title: Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Deep brain stimulation targeted to the vALIC.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  trialregister.nl Identifier: NTR2118.
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands2Amsterdam Brain and Cognition, Amsterdam, the Netherlands.
authors.forename: Isidoor O
authors.initials: IO
authors.lastname: Bergfeld
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Mariska
authors.initials: M
authors.lastname: Mantione
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Mechteld L C
authors.initials: ML
authors.lastname: Hoogendoorn
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands3Department of Psychiatry, Mood and Anxiety Disorders, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Henricus G
authors.initials: HG
authors.lastname: Ruhé
authors.affiliation: Department of Psychiatry, St Elisabeth Hospital, Tilburg, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Notten
authors.affiliation: Department of Psychiatry, St Elisabeth Hospital, Tilburg, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: van Laarhoven
authors.affiliation: PsyWorks, Amsterdam, the Netherlands.
authors.forename: Ieke
authors.initials: I
authors.lastname: Visser
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands2Amsterdam Brain and Cognition, Amsterdam, the Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Figee
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Bart P
authors.initials: BP
authors.lastname: de Kwaasteniet
authors.affiliation: Department of Psychiatry, St Elisabeth Hospital, Tilburg, the Netherlands.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Horst
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands6Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands7Donders Institute for Brain, Cognition and Behavior, Radboud Univ.
authors.forename: Aart H
authors.initials: AH
authors.lastname: Schene
authors.affiliation: Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Pepijn
authors.initials: P
authors.lastname: van den Munckhof
authors.affiliation: Department of Neurosurgery, St Elisabeth Hospital, Tilburg, the Netherlands.
authors.forename: Guus
authors.initials: G
authors.lastname: Beute
authors.affiliation: Department of Neurosurgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Schuurman
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands2Amsterdam Brain and Cognition, Amsterdam, the Netherlands10Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amste.
authors.forename: Damiaan
authors.initials: D
authors.lastname: Denys
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D046690:Deep Brain Stimulation / Q000009:adverse effects / Q000379:methods*; D003865:Major Depressive Disorder / Q000503:physiopathology / Q000628:therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000503:physiopathology / Q000628:therapy*; D004311:Double-Blind Method; D004567:Electrodes, Implanted; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D020772:Internal Capsule / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D016896:Treatment Outcome