Connectivity-guided theta-burst targeting gave faster early response

Design

Single-centre, randomised, double-blind, three-arm trial

Population

123 adults with treatment-resistant major or bipolar II depression

Primary outcome

Percentage reduction in HAM-D-17 at week 2

Effect

Structural vs 5-cm: +8.79 points (2.19 to 15.40); no difference at week 12

This single-centre, double-blind trial, published in August 2026, randomised 123 adults with major depression or bipolar II depression and at least one failed antidepressant to 20 sessions of accelerated intermittent theta-burst stimulation over two weeks. Targets were chosen by the 5-cm rule, by functional connectivity with the subgenual anterior cingulate, or by structural connectivity to the same region, all with robotic neuronavigation.

At week 2, structural targeting reduced Hamilton depression scores by 8.79 percentage points more than the 5-cm rule (95% CI 2.19 to 15.40). At week 6 both connectivity-guided arms beat the 5-cm rule, by 12.87 points for structural and 9.41 for functional targeting. By week 12 the groups no longer differed. Adverse events were similar, and there were no seizures or episodes of mania.

The result supports the idea that where the coil goes matters, but it comes from one centre with MRI-based targeting most services do not have. The fading difference at 12 weeks also matters: faster response is valuable in severe depression, but this trial does not show a more durable one.

• Treat connectivity-guided targeting as research-stage; the 5-cm rule remains the standard method.
• Note that the early advantage disappeared by week 12, so plan maintenance or follow-on treatment as usual.
• Watch for these methods in services with neuronavigation and MRI access before expecting them elsewhere.
• Continue to screen for seizure risk and bipolar switching before any theta-burst course.

Why it matters

Coil placement may change how quickly patients respond, which matters most when depression is severe.

Don't overread it

One single-centre trial with a benefit that faded by week 12 does not establish connectivity targeting as better care.

The statistics, in plain English

A Cohen's d of 0.70 at week 2 is a moderate-to-large effect, and the interval does not cross zero. But three arms and several time points multiply the chances of a positive finding, and the loss of difference by week 12 means the benefit was about speed rather than final outcome.

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