Comparison of multiple non‐invasive neuromodulation strategies for depressive episodes in major depressive disorder and bipolar disorder: A systematic review and network meta‐analysis of randomized controlled trials

Aim Noninvasive neuromodulation techniques, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial focused ultrasound stimulation (tFUS), are promising interventions for acute treatment of depressive episodes. However, the comparative efficacy and acceptability of stimulation protocols remain unclear. This network meta‐analysis (NMA) aimed to compare the efficacy and tolerability of various noninvasive neuromodulation strategies. Methods We conducted a systematic review and NMA of randomized controlled trials (RCTs) enrolling patients with major depressive disorder or bipolar depression, including nine repetitive TMS (rTMS) protocols, three theta burst stimulation (TBS) protocols, as well as tDCS and tFUS. Primary outcomes were response and all‐cause discontinuation rates. Subgroup analyses examined treatment‐resistant depression (TRD) and monotherapy versus add‐on therapy. Results A total of 129 RCTs (7667 patients; 272 treatment arms) were included. All protocols except low‐frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) showed higher response rates than sham. tFUS demonstrated the highest response rate (OR: 7.24, 95% CI: 1.35–38.47), followed by bilateral rTMS (OR: 5.75, 95% CI: 3.29–10.07) and bilateral TBS (OR: 5.37, 95% CI: 2.51–11.36), both effective for general depression and TRD. Bilateral TBS showed the highest response rate when administered as monotherapy, whereas bilateral rTMS was most effective as add‐on therapy. Most studies (87.6%) were rated as having low or unclear risk of bias. Conclusions Our findings provide preliminary evidence that bilateral stimulation over DLPFC is more beneficial than unilateral stimulation for treating depressive episodes. Nonetheless, tFUS may represent a highly promising novel intervention warranting further investigation.