What the Next Accelerated TMS Trial Should Test, With Jonathan Downar, MD

Jonathan Downar, MD, trial investigator of a new meta-analysis on dosing in accelerated repetitive TMS (rTMS) for major depressive disorder, said a purpose-built randomized controlled trial (RCT) is still needed to confirm optimal pulse count and intersession spacing. The current safety data leaves room to explore higher pulse doses in future protocol design.^1,2

“The first one would be for us to do a proper randomized trial looking at whether it's worthwhile to do more than the 3 minutes," said Downar, associate professor of psychiatry at the University of Toronto, in an interview with HCPLive. "The second big question would be…to try and figure out how long [it is] ideal to wait between sessions."

The meta-analysis found a roughly linear relationship between total pulse count and outcomes in sham-controlled trials. Total pulses significantly predicted symptom improvement (P =.0034), response (P <.0001), and remission (P =.0043).

Designing a Trial to Test Pulse Count and Intersession Timing

Downar said the field already has strong evidence behind a 3-minute theta-burst protocol, making the first open question whether extending sessions to 1200 or 1800 pulses adds meaningful benefit or simply adds time in the chair. He acknowledged RCTs are expensive and slow to run but called this comparison the more straightforward of the 2 questions to settle.

The second, harder question involves intersession interval, where Downar expects meaningful variability from person to person, consistent with most factors in neurophysiology. He raised the possibility of eventually developing a biomarker or brief test session to identify each patient's ideal spacing, but said the near-term goal is simpler: finding the shortest interval that still works for the large majority of patients, whether that turns out to be 60, 40, 30, or fewer minutes.

“Until that point, all we can do is try to do meta-analyses to put together different studies that have used different intervals and see how they do,” Downar said.

Pulse Count Safety and the Takeaway for Community Psychiatrists

On safety, Downar cited the SAINT protocol developed by Nolan Williams, MD, and colleagues at Stanford, which delivers 1800 theta-burst pulses hourly for 10 hours a day, roughly 18,000 pulses daily. Whether going meaningfully higher, to 36,000 or 72,000 pulses a day, remains untested, he said, since few published protocols exceed about 18,000 pulses in a single day.

Downar described TMS overall as a safe treatment, noting patients in his own clinic have received hundreds of sessions over more than a decade without an apparent upper limit. He also flagged low-frequency protocols, delivered below 5 Hz, as an underexplored area with an established safety record around seizure risk, worth watching as dose-response rules are tested outside high-frequency and theta-burst protocols.

For clinicians outside the dose-response literature, Downar's advice is to lean on FDA-cleared protocols backed by large trials: the 3-minute theta-burst protocol from THREE-D and a 60-minute intersession interval for accelerated courses.^3,4 Emerging evidence on 30-minute, and even shorter, intervals is worth watching, he said, but not yet required reading for routine practice.

This is part 3 of a 3-part series with Jonathan Downar, MD. Read parts 1 and 2 for his perspective on 2 decades of TMS practice and a closer look at the new dose-response meta-analysis here: TMS Sessions Reduced From 38 Minutes to 3, With Jonathan Downar, MD, PhD and More TMS Pulses Track with Better Depression Outcomes, With Jonathan Downar, MD, respectively.

Downar has no reported disclosures.

References

1. Wang VX, Mehta DD, Downar J, Tang VM, Li CT, Le Foll B. Dose-response associations of total pulse dose and intersession interval with clinical outcomes in accelerated rTMS for major depressive episodes: A systematic review and meta-analysis. Brain Stimul. 2026;19(4):103129. doi:10.1016/j.brs.2026.103129

2. Downar J. More TMS Pulses Track with Better Depression Outcomes, With Jonathan Downar, MD. HCPLive. Published August 26, 2026. Accessed August 26, 2026. https://www.hcplive.com/view/more-tms-pulses-better-depression-outcomes-jonathan-downar-md

3. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391(10131):1683-1692. doi:10.1016/S0140-6736(18)30295-2

4. Chen L, Klooster DCW, Tik M, et al. Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future. Harv Rev Psychiatry. 2023;31(3):142-161. doi:10.1097/HRP.0000000000000364