Background Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. Methods Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4–6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. Findings Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. Interpretation This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. Funding Abbott (previously St Jude Medical).
Bibliographical noteFunding Information:
PEH receives grant support from NIMH, BBRF, and Janssen Pharmaceuticals and previously consulted for St Jude Medical Neuromodulation but has not received consulting fees since 2014. MMH receives research grant support from NIH, NIMH, NIDA, NINDS, NIA , NARSD, Stanley Medical Foundation , Cyberonics, Neuronetics, Abbott (previously St Jude Medical), Magstim (equipment only), Brainsway, NeoSync , Alkermes, Assurex, and Avanir. He is on the Speaker Bureau/Research consultant for Acadia and AltheaDx. SHL is co-inventor on a patent, assigned to Columbia University, on an unrelated technology. This patent is not licensed and generates no royalties. SFT has received research support from Neuronetics, Abbott (previously St Jude Medical), and Vanguard Research Group. SM receives research support from NIH. He has also received a teaching honorarium from TMS Health Solutions. KVS is a member of advisory board or consultant for Abbott (previously St Jude Medical), Baxter, Biotronik, Boston Scientific, Insightec, Medtronic, Neuramodix, Nevro, Nuvectra, SPR Therapeutics, and stimRelieve; he has received research or fellowship funding from Abbott, Autonomic Technologies, Boston Scientific, Medtronic, Neuros, and Pfizer. PGP has received grant or research support from the National Institutes of Health and the A Alfred Taubman Medical Research Institute. BRR has received grant support from Abbott (previously St Jude Medical). AA has performed ad hoc consulting for Medtronic. RWL is a consultant for Allergan, Asia-Pacific Economic Cooperation, Bristol-Myers Squibb, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Janssen, Lundbeck, Medscape, Pfizer, and Takeda; receives speaker honoraria from AstraZeneca, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Lundbeck, Lundbeck Institute, and Otsuka; and receives or has received research funds (through UBC) from the BC Leading Edge Foundation, Brain Canada, Bristol-Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Janssen, Lundbeck, Movember Foundation, Pfizer, Abbott (previously St Jude Medical), University Health Network Foundation, Vancouver Coastal Health Research Institute, and VGH Foundation. He has the following patents/copyrights: Lam Employment Absence and Productivity Scale (LEAPS). He receives royalties from Cambridge University Press, Informa Press, and Oxford University Press. CRH has received grant support from Boston Scientific, Medtronic, Abbott (previously St Jude Medical), Rare Disease Foundation, Canadian Institutes of Health Research, and Trigeminal Neuralgia Association and consulting fees from Medtronic. JSN has been a consultant for Medtronic and Abbott (previously St Jude Medical). JMH is a consultant for Nevro Corp, Circuit Therapeutics, Enspire DBS, and Proteus Biomedical. He serves on the Surgical Advisory Board for Neuropace. CD has received grant support from Abbott (previously St Jude Medical), Brain Resources, Neuronetics, Assurex, and Janssen. AJR has received grant or research support from Allergan, Alkermes, Janssen, the National Institute of Mental Health, Abbott (previously St Jude Medical), and Takeda, and is a consultant to Eli Lilly and Company, GlaxoSmithKline, Pfizer, and Sanofi-Aventis. JGP is a consultant for Medtronic and Boston Scientific; has received grant support from Medtronic, Boston Scientific, St Jude Medical, Jazz Pharmaceuticals, GE Global Research, and NIH; and is a Medical Advisor for Centauri (stock equity). GP has received research support from NIMH, Stanley Foundation, Alkermes, Abbott (previously St Jude Medical), Janssen, and Proteus. AYM has received consulting fees and honoraria from Abbott (previously St Jude Medical) and Medtronic, and has received grant support from Abbott. KM has chaired advisory boards for studies of deep brain stimulation for obsessive-compulsive disorder sponsored by Medtronic; has received unrestricted educational awards from Cyberonics Inc and Schering Plough; has received research project funding from Lundbeck, Merck Serono and Reckitt Benckiser, Indivior, and Abbott (previously St Jude Medical), and has received travel and accommodation support to attend meetings from Medtronic and Abbott. DP is employed by Abbott (previously St Jude Medical). REG is a consultant for Abbott (previously St Jude Medical), Medtronic, MRI Interventions, SanBio, Neuralstem, Monteris, and Neuropace. He has received grant support from NIH, DARPA, NSF, Michael J Fox, CURE, American Epilepsy Society, Neuropace, Medtronic, SanBio, MRI Interventions, and Boston Scientific. CH was a consultant for Abbott (previously St Jude Medical) and has received honoraria from Medtronic. AML has been a consultant for Abbott (previously St Jude Medical), which has licensed his intellectual property (US 2005/0033379A1). HSM receives grant support from NIMH and the Hope for Depression Research Foundation and donation of non-FDA approved DBS research devices from Abbott (previously St Jude Medical) and Medtronic. She has consulted to Abbott, but has not received consulting fees since 2014. She has licensed intellectual property (US 2005/0033379A1) to Abbott. The terms of these arrangements have been reviewed and approved by Emory University in accordance with their conflict of interest policies. The other authors declare no competing interests.