A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention
Open accessAbstract
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 (χ(2)1 = 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).
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After SCC DBS discontinuation, depressive symptoms remained in remission at 3 months in 2 of 5 patients.
“depressive symptoms remained in remission 3 months after SCC DBS discontinuation in 2/5 patients [27]”
From Deep brain stimulation for depression. (2022) · cites this paper as [27]
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“…et al. 2018 MFB 6 Yes Holtzh imer et al. 2012 SCC 10 Yes Holtzheimer et al. 2017 SCC 85 No Merkl et al. 2013 SCC 6 Yes Merkl et al. 2018 SCC 4 Yes * Puigdemont et al. 2015 SCC 5 Yes Ramasubbu et al. 2013 SCC 4 Yes Raymaekers et al. 2017 IC/BST 5 Yes Raymaekers et al. 2017 ITP 5 Yes * Only half of…”
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“…antidepressant effects with continuous stimulation appear more consistent (Mayberg et al., 2005; Lozano et al., 2008, 2012; Guinjoan et al., 2010; Kennedy et al., 2011; Holtzheimer et al., 2012, 2017; Puigdemont et al., 2012, 2015; Merkl et al., 2013; Ramasubbu et al., 2013; Crowell et al., 2015).”
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“We are far less certain about the probability of sustained benefit when DBS is used as an antidepressant.”
InfluentialDeep brain stimulation and fluoxetine exert different long-term changes in the serotonergic system
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BackgroundInfluentialVariability of white matter anatomy in the subcallosal cingulate area
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“In another, where a sham controlled discontinuation phase was used, a long-term response was observed when the stimulation site was closer to Broadman area 24 (Puigdemont et al., 2015).”
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“Furthermore, an open label trial including a sham lead in phase also showed good results (60), and ongoing DBS in patients with successfully treated TRD appears to protect against remission (61).”
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BackgroundInfluentialHitti, F. L., Widge, A. S., Riva‐Posse, P., Malone, D. A., Okun, M. S., Shanechi, M. M., Foote, K. D., Lisanby, S. H., Ankudowich, E., Chivukula, S., et al. (2023) · Brain stimulation · doi:10.1016/j.brs.2023.05.011 · Cited by 21 · see citing works
“This trial design has successfully been applied in DBS for OCD [19] and DBS for TRD [28,31,36,38].”
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Deep brain stimulation for treatment-resistant depression: a safe and effective option
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“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, two patients remained in remission, two relapsed, and one showed a progressive worsening without reaching relapse criteria [21,22].”
BackgroundNeurosurgery for psychiatric disorders: reviewing the past and charting the future
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“15,61,62 Similar to OCD, severe, refractory Tourette syndrome is also thought to be associated with dysfunction in the cortico-striato-thalamo-cortical circuit.”
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“5 (8-34) Follow-up time after surgery (mo) 91 (12-144)”
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“Others have proposed enriched sample trial designs using withdrawal or discontinuation of DBS after optimization of stimulation and clinical outcomes.(9,10) To move forward in this field, new DBS trials are needed if they are to contribute to new scientific knowledge for the development of DBS therapy for TRD.”
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“DBS is an invasive brain stimulation technique considered as a new hope in the treatment of several intractable psychiatric diseases such as major depression (Mayberg et al., 2005; Puigdemont et al., 2015).”
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A narrative review on invasive brain stimulation for treatment-resistant depression
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“Further randomized, double-blind, controlled clinical trials confirmed that four out of five TRD patients achieved complete symptom relief (Puigdemont et al. 2015), with high-frequency electrical stimulation demonstrating superior long-term antidepressant effects compared to low-frequency…”
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“In a preliminary, double-blind, randomized, shamcontrolled, crossover trial, 4 out of 5 patients were remitted after 6 months of stimulation, and none of them experienced relapse (22).”
BackgroundPérez, V., Villalba‐Martínez, G., Elices, M., Manero, R. M., Salgado, P., Gines, J. M., Guardiola, R., Cedrón, C., Polo, M., Delgado-Martínez, I., et al. (2022) · European Eating Disorders Review · doi:10.1002/erv.2895 · Cited by 7 · see citing works
Self-citationLetter to the Editor: Deep brain stimulation for schizophrenia
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“3,7 Although topical vancomycin is used in intracranial surgeries by many surgeons, this is the first study showing its efficacy following craniotomy.”
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“Biol Psychiatry 2015; 78: 218–219 [64] Puigdemont D, Portella MJ, Pérez-Egea R et al.”
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Deep brain stimulation – A primer for psychiatrists
Sharma, L. P., Ganesh, U. M., Arumugham, S. S., Srinivas, D., Venkatasubramanian, G., & Reddy, Y. C. J. (2024) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2024.104354 · Cited by 3 · see citing works
Deep Brain Stimulation- A Novel Approach For Relieving Neurological Disorders: A Review
Gautam, A., Rai, M., Srivastava, R., Jyoti, B., & Priyadarshi, P. K. (2018) · International Journal of Contemporary Medicine Surgery and Radiology · doi:10.21276/ijcmsr.2018.3.3.19 · Cited by 3 · see citing works
Efficacy and feasibility of deep brain stimulation for patients with depression
Zhang, H., Wang, N., Yu, L., & Zhao, M. (2021) · Medicine · doi:10.1097/md.0000000000026044 · Cited by 3 · see citing works
Khan, A., Ahmed, R., Kotapati, V. P., Dar, S. K., Qamar, I., Jafri, A., Ibrahim, M., Kumar, P., & Begum, G. (2018) · International Journal of Medicine and Public Health · doi:10.5530/ijmedph.2018.3.26 · Cited by 3 · see citing works
Kilian, H. M., Bewernick, B. H., Klein, M., Meyer, D. M., Spanier, S., Reinacher, P. C., Coenen, V. A., & Schlaepfer, T. E. (2020) · Psych · doi:10.3390/psych2030015 · Cited by 2 · see citing works
“Negative expectations may have had an impact in studies where patients were aware of the moment of discontinuation or randomization to the OFF-phase [31,40].”
BackgroundInfluentialWomen in Neuromodulation: Innovative Contributions to Stereotactic and Functional Neurosurgery
Heiden, P., Pieczewski, J., & Andrade, P. (2022) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2021.756039 · Cited by 2 · see citing works
Combination Strategies in Treatment-Resistant Depression
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Subcaudate Tractotomy White Matter Anatomy and Variability: A Diffusion Tensor Imaging Study
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Novel Neurostimulation Therapeutic Approaches for Treatment-Resistant Psychiatric Disorders
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Treatment-Resistant Depression: Deep Brain Stimulation
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Can Deep Brain Stimulation Be a Promising Treatment for Treatment-Resistant Depression?
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Deep Brain Stimulation for Depression: An Update
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Deep Brain Stimulation for Treatment-Resistant Depression
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Overview of the Current Use of Deep Brain Stimulation in Psychiatric Disorders
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“The first double-blind randomized sham-controlled study conducted by Puigdemont and his co-workers [7] and elucidated that DBS (continuous electrical therapy) of SCG might represent a reliable and fruitful therapy for sustaining therapeutic impacts in those who presented with extreme depression.”
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“Como exemplos de tratamentos com corrente elétrica e com campo eletromagnético pode-se citar a eletroconvulsoterapia (ECT) [4,9], a estimulação do nervo vago [15], a estimulação elétrica profunda [16], a estimulação magnética transcraniana (EMT) [15,17] e a estimulação elétrica transcraniana (EET) [5,18-21].”
BackgroundEstado del arte: nuevas aplicaciones para la estimulación cerebral profunda.
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Neurotechnologies in Anxiety and Depression
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Deep brain stimulation for treatment-resistant depression
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“…28 RCTs included in the quantitative synthesis (MDD: 6 (Bergfeld et al., 2016; Dougherty et al., 2015; Holtzheimer et al., 2017; Merkl et al., 2018; Puigdemont et al., 2015; Raymaekers et al., 2017), OCD: 6 (Denys et al., 2010; Goodman et al., 2010; Luyten et al., 2016; Mallet et al., 2008; Mosley…”
Vicent-Gil, M., Trujols, J., Puigdemont, D., Portella, M. J., Alemany, C., Serrano-Gimeno, V., Aibar‐Durán, J. Á., Rodríguez, R. R., Ros, E., Cofán, M., et al. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111882
Self-citation
- Authors
- Puigdemont, D., Portella, M. J., Pérez-Egea, R., Molet, J., Gironell, A., de Diego-Adeliño, J., Martín, A., Rodríguez, R., Àlvarez, E., Artigas, F., & Pérez, V.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- 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
- Venue
- Journal of Psychiatry and Neuroscience
- Publisher
- Canadian Science Publishing
- Published
- 2015-07
- Volume
- 40
- Issue
- 4
- Pages
- 224-231
- ISSN
- 1180-4882 (ISSN-L)
- 1488-2434
- PMC
- PMC4478055
- OpenAlex
- W1869776851
- Cited by
- 100
- References
- 26
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 10 · 2021: 14 · 2020: 11 · 2019: 8 · 2018: 14 · 2017: 9 · 2016: 11 · 2015: 3
- FWCI
- 8.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Psychiatry and Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Ministerio de Ciencia e Innovación
- Centro de Investigación Biomédica en Red de Salud Mental
- Instituto de Salud Carlos III
- European Regional Development Fund
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- deep brain stimulation, treatment-resistant depression, relapse prevention, chronic stimulation, sham stimulation, depression remission, major depressive disorder
- MeSH terms
- Adult, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Female, Gyrus Cinguli, Humans, Male, Middle Aged, Pilot Projects, Psychiatric Status Rating Scales, Treatment Outcome, Cross-Over Studies, Deep Brain Stimulation, Secondary Prevention, Depressive Disorder, Treatment-Resistant
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