Four-Week Low-Frequency Right Dorsal Lateral Prefrontal Cortex Repetitive Transcranial Magnetic Stimulation Versus...

Generalized anxiety disorder (GAD) is a prevalent chronic condition affecting quality of life. While pharmacotherapy remains common, its limitations include delayed therapeutic response and intolerable adverse effects. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation technique, is emerging as a potential therapeutic option for GAD. However, its comparative efficacy against established pharmacotherapies, such as sertraline, remains unclear.

Is low-frequency right dorsal lateral prefrontal cortex (DLPFC) rTMS, alone or combined with low-dose sertraline, superior to low-dose sertraline monotherapy in reducing anxiety symptoms at 4 weeks in treatment-naïve GAD?

We conducted a randomized, single-blind, exploratory superiority trial comparing two active treatments (low-frequency right DLPFC rTMS monotherapy or combined with low-dose sertraline) against a common reference (low-dose sertraline monotherapy). The study enrolled 35 treatment-naïve patients with GAD randomized to three arms over 4 weeks.

Anxiety symptoms were assessed using the Hamilton Anxiety Rating Scale (HARS) at baseline and weeks 1, 2, and 4. The primary end point was change from baseline in HARS total score at week 4 (ΔHARS).

In the primary modified intent-to-treat population (n = 32), rTMS monotherapy demonstrated significantly greater symptom reduction compared with sertraline (adjusted mean difference = -3.13, P = 0.018, Cohen d = -0.47), confirmed in the intent-to-treat sensitivity analysis (n = 35). Combination therapy showed no significant advantage over sertraline (P = 0.684).

In this exploratory trial, low-frequency right DLPFC rTMS monotherapy reduced anxiety symptoms more than low-dose sertraline monotherapy during the initial 4-week period, whereas the combination therapy achieved efficacy comparable with sertraline monotherapy. These preliminary findings suggest rTMS may serve as an alternative for treatment-naïve patients with GAD, but larger confirmatory trials are required.