Deep brain stimulation (DBS) does not relieve long-standing treatment-resistant depression any more effectively than a sham control procedure, although administering it is both safe and feasible, a year-long randomized study indicates.
“Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression,” lead author Paul Holtzheimer, MD, Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, and colleagues write.
“However, this study did not demonstrate that 6 months of active versus sham stimulation was associated with statistically significant antidepressant effects,” they note.
“These findings are disappointing given the encouraging data from earlier open-label studies of subcallosal cingulate DBS,” they add.
The study was published online October 4 in Lancet Psychiatry.
Severe Depression
The trial included a total of 90 patients aged 21 to 70 years with major depressive disorder that had been diagnosed when they were younger than 45 years. Sixty of the patients received active stimulation, and 30 patients received sham control stimulation.
All patients had been unresponsive to a minimum of four antidepressant medications from at least three drug classes.
“Approximately 2 weeks after device implantation, participants were randomly assigned to receive immediate active stimulation (stimulation group) or 6-month delayed stimulation (sham group),” the investigators note.
The stimulation device used in the study was the Libra XP Deep Brain Stimulation System, St. Jude Medical, Plano, Texas.
Following the 6-month randomized phase of the trial, all patients were enrolled in a 6-month open-label extension to see whether longer duration of treatment might improve response to DBS.
The primary endpoint of the trial was response to DBS, defined as at least a 40% reduction in scores on the Montgomery-Åsberg Depression Rating Scale and no worsening from baseline in scores on the Global Assessment of Function.
“On average, patients in both groups showed a statistically significant improvement in depression and global functioning over 6 and 12 months,” the researchers report.
On the other hand, at the end of the randomized portion of the study, only 20% of patients in the active stimulation group had reached the primary endpoint, compared with 17% of the sham stimulation group.
“Clinically Meaningful” Long-term Outcomes
Remission rates were low and were similar in the two groups, at 5% and 7% in the stimulation and the control group, respectively.
After 12 months, 6 additional months of DBS did not increase the proportion of patients who responded to DBS or who achieved remission among those initially assigned to receive active stimulation or among patients who crossed over to active DBS at the end of 6 months.
Overall, a total of eight serious adverse events occurred that were related to the study device or implantation surgery. Two deaths by suicide also occurred during the 6-month open-label portion of the study, both in the control group. After 1 year, 77 patients were enrolled into a long-term extension of the study.
Not all patients reached the follow-up endpoint. At 30-month follow-up, the investigators found that antidepressant responses to DBS improved in 29% of patients at 12 months, 53% at 18 months, and 49% at 24 months. Remission rates also improved, from 14% of patients at 12 months to 18% at 18 months and 26% at 24 months.
“These long-term outcomes are clinically meaningful and greater than would be expected with treatment as usual in this highly treatment-refractory patient population,” the authors write.
The average duration of depression prior to receiving DBS in the current study was 12 years. This was significantly longer than the average duration of depression in patients treated in open-label trials of DBS, which was approximately 5 years.
The authors point out that depression improved to a greater extent after patients had crossed the 12-month endpoint, when physicians were allowed more flexibility in the stimulation contacts as well as the parameters used.
The potential placebo effect achieved in these kinds of intervention studies can also be “surprisingly high” and fairly long lasting, they add.
“Therefore, differences in benefit between active and sham stimulation might not be seen until after 1-2 years of treatment in this group,” the investigators suggest. They conclude that “the negative outcome of this trial should not be interpreted simply as a failure of subcallosal cingulate DBS for treatment-resistant depression.”
Don’t Abandon DBS
In an accompanying editorial, Mahendra Bhati, MD, and Casey Halpern, MD, both from Stanford University School of Medicine, in California, agree that the lack of an antidepressant effect observed in this study does not mean that DBS should be abandoned.
“This experience suggests that the 6-month primary endpoint for this study was premature,” they suggest.
“[I]nadequate time might not have allowed DBS optimisation to achieve an effect distinguishable from microlesion and placebo effects,” they add.
Results do suggest that future studies need to be designed with the limitations of DBS in mind.
For example, “appropriate patients and brain targets might need to be better identified than at present with use of standardised criteria,” the editorialists suggest.
Given that improvement in depression was seen with longer-term follow-up in the current study, future studies clearly need to be longer than 12 months, they add.
“DBS should be optimised over time and start with intraoperative testing as has been done for movement disorders, before comparing active with sham stimulation,” the editorialists write.
Dr Holtzheimer has received grants from Janssen Pharmaceuticals and has previously consulted for St Jude Medical Neuromodulation. The editorialists have disclosed no relevant financial relationships.
Lancet Psychiatry. Published online October 4, 2017. Abstract, Editorial
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