Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial
Open accessAbstract
Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/- 4) at baseline to 12.9 (SD +/- 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.
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In that 12-month randomized trial, significant response and remission rates were observed at 1 year, with response 100% and remission 50%.
“show significant response and remission rates at 1 year (RS: 100%, RM: 50%)”
From Deep brain stimulation for depression. (2022) · cites this paper as [72]
In a 12-month randomized trial, no significant difference was found between sham and stimulation groups during the first 2 months.
“Results do not demonstrate a significant difference between sham and stimulation groups during the first 2 months”
From Deep brain stimulation for depression. (2022) · cites this paper as [72]
Implementing tractography-based surgical targeting into routine clinical practice may be challenging because it requires high-quality patient-specific diffusion-weighted scans rather than normative connectomic data.
“implementing tractography based surgical targeting into routine clinical practice may be challenging since it requires high-quality patient-specific diffusion-weighted scans rather than normative connectomic data [72].”
From Deep brain stimulation for depression. (2022) · cites this paper as [72]
Notable exceptions include prospective targeting of a predefined responder map of specific white matter fibers connected to the SCC and individual tractography identification of the medial forebrain bundle.
“Notable exceptions include prospective targeting of a predefined responder map of specific white matter fibers connected to the SCC [29], and the individual tractography identification of the medial forebrain bundle [72]”
From Deep brain stimulation for depression. (2022) · cites this paper as [72]
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References 48 · Cited by 176
- Authors
- Coenen, V. A., Bewernick, B. H., Kayser, S., Kilian, H., Boström, J., Greschus, S., Hurlemann, R., Klein, M. E., Spanier, S., Sajonz, B., Urbach, H., & Schlaepfer, T. E.
- Affiliations
- University of Freiburg (DE)
- University Hospital Bonn (DE)
- University of Bonn (DE)
- University Medical Center Freiburg (DE)
- Johns Hopkins University (US)
- Corresponding author
- Schlaepfer, Thomas E.
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2019-03-13
- Volume
- 44
- Issue
- 7
- Pages
- 1224-1232
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC6785007
- OpenAlex
- W2922385364
- Cited by
- 176
- References
- 48
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 29 · 2023: 29 · 2022: 28 · 2021: 24 · 2020: 23 · 2019: 8
- FWCI
- 14.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropsychopharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medtronic
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Keywords
- deep brain stimulation, treatment-resistant depression, major depressive disorder, antidepressant effects, timeline analysis
- MeSH terms
- Adult, Aged, Major Depressive Disorder, Female, Humans, Male, Medial Forebrain Bundle, Middle Aged, Treatment Outcome, Deep Brain Stimulation, Depressive Disorder, Treatment-Resistant
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