: Columbia-Suicide Severity Rating Scale(C-SSRS) (suicidality score 0-5, severity 0-25; remission defined as suicidality score=0).

• Safety: adverse events per CTCAE 5.0 and reorientation time (minutes).

• Assessment points: baseline and 7 days post-final treatment.

Statistical analysis

• Efficacy comparison: independent-samples t-tests and χ2 tests compared MoCA and C-SSRS changes between groups.

• Correlation: Pearson correlation assessed the relationship between MoCA change and suicidality improvement.

• Mediation: Sobel test evaluated the mediating role of MoCA change.

• Interaction effects: RM-ANOVA analyzed time × group interactions.

• Software: SPSS 25.0 and R 4.3.1, with a two-tailed α=0.05.

Results

Participant flow and baseline characteristics

Of 120 randomized participants, 10 (16.7%) dropped out from the MECT group and 15 (25.0%) from the MST group, with no significant difference (χ2=1.263, p=0.261). Baseline characteristics (sex, age, BDI-II score, etc.) were similar (p>0.05) (figure 1 and table 1).







The BDI-II reduction rate was calculated as

[(Baseline score - Post-treatment score)/Baseline score] × 100%. Clinical outcomes were categorized: remission: ≥75% reduction; marked response: 50-74% reduction; partial response: 25-49% reduction; non-response: <25% reduction. Therapeutic response rate combined remission/ marked/partial responders. Among completers (n=95), the MECT group (n=50) demonstrated significantly higher mean BDI-II reduction (51.8% vs. 46.5%; t=3.76, p<0.001, Cohen’s d=0.62) but comparable response rates (90.0% vs. 91.1%; χ2=3.06, p=0.081) (table 2).




Cognitive function changes

MST significantly improved MoCA total score (+1.11±1.12 vs. -0.76±1.04, F=37.583, p<0.001). Subdomain analysis revealed:

• Memory: MST improved (+0.13±0.73 vs. -0.96±0.88, t=6.619, p<0.001).

• Orientation: MST enhanced (+0.71±0.70 vs. +0.14±0.64, t=4.688, p<0.001).

• Executive Function: MST maintained (+0.37±0.16 vs. -0.22±0.21, t=4.961, p<0.001) (table 3).




Subjective cognitive complaints were lower in MST (20% vs. 62%, χ2=15.750, p<0.001).

Suicidality outcomes: MST reduced C-SSRS suicidality scores more effectively (4.91±0.29 to 0.78±0.90 vs. 4.98±0.14 to 1.12±0.69, t=2.122, p=0.036), with a higher remission rate (33.3% vs. 16.0%, χ2=4.050, p=0.044). Severity scores showed no significant group difference (p=0.310).

Cognitive-suicidality relationship and mediation: MoCA change correlated strongly with suicidality reduction in MST (r=0.62, 95% CI: 0.48-0.74, p<0.001) versus MECT (r=0.38, 95% CI: 0.14-0.58, p=0.008). Sobel test confirmed a partial mediating role of MoCA improvement in MST suicidality reduction (indirect effect=0.32, 95% CI: 0.10-0.54, z=2.89, p=0.004) (table 4).




The remission rate was higher in the MECT group compared to the MST group (5/50 vs. 0/45, Fisher’s exact test, p=0.036). Remitted patients were characterized by first-episode MDD, illness duration <6 months, and absence of psychotic symptoms. A logistic regression model (dependent variable: remission; independent variables: treatment group, psychotic symptoms, recurrence, interaction terms; covariates: age, illness duration) revealed that the treatment group × psychotic symptoms interaction term suggested a potential effect (OR=4.12, 95% CI 1.21-14.07, p=0.024, p_adj=0.072, not reaching the Bonferroni-corrected threshold α=0.0167), with recurrence also significant (OR=3.15, 95% CI 1.09-9.12, p=0.034). Interaction term analysis indicated that first-episode patients without psychotic symptoms were more likely to achieve remission in the MECT group, with the interaction effect most pronounced 3-7 days post-treatment (table 5).




Safety: MST exhibited fewer adverse events (28.9% vs. 64.0%, χ2=22.880, p<0.001) and shorter reorientation time (6.9±1.8 vs. 18.7±6.8 minutes, t=-9.59, p<0.001, Cohen’s d=-2.36). Specific events included short-term memory loss (20.0% vs. 62.0%, p<0.001) and nausea (6.7% vs. 32.0%, p<0.001) (table 6).




Discussion

This analysis of an RCT unveils a nuanced efficacy-safety profile for MST versus MECT in adolescent MDD. While MECT outperformed MST in BDI-II reduction (51.8% vs. 46.5%, p<0.001), reflecting its rapid antidepressant action, MST’s superiority in cognitive preservation – evidenced by MoCA total score improvement (+1.11 vs. -0.76, p<0.001) and specific gains in memory, orientation, and executive function – highlights its potential to safeguard neurodevelopment in this vulnerable group. The “efficacy-cognition decoupling” observed suggests that MST’s focal stimulation minimizes disruption to cognitive networks, a critical advantage given the adolescent brain’s plasticity.

MST’s enhanced suicidality outcomes (p=0.036, remission 33.3% vs. 16.0%) and the robust correlation between MoCA change and suicidality reduction (r=0.62, p<0.001) align with neurocognitive models positing that preserved executive function and memory reduce rumination, thereby lowering suicide risk. The mediation analysis (Sobel z=2.89, p=0.004) further supports that cognitive improvement partially drives MST’s suicidality benefit, a mechanism underexplored in prior adolescent studies7. This finding is consistent with evidence suggesting that targeted neuromodulation can enhance cognitive control, reducing suicidal ideation by improving emotional regulation8. For instance, a recent study highlighted that MST’s focal stimulation preserves hippocampal function, which is critical for memory and emotional processing, potentially explaining its suicidality benefits in adolescents9. Moreover, the cognitive advantage of MST over MECT may be linked to its ability to minimize disruption to prefrontal cortical networks, supporting executive function and decision-making, which are often impaired in MDD10. This underscores MST’s potential as a targeted intervention, contrasting with MECT’s broader cognitive impact. Safety data reinforce MST’s advantage, with fewer adverse events (39.4% vs. 94.2%, p<0.001) and faster reorientation (6.9 vs. 18.7 minutes, p<0.001), likely due to reduced seizure spread. However, the higher dropout rate in MST (25.0% vs. 16.7%) may reflect perceived efficacy or adherence challenges, warranting further investigation.

Limitations

The 7-day follow-up limits long-term efficacy assessment; the single-center design restricts generalizability; reliance on clinical scales may introduce bias; and subgroup analyses require larger samples for robustness. Future multicenter, longitudinal studies are essential to validate these findings.

Conclusions

MST offers a balanced treatment for adolescent MDD, matching MECT’s antidepressant efficacy while excelling in cognitive protection and suicidality reduction. The mediating role of cognitive improvement suggests a novel mechanism, positioning MST as a promising option for preserving neurodevelopment and mitigating suicide risk. Long-term, multicenter trials are needed to optimize its clinical application.

Conflict of interests: the authors have no conflict of interests to declare.

Author contribution statements: Wei Wang formulated the research plan and data analysis. Wei Wang, Yi Lu, Guo-lin Mi, Xiao-Jing LI, Dan-ning Zhang and Sufang Qi were responsible for data collection and research follow-up. Wei Wang participated in the research follow-up. Wei Wang participated in the refinement and review of the draft. All authors contributed to and have approved the final manuscript.

Informed consent: all of the subjects who took part in the study provided written informed consent.

Funding. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was supported by the Shandong Medical and Health Science and Technology Project (Grant No. 202403090630). Shandong Province Traditional Chinese Medicine Science and Technology Project (M-2022199). The authors declare that no other funds, grants, or other support were received during the preparation of this manuscript. Orexternal funding was obtained for this study. The research utilized institutional resources routinely available to the authors at Shandong Mental Health Center for academic investigations.

Ethical statement: the research protocol (KYSJWLL 2024-1-077) was approved by the Ethics Committee of Shandong Provincial Mental Health Center on January 15, 2024. The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2500098032). For adolescent participants, assent procedures were implemented alongside guardian consent, with independent witness verification. All adverse events were reported to the ethics committee within 24 hours following ISO 14155:2020 guidelines.

Ethical disclosure: this study was approved by the Ethics Committee of Shandong Provincial Mental Health Center (Approval No. KYSJWLL2024-1-077) on January 15, 2024.

All participants and their legal guardians provided written informed consent after receiving detailed explanations of potential risks/benefits. The research team strictly adhered to Good Clinical Practice guidelines and implemented triple-level data encryption for protected health information storage.

Data availability: the data supporting the findings of this study are included in the article; further inquiries can be directed to the corresponding author.

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