Deep brain stimulation for treatment-resistant depression: optimizing interventions while preserving valid trial design

Major depressive disorder is a leading cause of disability worldwide, and nearly a third of patients do not respond to psychotherapy and trials of multiple medications (1). For these patients with treatment resistant depression (TRD), deep brain stimulation (DBS) has emerged as a possible therapeutic option. Several small, open-label studies have demonstrated encouraging results with DBS targeting various structures involved in the neurobiology of depression, including the subcallosal cingulate (2-5), ventral capsule/ventral striatum (VC/VS) (6), nucleus accumbens (7), and medial forebrain bundle (8). Despite these promising early studies, two recent randomized, sham-controlled trials were halted after interim analyses showed low likelihood of meeting endpoints, one targeting the VC/VS (9), and the other targeting the subcallosal cingulate (10). At the same time, randomized trials targeting the nucleus accumbens (11) and the ventral anterior limb of the internal capsule (vALIC) (12) for obsessive-compulsive disorder (OCD) observed a significant benefit for co-morbid depression. These disparate results suggest that we need to develop a better understanding of the circuitry that we are targeting in order to obtain more consistent outcomes.