Abstract
BackgroundTrials of deep brain stimulation (DBS) to the subcallosal cingulate gyrus (SCG) for treatment-resistant depression (TRD) have yielded mixed results. While open-label studies suggest effectiveness, randomized controlled trials (RCTs) have not consistently supported these findings. The study compared the efficacy of active versus sham SCG stimulation for TRD.MethodsParticipants (n = 35) in a major depressive episode and treatment resistance completed a 6-month double blind, crossover RCT, with an 18-month open-label phase. A Balaam design was applied with participants randomized to 1 of 4 stimulation groups over two 3-month phases. The primary outcome was a change in Hamilton Depression Rating Scale (HDRS) score at 6 months, with response defined as ≥50% reduction in HDRS-17 scores.ResultsWhile all groups showed improvement at 3 and 6 months, no significant differences were found among them. The OFF-OFF group had a numerically lower HDRS-17 score compared to the ON-ON group at the end of the RCT. No unexpected adverse events occurred. During the open-label phase, participants showed sustained reduction in HDRS-17 scores at 12, 18, and 24 months post-implantation, with successive observed-case response rates of 65.7%, 69%, and 73.1%, respectively. Improvements in life functioning were also noted.ConclusionsThis trial represents the largest single-centre, sham-controlled study of SCG DBS for TRD in the literature. Although the RCT showed no significant group differences, most participants achieved response during the open-label phase. Safety outcomes aligned with previous trials. Future RCTs should integrate insights from the past decade of DBS for TRD research to optimize outcomes. Key considerations include selecting DBS contact locations that ensure engagement of critical white matter tracts, employing novel and sufficiently long clinical trial designs to account for the non-specific effects of the DBS procedure, as well as incorporating biomarkers to guide DBS programming.