Dolors Puigdemont, MD; Maria J. Portella, PhD; Rosario Pérez-Egea, MD; Joan Molet, MD, PhD; Alexandre Gironell, MD, PhD; Javier de Diego-Adeliño, MD, PhD; Anna Martín, MD; Rodrigo Rodríguez, MD; Enric Àlvarez, MD, PhD; Francesc Artigas, PhD; Víctor Pérez, MD PhD
Background: To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation.
Methods: We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON–OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF–ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation.
Results: We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (Χ21 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria.
Limitations: The small sample size limited the statistical power and external validity.
Conclusion: These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects.
Trial registration: NCT01268137 (ClinicalTrials.gov).
Submitted Dec. 24, 2013; Revised Mar. 17, 2014; June 2, 2014; July 28, 2014; Oct. 7, 2014; Accepted Oct. 15, 2014; Early released Feb. 3, 2015.
Acknowledgements: This study was funded by several grants of the Fondo de Investigación Sanitaria (FIS, PI 06/0662, PS 09/00580) from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) intramural funding (P91G), the ‘VI Plan Nacional I+D+I 2008–2011’, and the ‘Iniciativa Ingenio 2010, programa CONSOLIDER, acción CIBER’. M. Portella is funded by the Ministerio de Ciencia e Innovación of the Spanish Government and by the Instituto de Investigación Carlos III through a “Miguel Servet” research contract (CP10/00393), co-financed by the European Regional Development Fund (ERDF) (2007-2013). J. de Diego- Adeliño is funded by the Instituto de Salud Carlos III through a “Río Hortega” Spanish government research fellowship. The authors thank the Department of Epidemiology of Hospital Sant Pau for comments on an earlier version of this manuscript and the staff of Hospital de la Santa Creu i Sant Pau, who generously provided their time and experience. The authors are extremely grateful to the patients and their families for their invaluable cooperation in this study.
Affilitions: From the Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, Institut d’Investigació Biomèdica Sant Pau (Puigdemont, Portella, Pérez-Egea, de Diego-Adeliño, Martín, Àlvarez, Pérez); the Department of Neurosurgery, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Institut d’Investigació Biomèdica Sant Pau (Molet, Rodríguez); the Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB). Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Institut d’Investigació Biomèdica Sant Pau (Gironell); and the Department of Neurochemistry and Neuropharmacology, Institut d’Investigacions Biomèdiques de Barcelona, IDIBAPS, Consejo Superior de Investigaciones Cientificas, IDIBAPS, Centro de Investigación Biomédica en Red de Salud Mental (Artigas).
Competing interests: V. Pérez declares educational honoraria from Sanofi-Aventis, Lundbeck, Pfizer, AstraZeneca and Eli Lilly. E. Alvarez has received consulting and educational honoraria from Eli Lilly, Sanofi-Aventis, Lundbeck and Pfizer, and he has participated as main local investigator in clinical trials from Eli Lilly, Bristol-Myers and Sanofi-Aventis and also as national coordinator of clinical trials from Servier and Lundbeck. F. Artigas has received lecture fees from Eli Lilly and Lunbeck A/S on the mechanism of action of antidepressant drugs and consultation fees from Lundbeck A/S. No other competing interests declared.
Contributors: D. Puigdemont, M. Portella, E. Àlvarez and V. Pérez designed the study. R. Pérez-Egea, J. Molet, A. Gironell, and A. Martin acquired the data, which D. Puigdemont, M. Portella, A. Gironell, J. de Diego-Adeliño, A. Martin, R. Rodriguez and F. Artigas analyzed. D. Puigdemont, M. Portella, R. Pérez-Egea and J. Molet wrote the article, which all authors reviewed and approved for publication.
Correspondence to: M.J. Portella, Psychiatry Department, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Salud Mental, Sant Antoni Ma. Claret 167, 08025 Barcelona, Catalonia, Spain; firstname.lastname@example.org