More DBS results.

January 5, 2012 A new study provides additional data on the safety and long-term efficacy of subcallosal cingulate (SCC) deep brain simulation (DBS) in patients with treatment-resistant depression, including those with bipolar disorder.

Results show that after 2 years of long-term stimulation, there was a 92% response rate and 58% remission rate in 12 patients in the study. No patient who achieved remission had a spontaneous depressive relapse.

"This is the first time that bipolar patients have been included in a study of deep brain stimulation in any substantial way," said lead author Paul E. Holtzheimer, MD, associate professor of psychiatry and surgery and Director, Mood Disorders Service, Dartmouth Medical School, Lebanon, New Hampshire. "Even though our sample had only 7 bipolar patients, its actually the largest bipolar disorder cohort to undergo DBS for depression."
Dr. Paul Holtzheimer

The findings were published online January 2 in the Archives of General Psychiatry.

The study included 17 adult patients 10 with major depressive disorder (MDD) as well as the 7 with bipolar disorder (BP) who had not responded to at least 4 antidepressant treatments. All had failed or were intolerant of electroconvulsive therapy (ECT), had a Hamilton Depression Rating Scale (HDRS) score of 20 or higher, and a Global Assessment of Functioning (GAF) score of 50 or less.

Surgeons implanted DBS electrodes bilaterally into the SCC white matter of the study subjects. They placed a pulse generator in the infraclavicular region and connected it to the DBS electrodes via subcutaneous extension wires.

After this surgery, patients entered a 4-week sham stimulation phase. They were told that they were being randomly seleected to receive either active or sham stimulation, but all, in fact, received sham stimulation. The patients then received open-label, active stimulation for 24 weeks.

After this active DBS phase, patients were to enter a discontinuation phase. They were told that they would randomly receive either active or sham stimulation at that point, although all were to receive sham stimulation. The first 3 patients to enter this phase experienced relapse within 2 weeks; after restimulation, their depressive symptoms did not improve immediately. This led to significant distress and increased suicidal ideation; as a result, this phase was eliminated for subsequent patients.

The primary outcome measure was the longitudinal change in HDRS over time; higher scores on this scale indicate increased depressive severity. Remission rates were defined as an HDRS score of less than 8; response was defined as a 50% or greater change in HDRS score. Patients who left the study were considered nonresponders.

All patients completed the 4-week sham stimulation phase, 16 completed the 24-week active stimulation phase, and 16 remain in the observational follow-up phase. Fourteen patients have completed 1 year of active stimulation, and 11 patients have completed 2 years of active stimulation.

The study showed significant improvement in all measures with no apparent large or statistically significant differences between the MDD and BP groups. HDRS scores decreased significantly at the end of the sham phase (estimate = -3.3 points, P = .02, n = 17), but the difference from the postoperative stimulation-off time point to the end of the sham phase was not significant. Compared with the end of the sham phase, the decrease in HDRS scores after 4 weeks of active stimulation approached significance.

The average HDRS score decreased 43.6%, 43.0%, and 70.1% by 24 weeks, 1 year, and 2 years, respectively. Remission and response was seen in 3 (18%) and 7 (41%) patients after 24 weeks (n = 17), 5 (36%), and 5 (36%) patients after 1 year (n = 14), and 7 (58%) and 11 (92%) patients after 2 years (n = 12) of active stimulation.

All patients reaching the 2-year time point were in remission or had only mild depressive symptoms. No patient achieving remission experienced a spontaneous relapse.

There were 22 adverse events (AEs) in 11 patients and 12 serious adverse events (SAEs) in 4 patients; 13 patients experienced at least 1 AE or SAE, but no event was directly related to acute or chronic stimulation. There were 2 suicide attempts, neither deemed related to the device or stimulation. Importantly, no hypomania or mania occurred, and there was no significant change in Young Mania Rating Scale scores in any patient.

The findings appear to indicate no clinically significant sham DBS effect. Although depression severity was significantly lower after sham stimulation compared with baseline, the mean decrease in HDRS score was small and not clinically significant. In addition, 11 patients did not enter the sham phase until at least 1 week after surgery.

"We actually had a depression rating on them following the surgery but prior to sham stimulation," said Dr. Holtzheimer. "In those patients, the depression came at the prerandomization period when the stimulator was off and they knew it was off. There was something about the surgery itself that leads to an improvement independent of stimulation."

The consistent subjective increase in depressive symptoms with battery depletion further supports an antidepressant effect of chronic active SCC DBS, said Dr. Holtzheimer.

It took much longer for depression symptoms to lift in some patients following DBS, but it is not clear why. Researchers have been trying to figure this out for some time, but so far "nothing is jumping out," said Dr. Holtzheimer. It appears to have little to do with the age of patients, the length of time they have been treated for depression, the duration of their current episode, the number of treatment failures, or any other of the "usual suspects," he said.

"One possibility is that some patients may need more active rehabilitation to maximize the benefits of stimulation. Their lives have been so disrupted by depression that even if theyre getting an effect from stimulation, they may need a more active process of getting them out of the house and back in activity." In a current study, he and his colleagues are incorporating a psychotherapeutic rehabilitation component.

The researchers are looking at potential biomarkers and brain imaging patterns for clues about which patients with depression might be the most appropriate candidates for DBS. "Were also looking at what we can learn about what the stimulation is actually doing inside the brain," said Dr. Holtzheimer, assessing whether brain activity is actually altered. Another important area to investigate is whether the most appropriate region of the brain is being targeted, he added.

In depression patients, the DBS battery can last up to 2.5 years. A warning light indicates when the battery is low, which usually gives patients enough time 2 to 4 weeks to have it replaced. Even before this warning, though, patients report feeling like they are "dwindling," Dr. Holtzheimer said. When the battery is off, patients typically do not become symptomatic for 2 weeks.

Approached for a comment on the study, Mark S. George, MD, Distinguished Professor of Psychiatry, Radiology and Neurosciences at Medical University of South Carolina, Charleston, SC, said there is a great deal of interest in DBS in depression and so every bit of information on the treatment is helpful, but this study does not add much to what is already known.

The exception is the new information that no BP patient developed mania or hypomania, said Dr. George.

An interesting element to the study, according to Dr. George, was that the researchers tried to do something approaching a double-blind study by incorporating a sham run-in after the DBS device was implanted. "They found that during that month after surgery, there was a decline in depression scores, hinting that even in a group of patients as treatment-resistant as this group, we still have to be concerned about sham or placebo responses."

The relapse of the first 3 patients to undergo the discontinuation phase demonstrates that a DBS response requires constant stimulation, said Dr. George. "Its not as if the brain has been pushed into a different mode; it really is being maintained undepressed as a function of the stimulation."

Dr. George also found it intriguing that the subgroup of patients who did not experience relapse for up to 2 years seemed to have made significant improvement. "It appears that their illness doesnt build and overwhelm the treatment theyre responding to," he said. "What you want to demonstrate is this idea of durability; so if someone does get better, is it worth all the trouble of putting wires in their head and can they use that to get their life back? The hint here is that the answer is yes.

Dr. George pointed out that the relatively high remission after 2 years may in part be the result of some selection bias, as patients who did not respond may have dropped out of the study.

This study was funded by grants from the Dana Foundation, Stanley Medical Research Institute, Woodruff Foundation, Emory Healthcare. Devices were donated by Advanced Neuromodulation Systems/St Jude Medical Neuromodulation. Dr. Holtzheimer has received grant funding from the Greenwall Foundation, NARSAD, National institute of Health Loan Repayment Program, and National Institute of Mental Health; he has received consulting fees from St. Jude Medical Neuromodulation. For conflict of interest information on the other authors, see original article.

Some see things as they are and ask why.
I dream of things that never were and ask why not.

- George Bernard Shaw

More DBS results.

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