Colleen A. Hanlon, Yiftach Roth, Richard A. Bermudes, Eliza Brink, Molly Davis, Dawn DeBrocco, Shelli Ellis, Lindsey Jones, Aftab Khan, Carlene McMillan, Aswin Kumar Mudunuru, Owen S. Muir, Gabriel S. Pell, Timothy Prestley, M.S. Reddy, Adi Rachelson, Elyssa Sisko, Samson Seplow, Natanya Slomowitz, Ahava Stein, Daniel B. Thistlethwaite, Russ Voltin, Aron Tendler
BACKGROUND: Transcranial magnetic stimulation with the H1-coil is an FDA-cleared treatment for major depressive disorder (MDD), traditionally delivered once daily over six weeks. Accelerated protocols condense treatment by administering multiple sessions per day. This multisite, randomized, blinded non-inferiority trial compared a five-times-daily accelerated intermittent theta burst stimulation (ACC-iTBS) protocol with the standard of care high-frequency (SOC-HF) H1 coil TMS protocol in adults with MDD. METHODS: 104 adults with moderate-to-severe MDD were randomized to: (1) ACC-iTBS (110%rMT, H1 coil): 5 sessions/day for 6 days (30 sessions) over 2 weeks, plus 2 sessions/day one day/week for 4 weeks (8 sessions); or (2) SOC-HF (120%rMT, H1 coil): once-daily sessions for 4 weeks (20 sessions), followed by 2 sessions/week for 2 weeks (4 sessions). The primary endpoint was change in HDRS-21 score at week 6. Secondary outcomes included response, remission, anxiety, and adverse events. RESULTS: 89 participants completed the 6-week study enrollment (ACC-iTBS: 41; SOC-HF: 48). Both groups showed significant HDRS-21 improvement at week 6 (ACC-iTBS: -19.02 points; SOC-HF: -19.79; p < 0.001), with a non-significant between-group difference (0.76, p = 0.78), and upper limit of the one-sided 97.5% CI was 2.73 (< inferiority margin δ = 3.0 points on the HDRS-21). ACC-iTBS showed faster symptom reduction by week 2 (median HDRS change: -11.70 vs. -8.590) and shorter time to remission (21 vs. 28 days; p = 0.0324). Week 6 response/remission rates were 87.8%/78.0% (ACC-iTBS) and 87.5%/87.5% (SOC-HF). Anxiety also improved in both groups. Adverse events, including treatment-site discomfort and headaches, were more common with ACC-iTBS. Blinding was preserved. CONCLUSIONS: ACC-iTBS TMS with the H1 coil is a safe, well-tolerated, and time-efficient alternative to standard HF H1-coil TMS, offering comparable outcomes and faster remission.