REVIEW OF: Dalhuisen I et al, Am J Psychiatry 2024;181(9):806–814; Papakostas GI et al, Mol Psychiatry 2024;29:2287–2295

Study Types: Randomized open-label controlled trials

Up to 35% of patients with major depressive disorder develop treatment-­resistant depression (TRD), defined as lack of meaningful response after ≥2 adequate antidepressant trials. Treatment options include pharmacological strategies (eg, switching antidepressants, augmentation) and nonpharmacological approaches like repetitive transcranial magnetic stimulation (rTMS). While rTMS has proven effective, its position in the treatment algorithm remains unclear. To address this, two trials—a Dutch multicenter study and ASCERTAIN-TRD—compared rTMS with antidepressant switching.

The Dutch open-label study randomized 89 adults with moderate to severe TRD (Hamilton Rating Scale for Depression [HAM-D] score >16) to 8 weeks of either rTMS or a different antidepressant based on Dutch treatment guidelines, both paired with psychotherapy. The primary outcome was a change in depression severity measured by HAM-D, and secondary outcomes were response and remission rates. 

The ASCERTAIN-TRD trial was an 8-week study with 278 participants randomized to augmentation with rTMS, augmentation with aripiprazole, or switching to venlafaxine XR or duloxetine. The primary outcome was a change in rater-blinded Montgomery-Åsberg Depression Rating Scale (MADRS) scores, with response and remission rates as secondary outcomes. 

Results

In both trials, rTMS outperformed medication strategies.

In the Dutch study, rTMS led to a significantly greater reduction in HAM-D scores (-10.02 vs -4.19), with higher response rates (38% vs 15%) and remission rates (27% vs 5%).

In ASCERTAIN-TRD, rTMS showed a larger MADRS reduction (-17.4 vs -13.2; p=0.015), with numbers needed to treat of 7 (response) and 11 ­(remission).

Patients’ expectations favored rTMS and modestly predicted outcomes.

CARLAT TAKE
rTMS outperformed meds in both trials, making a strong case for using it earlier in TRD. It is FDA approved in TRD and after just one antidepressant failure, but access, cost, and logistics remain hurdles. Still, when patients are open to it, rTMS is worth a serious look.