Efficacy and safety of adjunctive transcranial alternating current stimulation in bipolar depression: A randomized...

Bipolar depression represents a significant public health challenge, with limited efficacy and tolerability of available pharmacotherapies, driving interest in novel treatment approaches. Transcranial alternating current stimulation (tACS), a noninvasive brain stimulation technique capable of modulating neural oscillations, has not yet been clearly established as an effective treatment for bipolar depression. In this randomized, double-blind, sham-controlled trial, we evaluated the efficacy, safety, and electroencephalography (EEG) effects of adjunctive tACS in individuals with bipolar depression. Sixty participants were randomized to receive either active 10-Hz tACS or sham stimulation twice daily for two weeks, alongside lithium (500 mg/day). Each session delivered 2 mA current for 20 min bilaterally over the dorsolateral prefrontal cortices, with a 70-minute interval between sessions, totaling 20 sessions. Participants were followed for 6 weeks after treatment. The primary endpoint was antidepressant response at week 2, defined as a >=50% reduction in the 17-item Hamilton Depression Rating Scale (HAMD-17) score. Secondary outcomes included changes in anxiety, sleep, mania, cognition, and EEG. Compared with sham, active tACS showed significantly higher response rates at week 2 (46.7 vs. 20.0%) and week 4 (70.0 vs. 43.3%). Active tACS also showed greater reductions in anxiety and sleep symptoms and fewer manic symptoms, with no differences in cognitive outcomes. The most common treatment-related adverse events were headache and dizziness, with tolerability being comparable between the groups. Resting-state EEG assessments following the 2-week intervention revealed that, in the sham group receiving lithium alone, delta power significantly increased in the frontal and parietal regions, while no such changes were observed in the active tACS group. Moreover, increased parietal delta power was negatively correlated with HAMD-17 reduction in the sham group. This study provides preliminary evidence that adjunctive tACS was associated with greater early improvement in depressive, anxiety, and sleep symptoms, with a generally safe and well tolerated profile. Given the remaining methodological limitations, these findings should be considered hypothesis-generating and require confirmation in future studies with improved sham procedures, lithium-free designs, and longer follow-up.