Frequently Asked Questions

The prespecified primary end point was not statistically significant in the intent-to-treat analysis at 2 weeks. Both groups improved on the Beck Depression Inventory-II (BDI-II), with mean improvement of 16.65 points in the active tACS group and 14.36 points in the sham group; the between-group difference was 2.04 points (1-sided P = .056; 95% CI, -0.476 to 4.549).

The trial also found signals favoring active treatment on other analyses. In participants with 100% reported adherence during the first 14 days, active tACS produced greater BDI-II improvement than sham at 2 weeks, with a difference of 3.72 points (P = .005; 95% CI, 1.103 to 6.340).

Active tACS showed statistically significant advantages over sham at secondary time points and in adherent participants as early as 1 week. In secondary analyses of BDI-II scores, treatment effects favored active treatment at both week 1 and week 4 compared with baseline (P = .020 and .028, respectively), and the active treatment group showed a significantly greater change from baseline at week 1 (P = .048).

Among participants with 100% reported compliance in the first 14 days, the between-group BDI-II difference favored active treatment by 3.10 points at week 1 (P = .022) and by 4.10 points at week 4 (P = .018).

Adherence appeared to be clinically important. Self-reported adherence was high, with 85.1% of participants reporting twice-daily use throughout the first 14 days; this was 86.5% in the active group and 83.7% in the sham group.

In the post hoc analysis limited to participants with 100% compliance during the first 14 days, active tACS showed significantly greater BDI-II improvement than sham at 2 weeks (difference: 3.72; P = .005; 95% CI, 1.103 to 6.340). Significant differences in this adherent subgroup were also seen at week 1 (difference: 3.10; P = .022) and week 4 (difference: 4.10; P = .018).

Yes. By week 4, the active treatment group had a significantly higher BDI-II responder rate than the sham group, 65.08% versus 52.71% (P = .045).

In this trial, response was defined as at least 50% improvement from baseline on the BDI-II. The article reports that sex-specific responder analyses showed significantly higher response at most time points only in females.

The study found a stronger signal in females than in males. In preplanned subgroup analyses at week 2, females showed a nominally significant difference favoring active treatment over sham in the intent-to-treat analysis (17.9 vs 14.2; nominal subgroup P = .020) and in the per-protocol analysis (18.3 vs 13.76; nominal subgroup P = .008).

There was not a nominally significant difference for males. The discussion notes a post hoc imbalance in male baseline severity between groups, which the authors state may have contributed to the weaker effects observed in males.

The safety profile was favorable in this trial, with no serious adverse events reported. In the active group, 19 participants (15.1%) reported 34 adverse events, compared with 10 participants (7.8%) reporting 13 adverse events in the sham group.

Only 1 adverse event, skin discomfort, led to device discontinuation. The article describes the overall numbers of adverse events as small.

This trial allowed concurrent antidepressant use, and the exploratory analysis did not find a week 2 outcome difference within the active tACS group between participants who were taking antidepressants and those who were not (P = .543).

Antidepressant use was common: 43.7% of the active treatment group and 36.4% of the sham group reported using antidepressant medication. The study included these patients to better reflect real-world use.

Participants used a self-administered wearable tACS device at home for 20 minutes twice daily, once after waking and once before bed. The active device delivered 2 mA (±10% tolerance) of pulsed alternating current and shut off automatically after each 20-minute session.

Both active and sham devices appeared to function identically, but the sham device did not deliver electrical stimulation. The trial was triple-blind and fully remote, and blinding was successful based on a James Blinding Index of 0.718 (95% CI, 0.668 to 0.768).

The study enrolled adults aged 21 to 65 years in the United States who met DSM-5 criteria for major depressive disorder and had moderate to severe symptoms on the BDI-II. Participants needed a BDI-II score of 20 to 63 at both prescreening and baseline after a 14-day lead-in period.

The trial excluded people with active suicidal ideation with plan or intent in the past 30 days, a history of suicide attempt, recent psychiatric hospitalization, neuromodulation use within 1 year, recent medication changes, substance-related exclusions, psychiatric disorders other than MDD, certain cardiac conditions, trigeminal neuralgia, or implanted medical electronics.

The main limitations were reliance on self-reported depression measures and self-reported adherence, unknown effects beyond 4 weeks, and a strong sham improvement that makes it hard to separate direct device effects from placebo effects. The authors also note that having all participants spend 40 minutes per day in calm activities may itself have had therapeutic benefit.

Additional limitations were that the sham comparator could not assess natural mood changes without treatment, the study was not designed to detect differences in subpopulations such as females or severity strata, and the sample was predominantly Caucasian, which limits certainty about generalizability to more diverse populations.