AbstractDeep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has been reported to lead to rapid antidepressant effects. In this longitudinal study, we expand upon the initial results we reported at 26 weeks (Fenoy et al., 2016), showing sustained antidepressant effects of MFB DBS on six patients with treatment-resistant depression (TRD) over 1 year. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary assessment tool. Deterministic fiber tracking was used to individually map the target area; analysis was performed to compare modulated fiber tracts between patients. Intraoperatively, upon stimulation at target, responders reported immediate increases in energy and motivation. An insertional effect was seen during the 4-week sham stimulation phase from baseline (28% mean MADRS reduction, p = 0.02). However, after 1 week of initiating stimulation, three of six patients had a > 50% decrease in MADRS scores relative to baseline (43% mean MADRS reduction, p = 0.005). One patient withdrew from study participation. At 52 weeks, four of remaining five patients have > 70% decrease in MADRS scores relative to baseline (73% mean MADRS reduction, p = 0.007). Evaluation of modulated fiber tracts reveals significant common orbitofrontal connectivity to the target region in all responders. Neuropsychological testing and ¹⁸F-fluoro-deoxyglucose-positron emission tomography cerebral metabolism evaluations performed at baseline and at 52 weeks showed minimal changes and verified safety. This longitudinal evaluation of MFB DBS demonstrated rapid antidepressant effects, as initially reported by Schlaepfer et al. (2013), and supports the use of DBS for TRD.