SUMMARY  

• There are currently no prospective head-to-head studies examining the efficacy and safety of SPRAVATO compared to ECT.
• In a multicenter, observational, retrospective study of 59 patients with treatment-resistant depression (TRD), the efficacy and safety of accelerated repetitive TMS (arTMS) was evaluated in comparison to SPRAVATO.¹
  • A greater Montgomery and Åsberg Depression Rating Scale (MADRS) score decrease was observed in the arTMS group after 1 month of treatment (P=0.048) but not after 3 months. Eight patients (26.66%) in the arTMS group versus 24 (82.75%) patients in the SPRAVATO group experienced treatment-related adverse events (TrAEs).
• A secondary analysis comparing patients from THREE-D² and TRANSFORM-2³ studies who received repetitive transcranial magnetic stimulation (rTMS), SPRAVATO+oral antidepressants (OADs), or placebo+OAD reported that 17-item Hamilton Depression Rating Scale (HDRS) scores were reduced in both SPRAVATO (β=-2.89; 95% confidence interval [CI], -5.38 to -0.40) and rTMS (β=-5.35; 95% CI, -8.77 to -1.93]). Comparing patients with TRD who received rTMS to those who received SPRAVATO, the estimated marginal mean difference (EMMD) in HDRS was -1.56 (95% CI, -5.55 to 2.42).⁴ 

Clinical Data

Pettorruso et al (2023)¹ conducted a multicenter, observational, retrospective study in 59 patients with TRD evaluating the efficacy and safety of arTMS compared to SPRAVATO in reducing depressive symptoms. Patients were assigned treatment with arTMS (N=30) or SPRAVATO (N=29) based on clinicians’ discretion. MADRS total score was assessed at baseline (T0), one month (T1), and three months (T2) after treatment initiation. A greater MADRS score decrease was observed in the arTMS group at T1 (P=0.048) but not at T2 (See table: MADRS Total Score at Baseline, 1, and 3 months). Response rates (≥50% decrease of MADRS total score) were higher in arTMS than SPRAVATO at T1 (p=0.008). Remission rates (MADRS total score <10) between groups were not significant.¹

Eight patients (26.66%) in the arTMS group versus 24 (82.75%) patients in the SPRAVATO group experienced TrAEs. The most common TrAEs in the arTMS group were transient post-stimulation headache (13.3%) and scalp discomfort at the stimulation site (10%). One patient experienced agitation during the stimulation session. The most common TrAEs in the SPRAVATO group were temporary sedation (55.2%), transient dissociative symptoms (34.5%), short-lived hypertension (10%), and brief agitation (6.9%). Limitations of the study include lack of treatment randomization, unblinded assessors, and limited sample size.¹

Pooled Analysis

Kastner et al (2026)⁴ compared the safety and efficacy of rTMS and SPRAVATO based on data from 2 randomized clinical trials: THREE-D² and TRANSFORM-2³. Propensity score matching was conducted 1:1:1 (rTMS:SPRAVATO+OADs in TRANSFORM-2:placebo+OADs in TRANSFORM-2) to minimize potential differences in baseline depression severity. Then, linear regression modeling was conducted to evaluate each treatment group. The primary outcome of this study was depression severity based on HDRS at 4 weeks after treatment initiation. Other outcomes were response (≥50% reduction from baseline) and remission (<8 HRDS or <10 MADRS) rates.

After propensity-score matching, 282 patients were included in this analysis (rTMS, n=94; SPRAVATO, n=94; placebo, n=94); however, there were still baseline imbalances in patient characteristics, such as age, employment status, age of onset, anxiety comorbidities, benzodiazepine use, and antidepressant treatment history.⁴ After adjusting for baseline covariates, both rTMS (β=-5.35 [95% CI, -8.77 to -1.93]) and SPRAVATO (β=-2.89; [95% CI, -5.38 to -0.40]) resulted in statistically significant reductions in HDRS scores at 4 weeks.⁴ The EMMD (95% CI; P-value) in HDRS, MADRS, and HDRS in TRD between patients who received rTMS and SPRAVATO was -2.46 (-5.82 to 0.89), -3.12 (-7.50 to 1.26; P=0.16), and -1.56 (-5.55 to 2.42; P=0.441), respectively.^4,6 The adjusted response and remission rates for the rTMS group were 47.7% and 8%, respectively; the rates for the SPRAVATO group were 61.4% and 32.6%, respectively; the rates for the placebo group in TRANSFORM-2 were 48% and 22.1%, respectively.⁴ 

Key limitations from this analysis include the possibility of residual confounding due to the exploratory nature of the analysis, the fact that outcomes are only measured to week 4 when standard rTMS treatments last ≥4 weeks, and the study design differences in the THREE-D and TRANSFORM-2 trials, in which TRANSFORM-2 enrolled patients who failed    ≥2 antidepressant treatments.⁴ 

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 January 2026.