A Probe in the Brain May Relieve Resistant Depression Editorialist praises study design using extended optimization period

Deep brain stimulation (DBS) may be effective for relieving symptoms in treatment-resistant depression, Dutch researchers reported.
A significant decrease in depressive symptoms was observed in 10 of 25 patients given DBS of the central anterior limb of the internal capsule (vALIC), Isidoor Bergfeld, MSc, of the University of Amsterdam in the Netherlands, and colleagues reported online in JAMA Psychiatry.

The treatment was well-tolerated and elicited a partial response in six additional patients, and remission was achieved in five patients. Importantly, patients receiving sham stimulation experienced significantly more depressive symptoms than during the active treatment phase of the study, the researchers said.
“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,” they wrote. “Further specification of targets and the most accurate setting optimization as well as larger randomized clinical trials are necessary.”
The study design (an open-label, extended optimization period followed by a blinded, randomized, discontinuation experiment once a stable response was achieved) makes it “most compelling” and points the way to future studies, Helen Mayberg, MD, of Emory University in Atlanta, wrote in an accompanying editorial.
The discriminating effects of active-versus-sham stimulation demonstrated in phase II of the study were not seen in the recent industry-sponsored randomized clinical trial that used the more traditional, up-front active-versus-sham design, she noted.
“With increasing interest in targeted circuit modulation for depression and other psychiatric disorders, [this] study further highlights the need to seriously consider customized trial designs in planning any invasive device trials, be it DBS, vagus nerve stimulation, or a future novel technology,” she wrote.

The study also revealed the risk of a fixed optimization period and provided new insights into how time to stable response can vary between patients treated with vALIC, Mayberg said.
“The implicit instability of the DBS response reported in this study provides new evidence that experimental studies using invasive devices might best be structured so that they are not prematurely terminated at an arbitrary time point,” she wrote. “Such an approach will enable a more complete characterization of the trajectory and timeline of behavioral changes in individual participants prior to initiating large-scale, industry-sponsored trials.”
The open-label trial followed by a double-blind, randomized crossover phase enrolled 25 patients in two hospitals in the Netherlands between March 22, 2010, and May 8, 2014. A final follow-up was conducted on Dec. 19, 2014.
Patients were between 18 and 65 years of age, with a primary diagnosis of major depressive disorder lasting for more than 2 years. Other inclusion criteria included a 17-item Hamilton Depression Rating Scale (HAM-D-17) score of 18 or higher, and a Global Assessment of Function score of 45 or lower.
Eight of the patients were male and the mean age was 53.2 years. All patients received bilateral implants of four contact electrodes through the anterior limb of the internal capsule.

After 3 weeks’ recovery, a psychiatrist or psychologist assessed patients’ responses and adverse events after maintaining standardized optimization of DBS settings for at least 1 week. If there was no clinical improvement or only partial improvement, voltages greater than 6.0 V were tested and pulse width and frequency adjusted.
No psychotherapy was incorporated into the DBS treatment but psychiatrist-ordered medication adjustments — for symptom improvement, for instance — were permitted.
A stable response of at least 4 weeks — or a maximum of 52 weeks of DBS — signaled the end of the optimization period.
Following this, patients immediately entered the randomized, double-blind crossover phase consisting of two 6-week periods of either active or sham DBS.
In the optimization period, the mean HAM-D-17 scores decreased from 22.2 at baseline to 15.9 (P=0.001). Montgomery-Åsberg Depression Rating Scale scores fell from 34.0 to 23.8 (P<0.001) and Inventory of Depressive Symptomatology-Self-report scores went from 49.3 to 38.8 (P=0.005).

A total of 16 patients (nine responders and seven nonresponders) entered the randomized crossover phase. During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6) than during sham DBS (23.1) (P<0.001).
One patient experienced severe nausea during surgery, four patients attempted suicide, and two patients reported suicidal ideation.
In six patients, the optimization period exceeded the maximum of 52 weeks, and this may have led to a higher response rate, the researchers acknowledged. While two responders had minor changes in antidepressant medication during the optimization phase, “it is unlikely that these minor changes explained the full response.”
During the sham phase, an abrupt symptom increase was seen in 10 patients. Although they were blinded to treatment, they could “accurately predict the stimulation setting,” the researchers wrote.
They emphasized that in 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.”

An open-label adaptive design may be the most prudent approach for a high-risk procedure performed in a vulnerable population, Mayberg said, noting that patients with implanted devices continue to receive the experimental therapy after the study has ended.
One of the “unexplored” variables in this study is patient heterogeneity in treatment-resistant depression, she said, suggesting that retrospective analysis of patients who responded well to DBS could be followed by new studies to test these variables prospectively.
Finally, ongoing support for patients with treatment-resistant depression, including additional rehabilitation, must be built into studies of DBS, she emphasized, calling it “an obligation to the patients who engage in these demanding and risky trials.”
This study was supported by Medtronic, which provided the devices, as well as the Netherlands Organisation for Scientific Research/ZonMw.

One of the study authors also disclosed a relationship with Lundbeck.

Mayberg disclosed a consulting agreement with St Jude Medical to develop deep brain stimulation for the treatment of severe depression. She disclosed funding from the Hope for Depression Research Foundation, the National Institute of Mental Health, the National Institutes of Health Loan Repayment Program, and Medtronic.

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