Ranking Brain Stimulation for Depression: Bilateral Protocols and Focused Ultrasound Come Out on Top

For most of us, "TMS" is a single line on a referral form – but the field underneath that line has quietly fragmented into a dozen protocols with very different track records. This network meta-analysis, published in Psychiatry and Clinical Neurosciences, is the first to put nine rTMS variants, three theta-burst protocols, transcranial direct current stimulation, and the newcomer transcranial focused ultrasound onto one comparative map. For a clinician deciding whether and where to send a patient, that map is more useful than any single trial.

What the data shows

The synthesis is large: 129 randomized controlled trials, 7667 patients, 272 treatment arms, with response and all-cause discontinuation as co-primary outcomes. Almost everything beat sham. The one exception was low-frequency rTMS over the left dorsolateral prefrontal cortex, which did not separate from placebo stimulation – a reminder that "TMS" is not one thing and that laterality and frequency matter.

At the top of the ranking, transcranial focused ultrasound posted the highest response rate (odds ratio 7.24, 95% CI 1.35 to 38.47). Read that confidence interval before you get excited: the lower bound sits just above 1 and the upper bound runs past 38, which is the statistical signature of very few trials and small samples. The more trustworthy signal comes from the bilateral protocols. Bilateral rTMS reached an odds ratio of 5.75 (95% CI 3.29 to 10.07) and bilateral theta-burst stimulation an odds ratio of 5.37 (95% CI 2.51 to 11.36), both with intervals that stay comfortably above the null and both effective in treatment-resistant subgroups, not just first-line depression.

The subgroup analyses are where this becomes practical. Bilateral theta-burst stimulation ranked highest when used as monotherapy, whereas bilateral rTMS was the strongest option when added on top of an antidepressant. The authors read the whole pattern as preliminary evidence that bilateral stimulation over the dorsolateral prefrontal cortex may outperform unilateral stimulation for a depressive episode – a signal the ranking suggests rather than establishes. Reassuringly, 87.6% of the included trials were rated low or unclear risk of bias, so the ranking is not being driven by a pile of low-quality studies.

For your practice

The referral conversation changes. When a center offers "TMS," it is worth asking which protocol they run: unilateral high-frequency left-sided stimulation is the historical default, but this analysis favors bilateral montages. If your patient is staying on their antidepressant and you are adding neuromodulation, bilateral rTMS has the strongest comparative signal as an add-on. If the patient is medication-intolerant or you are pursuing neuromodulation as a standalone, bilateral theta-burst stimulation ranked best as monotherapy and has the practical bonus of much shorter sessions.

Two cautions. First, do not let the headline number reorganize your practice around focused ultrasound yet: its top ranking rests on a handful of trials, and the confidence interval is honest about how little we know. It is a "watch this space" technology, not a menu item. Second, a network meta-analysis ranks probabilities, not individual patients – it narrows the reasonable choices, it does not pick one for the person in front of you.

The concrete takeaway: for a patient with a moderate-to-severe depressive episode heading toward neuromodulation, steer toward a bilateral dorsolateral prefrontal protocol rather than the older unilateral default – bilateral rTMS if they are continuing medication, bilateral theta-burst if they are not – and treat transcranial focused ultrasound as a promising trial-only option rather than something to offer today.