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Figure 1.
Overview and Flowchart of Study Design
Overview and Flowchart of Study Design

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

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
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).

Table 1.  
Descriptive Characteristics of Patients With TRD
Descriptive Characteristics of Patients With TRD
Table 2.  
Mean Depression Scores Over Time
Mean Depression Scores Over Time
Table 3.  
Adverse Events During Optimization and Crossover Phases
Adverse Events During Optimization and Crossover Phases
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Original Investigation
May 2016

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

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
 

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Psychiatry. 2016;73(5):456-464. doi:10.1001/jamapsychiatry.2016.0152
Abstract

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

Introduction

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, with an estimated lifetime prevalence of 14.6% across high-income countries.1 Effective therapeutic options for MDD include psychotherapy, different classes of antidepressants, and electroconvulsive therapy. Nevertheless, up to 30% of patients do not respond to 4 consecutive antidepressant strategies,2 and 52% of pharmacotherapy-resistant patients do not respond to electroconvulsive therapy.3 Such patients are considered to have an advanced stage of treatment-resistant depression (TRD),4 which is associated with more hospitalizations, more suicide attempts, and higher costs compared with non-TRD.5-7

Deep brain stimulation (DBS) is a promising therapeutic option for patients with TRD. Deep brain stimulation consists of implanting electrodes in specific brain areas and then optimizing stimulation settings (eg, voltage and frequency) to modulate brain activity of the targeted area. Since 2005, several open-label trials have reported promising effects of DBS in TRD by targeting different brain structures involved in the neurobiology of MDD: the subcallosal cingulate gyrus,8-11 medial forebrain bundle,12 ventral capsule/ventral striatum,13 and nucleus accumbens.14,15 However, results of randomized trials are scarce. The first randomized clinical trial16 of ventral capsule/ventral striatum DBS in TRD did not find differences in response rates following active or sham stimulation in an interim analysis and was prematurely stopped. In contrast, a strong antidepressive effect has been identified17,18 in patients with obsessive-compulsive disorder following active nucleus accumbens and ventral anterior limb of the internal capsule (vALIC) DBS as opposed to sham stimulation.

We aimed to assess the efficacy and tolerability of DBS targeting the vALIC in patients with TRD in a trial with an open-label optimization phase, controlling for placebo effects by a randomized, double-blind, crossover active-sham phase.

Box Section Ref ID

Key Points

  • Question Is deep brain stimulation of the ventral anterior limb of the internal capsule effective in reducing depressive symptoms in treatment-resistant depression?

  • Findings In this randomized cross-over trial of active deep brain stimulation and sham treatment, 10 of 25 patients (40%) responded to deep brain stimulation and an additional 6 patients (24%) partially responded; patients experienced significantly more depressive symptoms during sham compared with active stimulation.

  • Meaning To our knowledge, this is the first study showing the efficacy of deep brain stimulation of the ventral anterior limb of the internal capsule that cannot be attributed to placebo effects.

Methods
Participants

We performed an open-label trial followed by a double-blind, randomized crossover phase in 2 hospitals in the Netherlands (Academic Medical Center, Amsterdam [AMC] and St Elisabeth Hospital, Tilburg [SEH]). The study was approved by the medical ethics boards of both hospitals (protocol available in Supplement 1). All included patients provided written informed consent; they did not receive financial compensation.

Patients with TRD had to meet a primary diagnosis of MDD (single episode or recurrent) with an illness duration of more than 2 years, a 17-item Hamilton Depression Rating Scale (HAM-D-17)19 score of 18 or higher, and a Global Assessment of Function score of 45 or lower.20 Patients had to be treatment resistant, defined as a failure of at least 2 different classes of second-generation antidepressants (eg, selective serotonin reuptake inhibitor), 1 trial of a tricyclic antidepressant, 1 trial of a tricyclic antidepressant with lithium augmentation, 1 trial of a monoamine oxidase inhibitor, and 6 or more sessions of bilateral electroconvulsive therapy. Patients who fulfilled the above criteria and remained stable with maintenance electroconvulsive therapy, but relapsed after discontinuation of that therapy, were also eligible. Patients had to be between 18 and 65 years old, able to understand the consequences of the procedure (IQ >80), and capable of making choices without coercion. Exclusion criteria were schizophrenia or history of psychosis unrelated to MDD, bipolar disorder, an organic cause of depression, substance abuse during the past 6 months, antisocial personality disorder, Parkinson disease, dementia, epilepsy, current tic disorder, unstable physical condition, pregnancy, or general contraindications for surgery.

DBS Treatment and Study Design

All patients received bilateral implants of 4 contact electrodes (lead model 3389; Medtronic) following a trajectory through the anterior limb of the internal capsule with the deepest contact point in the nucleus accumbens and the 3 upper contact points in the ventral part of the capsule (eMethods in Supplement 2). Target coordinates for the electrode tip were approximately 7 mm lateral to the midline, 3 mm anterior to the anterior border of the anterior commissure, and 4 mm inferior to the intercommissural line with adjustments based on individual anatomy (eFigure 1, eFigure 2, eTable 1, and eTable 2 in Supplement 2). Electrodes were connected via subcutaneous extensions to stimulators (Activa PC; Medtronic) placed in an infraclavicular pocket. Postoperative computed tomographic scans were fused with magnetic resonance imaging scans used for surgical planning to verify the position of the electrodes. Following surgery, standardized DBS setting optimization was started after a 3-week recovery period. A psychiatrist or psychologist assessed patients’ responses and adverse events after maintaining DBS settings for at least 1 week. Optimization of the settings was restricted to changes in active contact points and voltage (ranging from 2.5 to 6.0 V). Pulse width and frequency were kept stable (90 microseconds and 130 or 180 Hz, respectively). If no or partial clinical improvement was achieved following standardized optimization, we tested voltages greater than 6.0 V and adjustments in pulse width and frequency. Detailed information on optimization is provided in eMethods and eTable 3 in Supplement 2. The optimization phase ended when a stable response of at least 4 weeks was reached or after a maximum of 52 weeks. We strived to keep medication therapy stable during the open-label phase, but psychiatrists were allowed to make changes for clinical indications, such as tapering medication in the event of symptom improvement (eTable 4 in Supplement 2 presents a summary of medication use over time). No psychotherapy was added to the DBS treatment.

Immediately after the open-label phase of the study, patients entered the randomized, double-blind crossover phase consisting of 2 blocks of 6 weeks during which the DBS stimulator was on (active) or off (sham) (Figure 1). The phases were terminated if the treating psychiatrist or research team deemed it clinically indicated and the HAM-D-17 score was at least 15 or if patients requested termination. In case of termination, patients were crossed over to the next phase; blinding was maintained. Medication and DBS settings were kept stable during the crossover phase.

Symptom severity was evaluated 3 weeks before DBS surgery (baseline), 3 weeks following surgery with stimulation still off (time 1 [T1]), at every visit in the optimization phase, after optimization of DBS settings (T2), and following the first (T3) and second (T4) crossover blocks.

Randomization and Blinding

Two researchers independent from this study randomized blocks of 4 randomization orders using a computerized random number generator. The blocks included 2 of both randomization orders (ie, active-sham and sham-active) and were stratified by hospital. The same independent researchers randomized patients in the crossover phase by switching DBS on or off using a clinician programmer (N’Vision; Medtronic). Patients, treating health care professionals, and raters were blinded to stimulation settings and remained blinded until the last patient had ended the crossover phase. The blinding was removed for the researcher performing the analysis (I.O.B.) when the last patient ended the crossover phase.

Outcomes

The outcome of the open-label phase of the study was the change of the investigator-rated HAM-D-17 score (range, 0-52)19 from baseline to T2. In addition, we classified patients as responders (≥50% reduction of HAM-D-17 score at T2 compared with baseline) or nonresponders (<50% reduction of HAM-D-17 score at T2 compared with baseline). Remission was defined as a HAM-D-17 score of 7 or less at T2. The primary outcome measure of the randomized, double-blind crossover trial was the difference in HAM-D-17 scores between the active and sham stimulation phases. In a post hoc analysis, we tested whether a subset of nonresponders showed a partial response (≥25% but <50% reduction of HAM-D-17 score at T2 compared with baseline).

Secondary outcome measures were the investigator-rated Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60)21 and the patient-rated Inventory of Depressive Symptomatology–Self-report (IDS-SR) (range, 0-84).22 Higher scores indicate more severe symptoms on both scales. In addition, a psychiatrist or psychologist rated adverse events (AEs) on the basis of observations, spontaneous reports, and interviews conducted at all optimization visits and during the crossover phase. An AE was rated as serious when it resulted in (1) death, (2) a life-threatening situation, (3) hospitalization (or prolonged hospitalization if the patient was already hospitalized), or (4) chronic disability. We assessed whether serious AEs were probably related to surgery, the device, or DBS (ie, occurring 1-2 days after DBS initiation or adjustment) or had an unknown association with DBS.

Statistical Analysis

Three restricted, maximum-likelihood, linear mixed models were used to test the change of depressive symptoms during the optimization phase.23 The HAM-D-17, MADRS, or IDS-SR scores measured at baseline, T1, all optimization visits, and T2 were included as dependent variables, and log-transformed days from baseline were used as independent random variables with individual patients as grouping factors. Days from baseline were log transformed to meet assumptions of linearity. All analyses were based on intention to treat, so observations of all patients were included in the analyses. In addition, percentages of responders, nonresponders, and partial responders are presented descriptively. In case of withdrawal before T2, the last observation in the optimization phase was used to define response status.

To analyze differences in depressive symptoms in the crossover phase, we executed 3 restricted, maximum-likelihood mixed models as described by Díaz-Uriarte.24 We included HAM-D-17, MADRS, or IDS-SR scores as dependent variables; period (T3 and T4) and treatment (active and sham) as independent variables; and testing for carryover effects with the period times treatment interaction. According to the dependent variable, the HAM-D-17, MADRS, or IDS-SR score at T2 was included as a covariate. The P values are the outcomes of the effects in the mixed models. We considered P < .05 to indicate a significant finding.

A sample size of 16 patients in the crossover phase was estimated to have sufficient power to detect relevant changes between sham and active DBS. To compensate for potential dropouts before initiation of the crossover phase, we increased the sample size to 26 patients to start in the open-label optimization phase. A data safety monitoring board monitored the study and performed a safety and efficacy interim analysis after 20 patients were enrolled.

Data analysis was conducted from January 12 to February 24, 2015. We used R, version 3.1.2, to analyze the data.25

Results

We screened 52 patients with TRD for eligibility and included 25 of these patients in the study (13 from SEH and 12 from AMC) between March 22, 2010, and May 8, 2014, with the final follow-up conducted on December 19, 2014. Table 1 describes the characteristics of the study population.

Four patients withdrew from the study after 3, 5, 10, and 10 months of optimization (Figure 1). The mean (SD) duration of the optimization phase was 51.6 (22.0) weeks. Six patients exceeded the maximum duration of 52 weeks because we needed to delay the crossover phase: 3 nonresponders were too psychiatrically unstable and 1 responder was too somatically unstable to participate after 52 weeks, but these 4 patients could participate at a later time point. Furthermore, we suspected battery depletion within the blinded crossover phase in 2 responders. The mean time to first response in responders was 53.6 (50.6) days (range, 6-154 days) after the start of the factor optimization. The 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) at T2, MADRS from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1), and IDS-SR from 49.3 (95% CI, 45.4-53.2) to 38.8 (95% CI, 31.6-46.0) (Table 2 and Figure 2). The mixed models showed a significant decrease of HAM-D-17 (P = .001), MADRS (P < .001), and IDS-SR (P = .005) scores over time between baseline and T2 for the entire group. Based on the HAM-D-17 score at T2, we classified 10 of 25 patients (40%) as responders (SEH, 7 [54%]; AMC, 3 [25%]), of whom 5 (20%) were in remission (SEH, 3 [23%]; AMC, 2 [17%]), and 15 of 25 patients (60%) as nonresponders (SEH, 6 [46%]; AMC, 9 [75%]). In post hoc analysis, 6 of these 15 nonresponders (24% of the entire sample) were classified as partial responders (SEH, 1 [8%]; AMC, 5 [42%]).

Of the 21 patients remaining at T2, 5 patients (24%) (1 [20%] responder; 4 [80%] nonresponders) withdrew (Figure 1), leaving 16 patients (9 [56%] responders, 7 [44%] nonresponders) to start the crossover phase. The ratio of nonresponders to responders was different between patients who withdrew before the crossover phase (1:8) and those who participated in the crossover phase (7:9) (Fisher exact test, P = .04), but no differences in any other descriptive variables were found.

Nine patients were randomized to active-sham and 7 to sham-active DBS. The first crossover phase lasted a mean of 21.13 (11.14) days, and the second lasted 18.56 (13.14) days. The active phase was 25.3 (11.3) days. Three responders and 6 nonresponders had to be prematurely crossed over (reasons presented in eTable 5 in Supplement 2). The sham phase lasted 14.4 (10.5) days. All responders and 3 nonresponders had to be prematurely crossed over. In 8 responders and 2 nonresponders, depressive symptoms increased within a day, regardless of whether sham DBS was the first or second phase. Response in responders was recaptured within a day following the sham phase. Mean depression scores of the responders, nonresponders, and entire group are reported in Table 2. Patients had a mean HAM-D-17 score of 13.6 (95% CI, 9.8-17.4) following the active and 23.1 (95% CI, 20.6-25.6) following the sham phase, a MADRS score of 21.3 (95% CI, 14.7-27.9) following the active and of 34.1 (95% CI, 30.7-37.4) following the sham phase, and an IDS-SR score of 32.6 (95% CI, 23.3-42.0) following the active and of 46.6 (95% CI, 41.1-52.2) following the sham phase. No significant carryover effects were found on any of the scales (HAM-D-17: P = .05; MADRS: P = .08; and IDS-SR: P = .14). After correction for carryover effects, period, and depression score at T2, the mixed models showed a significantly lower score in the active DBS phase compared with the sham DBS phase on all depression scales (HAM-D-17: P < .001; MADRS: P = .001; and IDS-SR: P = .001).

In post hoc analysis, we explored possible bias introduced by the 9 patients (1 responder, 8 nonresponders) who did not participate in the crossover phase. We randomized these 9 patients by a random number–generated coin flip and imputed depression scores 500 times with period, stimulation setting, responder status, depression scores, and depression scores at T2 as predictors. We repeated the same mixed models and pooled them; depression scores remained significantly lower during active than sham (HAM-D-17: βSham − Active, 7.1 [95% CI, 2.4-11.8], P = .005; MADRS: βSham − Active, 9.2 [95% CI, 1.4-17.0], P = .02; and IDS-SR, βSham − Active, 10.8 [95% CI, 3.2-18.4], P = .008).

Adverse events reported by patients are described in Table 3 and eTable 6 in Supplement 2. We noted 1 surgery-related serious AE and 7 serious AEs with an unknown association with DBS. The surgery-related serious AE concerned 1 patient who developed extreme nausea during surgery, resulting in termination of the procedure. The operation was successfully completed 2 weeks later. There were 5 suicide attempts in 4 nonresponders, and 2 patients (1 nonresponder and 1 responder who was a nonresponder at the time of AE) had an increase of suicidal ideation requiring hospitalization. Two nonresponders died several weeks after they withdrew from the study and DBS had been stopped (1 suicide, 1 euthanasia). Another important surgery-related AE concerned a hemorrhage in the supplementary motor area; however, the patient did not experience lasting functional disabilities. The most invasive DBS-related AEs were transient symptoms of mania in 2 patients, which persisted for 1 day in 1 patient and for 3 or more days in the other, and hypomania in 1 patient, which persisted for 6 days. These symptoms were resolved within hours by lowering the voltage. Patients tolerated AEs generally well, or they were resolved by setting adjustments except for 2 permanent AEs (pollakiuria and nocturia). Adverse events that were reported by 2 or more patients only during active DBS were blurred vision, sleep disturbances, and disinhibition (eg, excessive talking).

Discussion

We found a significant reduction of depressive symptoms following vALIC DBS, resulting in response in 10 patients (40%) and partial response in 6 (24%) patients with TRD. Remission was achieved in 5 (20%) patients. The randomized active-sham phase study design indicates that reduction of depressive symptoms cannot be attributed to placebo effects.

The response rate in our sample is in the range of open-label studies targeting the nucleus accumbens in 11 patients (45.5%),14 subcallosal cingulate gyrus in studies with 8 to 21 patients (28.6%-62.5%),9-11,26 or ventral capsule/ventral striatum in 15 patients (53.3%).13 However, our response rate falls below the rate reported in a study of medial forebrain bundle DBS in 7 patients (87.5%).12

However, the results from our active-sham phase are in contrast with those of a recently published randomized clinical trial16 of ventral capsule/ventral striatum DBS that found no significant differences between active and sham DBS. First, this difference could be due to the slightly more anterior and ventral position of the electrode in the ALIC than in the ventral capsule/ventral striatum randomized clinical trial. Second, we could have overestimated efficacy because of the dropout of 9 patients before the active-sham phase. Although differences between active and sham DBS were smaller when correcting for the dropouts, symptoms remained significantly lower following active than sham DBS. Third, Dougherty et al16 could have underestimated efficacy because of the strategy in DBS optimization. Our optimization phase lasted 52 weeks during which we evaluated DBS settings after at least 1 week compared with their optimization phase of 4 weeks and evaluation within a day. Acute DBS effects might not predict long-term stable effects and might have led to suboptimal DBS settings in the randomized phase. When designing future randomized clinical trials, optimal optimization paradigms should be established so that effective treatment in the active arm is ensured. Based on our study, we would advise an optimization phase of sufficient duration (eg, 6 months) with the possibility to evaluate setting combinations over an extended period of time (eg, 1 week).

Although vALIC DBS was effective in 10 patients, symptoms of other patients did not improve or only partially improved. Deep brain stimulation targeting did not systematically differ between responders and nonresponders (eFigure 2 in Supplement 2), but efficacy probably depends on the modulation of specific axon bundles traveling through the vALIC.27-29 Specifying which axon bundles are most effective might increase response. Previously, specification of effective trajectories has resulted in potential targets (medial forebrain bundle)12,30 and trajectories around the subcallosal cingulate gyrus that are linked to optimal response.31,32 Furthermore, the addition of cognitive behavioral therapy could improve symptoms by targeting inactivity and persistent depressive cognitions since augmenting cognitive behavioral therapy with DBS resulted in symptom improvement in patients with obsessive-compulsive disorder.33

Regardless of responder status, patients tolerated vALIC DBS generally well. Although we recorded several AEs, we could not reliably associate most of these AEs with DBS. Similar to other studies targeting striatal areas, 3 patients experienced symptoms of hypomania, which were resolved by setting adjustments. In addition, we recorded several incidents of suicidality (4 patients attempting suicide and 2 patients ending their lives after withdrawal from the study). Although patients with TRD have a higher risk of suicide attempts than do patients with MDD in general,7 suicidality should be carefully recorded to establish whether DBS might increase this risk.

A limitation of this study is that the optimization phase exceeded the maximum of 52 weeks in 6 patients, which could have led to a higher response rate. However, none of the nonresponders at 52 weeks responded in the crossover phase. In addition, during optimization, 2 responders had minor changes in antidepressant medication, but it is unlikely that these minor changes explained the full response. Another limitation is the abrupt symptom increase in 10 patients during the sham phase. Although these patients were blinded to active vs sham DBS, they could accurately predict the stimulation setting. In addition, future crossover studies should consider phases of no more than 1 week to ensure patient safety, with a washout period between phases to minimize possible carryover effects.

Conclusions

This trial shows efficacy of DBS in patients with TRD and supports the possible benefits of DBS despite a previous disappointing randomized clinical trial. Further specification of targets and the most accurate setting optimization as well as larger randomized clinical trials are necessary.

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Article Information

Corresponding Author: Isidoor O. Bergfeld, MSc, Department of Psychiatry, Room PA3.114, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands (i.o.bergfeld@amc.nl).

Submitted for Publication: August 14, 2015; final revision received January 20, 2016; accepted January 24, 2016.

Published Online: April 6, 2016. doi:10.1001/jamapsychiatry.2016.0152.

Author Contributions: Mr Bergfeld had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mantione, Hoogendoorn, Ruhé, Notten, van Laarhoven, Figee, Horst, Schene, Beute, Schuurman, Denys.

Acquisition, analysis, or interpretation of data: Bergfeld, Hoogendoorn, Ruhé, van Laarhoven, Visser, Figee, de Kwaasteniet, Horst, Schene, van den Munckhof, Beute, Schuurman, Denys.

Drafting of the manuscript: Bergfeld, Mantione, Hoogendoorn, Denys.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bergfeld, Mantione.

Obtained funding: Bergfeld, Ruhé, Schuurman, Denys.

Administrative, technical, or material support: Bergfeld, Notten, van Laarhoven, Visser, de Kwaasteniet, Horst, Schene, Beute, Schuurman.

Study supervision: Mantione, Hoogendoorn, Ruhé, Figee, Schene, Beute, Denys.

Conflict of Interest Disclosures: Drs Schuurman and Denys receive occasional fees from Medtronic for educational purposes. Dr Denys is a member of the advisory board of Lundbeck. No other conflicts were reported.

Funding/Support: This deep brain stimulation intervention was supported by an unrestricted, investigator-initiated research grant by Medtronic Inc (Drs Schuurman and Denys), which provided the devices used. Furthermore, the project was sponsored by Vroege Evaluatie van Medische Innovaties (Early Evaluation of Medical Innovations) grant 171201008 from ZonMw (Mr Bergfeld and Drs Ruhé, Schuurman, and Denys). Dr Ruhé is supported by Netherlands Organisation for Scientific Research/ZonMw VENI grant 016.126.059.

Role of the Funder/Sponsor: The funding sources had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: This study could not have been carried out without the cooperation of all participating patients, for which we would like to express our utmost gratitude. Pieter Ooms, MSc, Etienne de Jongh, and Dominique Scheepens, MD, contributed to the treatment of the patients, and Judy Luigjes, PhD, and Ruud Smolders, MSc, assisted in randomizing patients during the active/sham phases of the study (Department of Psychiatry, Academic Medical Center). Bettie Heeffer (Department of Psychiatry, St Elisabeth Hospital) and Renske van Dijk, MSc (Department of Psychiatry, Academic Medical Center), documented the data. There was no financial compensation.

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