Does DBS Have a Future in Depression Treatment?

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While working for the medical technology company Medtronic in the early 2000s, neurosurgeon Robert Coffey, M.D., was assigned to a new clinical study the company was undertaking. Medtronic wanted to assess whether deep brain stimulation (DBS)—a surgical procedure in which 1-mm electrodes are implanted in the brain to stimulate the surrounding neurons—could lead to improvements in patients with treatment-resistant depression.

The company’s interest in the technology for patients with depression came on the heels of a 1999 study in which researchers in Belgium reported that DBS was associated with mood improvements in patients with severe obsessive-compulsive disorder.

Coffey was skeptical from the start. While DBS is approved by the Food and Drug Administration (FDA) for the treatment of severe movement problems related to Parkinson’s disease or essential tremor, a pair of studies conducted by Medtronic in the 1990s examining DBS to treat chronic pain had failed. He saw no evidence that the depression studies would be any different.

His concerns seemed warranted. After officially commencing the DBS trial for treatment-resistant depression called RECLAIM in 2009, the trial was stopped by the study’s review board since the data gave no indication that DBS was helping the 30 depressed patients who had received the treatment. In fact, the participants who did not receive active stimulation had a greater reduction in depression symptoms than those who received active stimulation. A separate study examining DBS for treatment-resistant depression called BROADEN (launched in 2008 by St. Jude Medical, now Abbott) also suggested that the therapy was not demonstrating any effect.

A decade later, DBS finds itself at a crossroads in psychiatry. Advances in pharmacology and noninvasive stimulation therapies such as transcranial magnetic stimulation (TMS) mean there are more options for treating patients with treatment-resistant depression than ever before. Still, proponents of DBS maintain that while DBS may not be the answer for all patients with treatment-resistant depression, they believe it may be the best option for some patients.

“There are enough people committed to understanding brain circuits that I have optimism DBS will succeed as a depression treatment,” said Helen Mayberg, M.D., a neurologist and the director of The Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai and lead investigator on the BROADEN study. “To simply trash this line of research and start over is a missed opportunity.”

In this two-part series, Psychiatric News will examine why proponents and skeptics of the procedure remain at odds over whether the potential benefits of the procedure outweigh the risks.

Psychosurgery Comes With Risks

DBS may be a modern invention, but its principles date back centuries, perhaps even millennia. This procedure is a form of psychosurgery (treating a mental disorder by removing or altering “diseased” brain tissue), which throughout history has been considered controversial. Critics of these practices are as old as the procedures themselves.

“As far back as 1500, social critics and artists like Hieronymus Bosch and Pieter Bruegel the Elder were warning that complex behavioral ills could not be cured by a quick surgical fix,” said Stanley Caroff, M.D., an emeritus professor of psychiatry at the University of Pennsylvania Perelman School of Medicine. These Renaissance artists created works like “The Stone Operation,” which satirized physicians who promoted unproven surgical procedures to remove the “stone of madness” from the brains of people with behavioral and developmental disorders.

Caroff, who spent his career treating patients with schizophrenia and other severe mental illness, acknowledged that some patients with mental illness may not fully respond to conventional medications and reach a chronic, debilitating state. He feels, however, that even for these desperate patients, invasive brain surgery currently lacks sufficient evidence of efficacy and is too risky.

Donald Malone, M.D., the chair of psychiatry at the Cleveland Clinic, conducted some of the first DBS procedures for OCD and depression in the United States. He noted that DBS is different from psychosurgical procedures of the past, including the notorious frontal lobotomy. Though DBS requires the implantation of electrodes in the brain—an invasive surgery—no brain tissue is removed as part of the procedure. Thus, DBS can be reversed if something does not work out, he said. DBS is also more precise than older surgeries, as the implants are placed in specific regions known to influence mood.

Regions is the operative word since there is no consensus on the precise brain site to target for depression. There are several variations of DBS based on where the electrodes are placed. One prominent target reflects the procedure that was pioneered in Belgium with OCD patients and was used in Medtronic’s RECLAIM study; this procedure involves the placement of electrodes in between the ventral striatum and ventral capsules, in the back of the brain’s cortex. The other variation places electrodes in a forward portion of the cortex known as the subcallosal cingulate; this is the surgery that was developed by Mayberg and neurologist Andres Lozano, M.D., while they were at the University of Toronto. This was the method tested in the BROADEN study.

As Mayberg explained, these two locations take different paths to improving mood when stimulated: “The principle of the ventral stimulation is that you turn on positive emotional activity, but in our approach, you turn off the negative.”

Mayberg said her approach has an advantage in that ventral DBS has been associated with rapid mood crashes if the electrodes stop working, whereas subcallosal DBS implants produce a more gradual return of depressive symptoms should they stop.

Coffey, who was the medical safety officer for the RECLAIM study, counters the idea that either version can be called precise. It is a complex procedure to get these small electrodes deep into the brain, and he noted that several of the participants in the RECLAIM study had misplaced electrodes. “In some cases, the implant was a centimeter from the proposed target,” he told Psychiatric News. “It may sound minor, but in the brain a centimeter is like the opposite side of a football field.”

Proponents Call for More Studies

In early pilot studies, which evaluated both ventral and subcallosal DBS in open-label trials of patients with treatment-resistant depression (every patient received active DBS and knew what they were getting), patients reported improvements in depression symptoms.

While all patients received implantation with electrodes in the RECLAIM and BROADEN trials (led by Malone and Mayberg, respectively), neither patients nor investigators knew whether patients had received active DBS stimulation or sham stimulation (electrodes not turned on) once the trial was under way.

As noted, both studies proved fruitless at showing that active stimulation was any better than a sham procedure. BROADEN completed implants on 90 of a proposed 200 patients before being stopped due to futility.

These negative results were not the end of the story, though.

In 2015, following the discontinuation of the RECLAIM and BROADEN trials, the American Society for Stereotactic and Functional Neurosurgery released a statement reaffirming the organization’s commitment to the neuromodulation for the treatment of psychiatric disorders.

“An unintended consequence of the discontinuation of these two trials is the interpretation by the public, industry, regulatory bodies, and health care professionals that trial discontinuation represents a failure of the therapy, rather than just an unsuccessful trial,” the statement reads. “[W]e must distinguish between the failure of a therapeutic strategy and an unsuccessful implementation of that particular strategy.” They and others believe that factors like patient selection or trial duration may have affected the outcome and are committed to conducting the research to answer these and other questions about DBS.

In the second article in this two-part series, Psychiatric News will explore why proponents of DBS think RECLAIM and BROADEN studies may have failed, and the efforts under way to identify patients who might be most likely to benefit from DBS. ■