The use of deep brain stimulation (DBS) for neuropsychiatric disorders recently suffered a setback after industry invested millions of dollars into depression studies that yielded negative outcomes. Despite these disappointments, the concept of using DBS for psychiatric disorders is still worth pursuing, according to a panel of experts at Cleveland Clinic’s neuroscience-focused 13th Annual Medical Innovation Summit, held in late 2015.
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In a panel discussion titled “Lessons Learned: Getting DBS to Market for Neuropsychiatric Disorders,” several leading investigators in the field discussed what went happened during the trials, insights gained and how research will likely proceed.
Roots reach back to mood effects in OCD trials
Interest in DBS for neuropsychiatric disorders stemmed from the technology’s success in treating obsessive-compulsive disorder (OCD), which is now an FDA-approved DBS indication under a Humanitarian Device Exemption (HDE), in addition to the initial approvals of DBS for movement disorders.
“As a clinician who was consistently being referred patients with treatment-refractory depression, I was trying to find alternative avenues of treatment for very ill individuals,” explained panel moderator Donald A. Malone Jr., MD, Chair of Cleveland Clinic’s Department of Psychiatry and Psychology and a staff member in its Center for Neurological Restoration. Dr. Malone noted that he has been involved in DBS research for neuropsychiatric disorders since 1999.
That was shortly after fellow panelist Paul Stypulkowski, PhD, got into research in this field. Dr. Stypulkowski, who is now Distinguished Scientist in the Neuromodulation Division of Medtronic, explained that four research teams, including Dr. Malone’s at Cleveland Clinic, came together in 2008 as a collaborative working group and published their worldwide experience of DBS for OCD, with a total of 26 patients.
That data set was used in a 2009 HDE application to the FDA and for CE marking in the European Union. “Even though it was small, it was a really strong data set that held up to scrutiny of two different regulatory agencies,” Dr. Stypulkowski noted.
“While those studies were ongoing,” he continued, “investigators noticed very clear mood effects in OCD patients. In fact, many noted that patients’ mood improved prior to improvement of their OCD symptoms. These observations led some in the group to begin studying the ventral capsule/ventral striatum — or VC/VS — as a DBS target for treatment-resistant depression.”
Highly encouraging pilot results
Three centers — Cleveland Clinic, the Warren Alpert Medical School of Brown University and Massachusetts General Hospital — collaborated in open-label pilot trials of DBS for refractory depression, while other trials were underway at Emory University and in Canada. Panelist Paul E. Holtzheimer, MD, MS, was involved in the latter.
“We had very impressive open-label pilot results,” said Dr. Holtzheimer, Director of the Mood Disorders Service at Geisel School of Medicine at Dartmouth. “We had a 40 to 50 percent response rate at six months, and long-term results showed about 80 to 90 percent response at two years with a 50 to 60 percent remission rate. And this was in very severely ill patients.” This study utilized the subgenual cingulate (Brodmann area 25) as the target for DBS.
Dr. Holtzheimer noted that the most striking finding was that patients who were admitted did not relapse. “Once we got people well, they stayed well over time, which is often not the case with other treatments for depression,” he said. “Also, none of the patients with bipolar disorder had a manic or hypomanic episode. So this seemed to be a safe treatment in the bipolar population, where it is often difficult to treat depression.”
“What you see is that the open-label, non-sham-controlled studies are almost uniformly positive, with remission and response rates that are remarkably similar across different anatomical targets,” added Dr. Malone. “The results are similar whether it’s the VC/VS or the subgenual cingulate cortex or a couple of other targets as well. That’s what prompted us to move to a sham-controlled study design.”
“The open-label data were striking,” Dr. Stypulkowski agreed. “It was undeniable that patients were better. There were acute effects with stimulation when patients were blinded. You could see their affect change. We got to the point where what we saw in the OR was being described as stereotypical.”
Promise fails to translate to controlled trials
So in the wake of these positive pilot results, two randomized, sham-controlled trials were conducted between 2009 and 2010: the Medtronic-sponsored Reclaim study and the St. Jude Medical-sponsored BROADEN trial.
At the end of the 16-week controlled phase of the Reclaim trial, no significant difference in response rates was observed between the DBS and control groups, noted Dr. Malone, who was a co-author of the Reclaim study report published in Biological Psychiatry in August 2015. He added that data from the BROADEN trial, which was halted after it failed a futility analysis in 2013, have not been published.
How to explain marked improvement in selected patients?
All panelists expressed disappointment in these pivotal trial results while underscoring their continued interest in the technology.
“As I continue to follow a number of these patients at Cleveland Clinic, many are doing remarkably well, given the initial severity of their illness,” said Dr. Malone. “We have patients who hadn’t been well for 10 to 15 or even 20 years who have now been well for 10 years [after DBS implants] and are staying well. For those of us who have been at this for a while, it’s hard to believe there is nothing there and that these improvements would have happened [without intervention]. This simply does not happen in these patients.”
“We have to admit it could be placebo effect,” Dr. Holtzheimer added. “Yet to think that 50 percent of patients who are this severely ill, this treatment-resistant, would get better and stay better for this period of time — it defies reason. We have two failed large studies and two amazing open-label pilot studies. It is hard to reconcile the two.”
Guideposts for the road ahead
“We took one step forward with the pivotal trials,” observed Dr. Stypulkowski. “We now need to take two steps back and return to the early research phase and try to improve patient selection.”
The panelists agreed that the next study design should take into account the need for rehabilitation in patients who have undergone DBS for refractory depression.
“These patients have been sick for a long time,” Dr. Holtzheimer pointed out. “Their brains are accustomed to being sick, and their habits are consistent with depression. In the open-label trials, we felt free to encourage patients to get out and do things. In the controlled trial setting, it was appropriate — but also frustrating — that we could not do that. You pull back a bit and don’t engage with the patient as much as you would in a clinical setting. This is worth discussing and may help explain why we did not have good response rates.”
Panelists also stressed the need to optimize brain targeting and develop more accurate scales for measuring improvement in depression. The latter could include biological markers such as galvanic skin response or mobile technologies such as smartphones or fitness trackers as proxies for how depression is responding to treatment.
Trials of DBS for psychiatric and neurological disorders — including depression, epilepsy, Alzheimer disease, addiction and anorexia nervosa — will continue, the panelists predicted. They also agreed that the approach to research will be more conservative for a few years with greater skepticism surrounding open-label data.
A video of this panel discussion and other 2015 Medical Innovation Summit sessions is available here (select “Videos” tab and go to video 38 for this session).