Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression

Abstract

Context: Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited.

Objective: To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP).

Design: Open-label trial with a sham lead-in phase.

Setting: Academic medical center. Patients Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation.

Main outcome measures: Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation.

Results: A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase.

Conclusions: The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration clinicaltrials.gov Identifier: NCT00367003.

Figure 1

Surgical targeting. Preoperative magnetic resonance imaging (MRI) shows the sagittal (A) and coronal (B) views of the planned optimal subcallosal cingulate (SCC) white matter target (red circle). The dotted black line indicates the subcallosal plane of interest, parallel to the anterior-posterior commissural line; the dotted white line indicates the rostral limit of the subcallosal plane; and the dotted red line indicates the midsubcallosal plane. The red circle indicates demarcation of the SCC white matter target and surrounding gray matter (best seen in the coronal view [B]). C and D, Postoperative computed tomography scan merged with preoperative MRI showing a typical case with the deep brain stimulation electrodes in situ. Note that the contacts span the SCC gray and white matter in the vertical plane proximal to the split of the cingulum bundle and rostral medial frontal white matter tracts (C, red arrows, sagittal view). Contacts are numbered by convention (1–4 on the left, 5–8 on the right), inferior to superior. Contacts 2 and 3 are directly in the SCC white matter, and contacts 1 and 4 are in the inferior and superior gray matter, respectively. AC indicates anterior commissure; CC, corpus callosum.

Figure 2

Change in depression severity (left axis) and function (right axis) over time for the entire sample (A) and by diagnosis (B–D). Error bars represent standard error. *Twenty-four weeks was the primary end point, as this was the time point up to which medications and psychotherapy were maintained. After 24 weeks of active deep brain stimulation, medication changes and psychotherapy were allowed, as described in the text. BDI-II indicates Beck Depression Inventory II; BP, bipolar II disorder; GAF, Global Assessment of Functioning; HDRS, Hamilton Depression Rating Scale; MDD, major depressive disorder; and Pre-ran, at least 1 week after surgery before the 4-week sham stimulation phase.

Figure 3

Depression severity over time using Hamilton Depression Rating Scale (HDRS) cutoffs (moderate-severe [HDRS, >15], mild [HDRS, 8–15], or remission [HDRS, <8]).

Figure 4

The 17-item Hamilton Depression Rating Scale (HDRS) scores in 3 patients who received 4 weeks of sham stimulation followed by 24 weeks of open stimulation and then blinded discontinuation. Stimulation was reinitiated if a patient met criteria for a depressive relapse or if symptom severity returned to baseline level.