DBS Cuts Depression in Treatment-Resistant Patients

Pauline Anderson

May 11, 2016

In contrast to some previous research, a new study shows that stimulation of the ventral anterior limb of the internal capsule (vALIC) of the brain significantly reduces depressive symptoms in patients with treatment-resistant depression.

The intervention resulted in a treatment response in about 40% of patients and a partial response in about 24% of patients. Results of a randomized, active-vs-sham part of the study suggest that the reduction in depressive symptoms is not due to a placebo effect.

"This study confirms the promise of DBS [deep brain stimulation] as a treatment for depression and could serve as a starting point for larger trials," said lead author Isidoor O. Bergfeld, Department of Psychiatry, Academic Medical Center, and Amsterdam Brain and Cognition, the Netherlands.

The research was published online April 9 in JAMA Psychiatry.

Mechanism Unclear

In the two-part study, all 25 patients in the open-label phase received bilateral implants of four contact electrodes following a trajectory through the anterior limb of the internal capsule. The electrodes were connected via subcutaneous extensions to stimulators placed in an infraclavicular pocket.

Following the surgery and a 3-week recovery period, researchers initiated standardized DBS. The optimization period ended when a stable response of at least 4 weeks was reached or after a maximum of 52 weeks. During this phase, DBS settings were adjusted on the basis of symptoms, side effects, and response.

Initially, the optimization phase was to have a maximum duration of 6 months, but the duration was extended after some of the initial patients failed to respond. Around this time, newly published open-label studies reported use of higher voltages than Bergeld's group had been employing.

"So we could not be sure whether the nonresponse was due to suboptimal DBS settings, and this led to the decision to extend optimization to 12 months," he said.

For this phase, the primary outcome was change in scores on the investigator-rated 17-item Hamilton Depression Rating Scale (HAMD-17). Researchers classified patients as responders (those for whom there was a 50% or greater reduction in HAMD-17 score) and nonresponders. Remission was defined as having a HAMD-17 score of 17 or less.

Immediately following the open-label phase, 16 patients entered the randomized, double-blind, crossover phase. This part of the study consisted of two periods of 6 weeks during which the DBS stimulator was either on (active) or off (sham).

The primary outcome for this second phase was the difference in HAMD-17 scores between active and sham stimulation phases.

In the first phase, the mean HAMD-17 scores decreased from 22.2 to 15.9. On the basis of these scores, 10 of 25 patients (40%) were classified as responders, of whom five (20%) were in remission. In a post hoc analysis, five of the 15 nonresponders (24% of the entire sample) were classified as partial responders (≥25%, but <50% reduction in HAM-D score.)

In the second phase, the mean HAMD-17 score was 13.6 following the active phase and 23.1 following the sham phase (P < .001).

It is not clear how DBS works to improve depressive symptoms, although it is likely that stimulation of axon bundles leads to altered functional connectivity in brain networks around the stimulated site, said Bergfeld.

In a study published in 2013, his research group found altered connectivity between frontal and striatal areas during stimulation of the same region in patients with obsessive-compulsive disorder.

There was a total of five suicide attempts in four nonresponders, and two patients (one nonresponder and one responder who was a nonresponder at the time of the adverse event) experienced an increase in suicidal ideation that required hospitalization.

Another patient suffered a surgery-related hemorrhage in the supplementary motor area but had no lasting functional disabilities. There were also reports of mania and hypomania, although these symptoms resolved within hours of reducing the voltage of the stimulation.

Opportunity for Patient Selection

In an accompanying editorial, Helen S. Mayberg, MD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, and colleagues describe the study's second phase as "most compelling."

They also praised the flexible trial design. Increasing the duration of the optimization period to accommodate variability in the time needed to reach a stable response "provides new insights into intersubject variability with vALIC stimulation," they write.

"The authors' tenacious attempts to establish a stable response by extending the optimization period for the initial protocol using 3 to 6 months to a full year is commendable and provides critical information for future trials."

The study highlights the need to seriously consider customized trial designs in planning any trials involving an invasive approach, "be it DBS, vagus nerve stimulation, or a future novel technology," the editorialists write.

"Matching a patient to the best treatment as well as avoiding therapies that are unlikely to be effective are the goals for treatment selection for patients at all stages of depression," they note.

In particular, patient heterogeneity in cases of treatment-resistant depression remains an "unexplored variable" in this, and other, DBS studies.

The editorialists also note that surgical accuracy and contact selection are not only potential contributors to response but also are variables that can be systemically evaluated and rectified. Specific fiber bundles and effects in remote targets can be determined.

They view this research as "a tremendous opportunity to retrospectively characterize the various features that best define patients who responded well to this treatment."

"Encouraging" Results

Commenting for Medscape Medical News, Darin D. Dougherty, MD, director, Division of Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital, and associate professor of psychiatry, Harvard Medical School, Boston, said the findings were encouraging.

Dr Dougherty led one of the studies that Bergfeld referred to in his article. That study (called Reclaim) included 30 patients with treatment-resistant depression who were randomly assigned to sham or active DBS at the ventral capsule/ventral striatum target. An open-label continuation phase followed.

The primary outcome of that study was a 50% or greater improvement in scores on the Montgomery-Åsberg Depression Rating Scale. That outcome was not reached.

According to Dr Dougherty, a main difference between his study and the current study was that his study used a "front-end" design, in which patients were randomly assigned to active or sham stimulation in a double-blind fashion at the beginning of the study.

"However, given the differential response time between patients, the 'back-end' design" used in the current study "may be preferable, and it is encouraging that this trial has positive results," he said.

There were other notable differences between the two studies. "Our study used a slightly different target ― more ventral and anterior ― and applied monopolar instead of bipolar stimulation," said Bergfeld.

His study also optimized DBS settings (eg, active contacts, voltage) throughout a 12-month period with weekly adjustments of settings, whereas Dr Dougherty's study optimized settings during a 4-week period with daily adjustments, he added.

Isidoor Bergfeld and Dr Dougherty have disclosed no relevant financial relationships. Dr Mayberg has a paid consulting agreement with St. Jude Medical Inc, which licensed her intellectual property to develop deep brain stimulation for the treatment of severe depression. The terms of this agreement have been reviewed and approved by Emory University in accordance with their conflict of interest policies.

JAMA Psychiatry. Published online April 6, 2016. Abstract, Editorial


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