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Original Investigation |

Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression A Randomized Clinical Trial

Isidoor O. Bergfeld, MSc1,2; Mariska Mantione, PhD1; Mechteld L. C. Hoogendoorn, PhD1; Henricus G. Ruhé, MD, PhD1,3; Peter Notten, MD4; Jan van Laarhoven, MD4; Ieke Visser, MD5; Martijn Figee, MD, PhD1,2; Bart P. de Kwaasteniet, MD, PhD1; Ferdinand Horst, MSc4; Aart H. Schene, MD, PhD1,6,7; Pepijn van den Munckhof, MD, PhD8; Guus Beute, MD9; Rick Schuurman, MD, PhD8; Damiaan Denys, MD, PhD1,2,10
[+] Author Affiliations
1Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
2Amsterdam Brain and Cognition, Amsterdam, the Netherlands
3Department of Psychiatry, Mood and Anxiety Disorders, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
4Department of Psychiatry, St Elisabeth Hospital, Tilburg, the Netherlands
5PsyWorks, Amsterdam, the Netherlands
6Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands
7Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, the Netherlands
8Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
9Department of Neurosurgery, St Elisabeth Hospital, Tilburg, the Netherlands
10Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam
JAMA Psychiatry. 2016;73(5):456-464. doi:10.1001/jamapsychiatry.2016.0152.
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Importance  Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out.

Objective  To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases.

Design, Setting, and Participants  Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses.

Interventions  Deep brain stimulation targeted to the vALIC.

Main Outcomes and Measures  The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but <50% decrease of the HAM-D-17 score).

Results  Of 25 patients included in the study, 8 (32%) were men; the mean (SD) age at inclusion was 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95% CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) (P = .001), Montgomery-Åsberg Depression Rating Scale scores from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1) (P < .001), and Inventory of Depressive Symptomatology–Self-report scores from from 49.3 (95% CI, 45.4-53.2) to 38.8 (95% CI, 31.6-46.0) (P = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40%) were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) (P < .001). Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients).

Conclusions and Relevance  Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham.

Trial Registration  trialregister.nl Identifier: NTR2118

Figures in this Article


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Figure 1.
Overview and Flowchart of Study Design

DBS indicates deep brain stimulation; ITT, intention-to-treat; and T, time.

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Figure 2.
17-Item Hamilton Depression Rating Scale (HAM-D-17), Montgomery-Åsberg Depression Rating Scale (MADRS), and Inventory of Depressive Symptomatology–Self-report (IDS-SR) Scores in the Optimization and Crossover Phases

A, Scores for each measure during the optimization phase. B, Scores for each measure during the active-sham crossover phase. Error bars represent 95% CIs. Response and nonresponse were based on the HAM-D-17 score at the end of the optimization phase (T2).

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