Clinical studies

The first publication of DBS in depression was published in 2005. Six severely treatment-resistant depressed patients were implanted in the SCC. After 6 months of stimulation four of the six patients responded (50% decline in depression severity from baseline), with three of them achieving symptomatic remission. The Hamilton Depression Rating Scale (HDRS-17) was reduced in 71% ( ). That original cohort of six patients was expanded to 20 patients. One month after surgery, 35% of patients met criteria for response with 10% of patients in remission. After 6 months, 60% of patients were responders and 35% met criteria for remission. Notably, the response was largely maintained at 12 months and beyond ( ). After 1 year of stimulation, 62.5% of patients were responders, and the response rate after 2 years was 46%, with 75% response rate after 3 years of stimulation. The baseline severity of patients included in these studies was very high and with long duration in the index episode, approximating seven years. Only 10% were employed and had previously tried and relapsed after ECT. SCC DBS did not only generate a sustained symptomatic improvement, but patients regained overall function in physical health and social functioning, although two patients died of suicide during depressive relapses ( ). After these initial promising reports, several single and multicenter studies were published, demonstrating comparable degrees of efficacy in open-label designs ( Table 22.1 ). Seventeen patients (seven of them with chronic depression in bipolar 2 disorder) were implanted at Emory University. After 6 months of stimulation, the response rate was 41% (7/17), and 92% after 2 years of stimulation (12 of the 17 patients having reached the latter time point by the time of publication) ( ). Both patients with unipolar and bipolar 2 depression responded similarly. Again, no side effects were attributable to stimulation, such as mania or cognitive changes ( ). Other centers have described similar outcomes, with many case series ( ; ; ; ). Puigdemont et al. reported outcomes in eight patients with severe TRD with 6 months response and remission rates of 87.5% and 37.5%, respectively ( ). These dramatic improvements were sustained after 12 months, with 62.5% response and 50% remission rates. Another group in Germany implanted six subjects and explored acute effects of stimulation, but also described long-term antidepressant effects, with two of the six patients in remission of depression after 6 months of stimulation. As described in the other case series in the SCC, high voltage stimulation did not cause side effects ( ). An early metaanalysis of four studies by Berlim et al. confirmed the sustained positive results up to 1 year, with response and remission rates of 36.6% and 16.7%, 53.9% and 24.1%, and 39.9% and 26.3% at follow-up endpoints of 3, 6, and 12 months respectively ( ). There was an additional multicenter study conducted in three different sites in Canada that implanted 21 patients ( ). Forty-eight percent of patients were responders at 6 months.

An industry-sponsored, double-blind, randomized controlled multicenter study was conducted, with the initial intention of recruiting 200 patients in North America. The study was halted after a futility analysis determined that the likelihood of it achieving its primary outcome was low ( ). Ninety patients had been implanted by the time the study was stopped. Its primary outcome was response (40% reduction in Montgomery–Äsberg Depression Rating Scale (MADRS) from baseline) averaged over months 4–6 of a double-blind phase (24 weeks). Participants were 2:1 randomized to either active ( n = 60) or sham ( n = 30) stimulation for the initial 6 months, then all participants received active simulation. There was no statistically significant difference in response during the blinded phase (twelve (20%) patients in the stimulation group vs five (17%) patients in the control group). These results were lower than the reports in the prior studies, but interestingly the long-term (open-label) follow-up phase described a gradual increase in response to treatment with half of the patients endorsing positive responses of chronic DBS.

Long-term sustained antidepressant effectiveness has been demonstrated in other groups as well ( ). A case series long-term report with up to 8 years of follow-up described that in 28 patients implanted at a single center, response was ≥ 50% and remission rates were ≥ 30%, after the second year since surgery. Crowell et al. reported that three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. There were three patients who dropped out, and there were no suicides during the follow-up period ( ). Stimulation appears to be most effective with high frequency parameters, and delivery of stimulation needs to be uninterrupted, with return of symptoms over periods of weeks if it were to be stopped ( ).

The realization that variability in the surgical implantation was crucial generated a change from a standard anatomical coordinate-based to a connectomic approach. The use of tractography-based target selection was derived from the initial analysis of white matter structural connectivity in responders to SCC DBS, and then was implemented prospectively ( ). Up until then, the SCC target had chosen the surgical region for implantation of the DBS leads extrapolating the functional imaging findings that implicated the subcallosal region and Brodmann Area 25 in depression, but lacked precision, especially in an area with high anatomical variability. Knowledge of the white matter fibers and the network that were stimulated in the SCC became more apparent when newer methods combining tractography imaging and engineering methods that estimated the volume of activated tissue were combined ( ). Small differences in electrode location caused substantial differences in the activated pathways and confirmed widespread network changes associated with DBS induced antidepressant effects ( ). Using models that calculated volume of stimulation with individualized stimulation parameters, each contact had a unique set of white matter fibers. All the DBS responders shared a combination of white matter tracts connecting the SCC to the rest of the cingulate cortex (via the cingulum bundle), bilateral medial frontal cortices (through the forceps minor), subcortical nuclei and the thalamus (via uncinate fasciculus and frontostriatal fibers). With this response fingerprint, it became possible to test the hypothesis prospectively. Eleven subjects were implanted using target selection for the DBS that was based on the connectivity map that was present in responders ( ). The response rate increased, with 8/11 (72.7%) of patients improving by more than 50% from baseline after 6 months, with an additional subject becoming a responder at the 12-month time point (9/11, 81.8% response rate). Prospective targeting allowed for personalized, patient-specific, target selection. This targeting method confirmed and validated the conceptualization of a network model with the cingulate as a hub, where engagement of remote areas of the depression network is needed for the adequate antidepressant effect. Furthermore, there have been additional reports that confirmed the network model rationale behind the SCC DBS. Distinct patterns of white matter activation have been found to be related to the intraoperative responses when there are changes in autonomic behavior (heart rate elevation) as well as positive antidepressant responses ( ; ). Tractography-based targeting in the SCC not only resulted in better clinical outcomes in the months after implantation, but has also resulted in faster and more robust acute behavioral responses in the operating room ( ). It has also allowed collecting more reliable electrophysiological signals, derived from a certainty of the ideal location of the stimulating contacts ( ).

Clinical studies

The surgical technique for VC/VS DBS involves stereotactic anatomic targeting, using high-resolution volumetric magnetic resonance imaging for planning. The anterior limb of the internal capsule and the VS can be easily visualized on T2 and inversion recovery images for direct targeting. Typical coordinates are 4–10 mm lateral to the midline, 3–5 mm ventral to the anterior commissure, and 1–3 mm anterior to the posterior border of the anterior commissure. DBS electrodes are implanted bilaterally through the shaft of the internal capsule with the most ventral aspect in the NAcc ( ; ). In recent years, the introduction of tractography in this target for OCD, and in other targets for depression, has changed the older standard anatomical approach ( ). The first open-label study commented on VC/VS-DBS of 17 TRD patients and found response rates of 53% at 12-month follow-up and 71% at the last follow-up after 14–67 months (and remission in 40%) ( ; ). Such open-label results were promising, and a multicenter randomized clinical trial was designed with the goal of providing a higher level of evidence supporting this target for treatment in TRD. Importantly, advanced targeting technologies that would be considered essential for the surgery were not applied. DBS for OCD had already received a humanitarian device exemption in 2009 ( ; ). A 16-week, randomized, sham-controlled trial in the United States did not find clinical significance in treatment response rates. Only 3 of the 15 patients randomized to active stimulation (20%) had achieved response, while 2 of the 14 (14.3%) who received sham therapy responded. The response rates in the open-label phase of 24 months of follow-up were also low, with 20%–26.7% achieving response at any time during that period ( ).

A different study, designed and conducted in the Netherlands, had better results although they were not directly comparable to the initial clinical trial. Patients had an initial open-label optimization phase that lasted 52 weeks. This phase described a 40% overall response rate in 25 patients. Mean depression scores decreased 28.3% (HDRS-17) and 30% (MADRS). Of these 25 patients, 16 (9 responders and 7 nonresponders) were entered in a randomized crossover period (active-sham vs sham-active). All responders had a return of symptoms within less than 2 weeks when stimulation was discontinued ( ). There are reasons to think that different targets may have variable times to have relapse in symptoms when stimulation is stopped ( ). Of the original 25 patients who had entered the clinical trial, 21 entered and 18 completed the maintenance phase for the following 2 years. 44% of patients were classified as responder. Patients who had not responded during the initial optimization phase did not become responders afterwards ( ).

Studies of DBS for OCD in this same target have started to identify neuroimaging techniques such as tractography, identifying certain fibers that are responsible for response in patients ( ; ). In OCD, active stimulation of the capsule fibers closer to the MFB than the anterior thalamic radiations was associated with better treatment outcome ( P = .04; r ² = 0.34). Confirming the differences in tractography imaging and standard anatomical imaging (like in SCC), stimulation sites were largely overlapping and could not differentiate responder status, suggesting response is independent of the anatomically defined electrode position. As it was discussed earlier, the concept of the optimal target has evolved, from thinking of the target as a coordinate-determined gray or white matter structure, to conceiving of the target as “tapping into” a circuit connects to several regions of the symptomatic network ( ). Innovative trial design, introduction of newer imaging methods, and engagement of specific biomarkers, whether physiologic, imaging, or neuropsychological, will continue to elucidate the mechanisms of action of DBS and making this target a viable therapy for patients with TRD ( ).

Clinical studies

While septal stimulation had been conducted many decades ago, the “modern” beginnings of DBS in NAcc started when a group in Germany implanted three patients with severe refractory depression ( ). The three participants improved “immediately” in their depression when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. The cohort was extended to 10 participants. After 1 year of stimulation, half (50%) were responders and three patients were in remission ( ). Similar PET results were seen in this larger cohort, with decreased metabolism in the SCC and in prefrontal regions including orbital prefrontal cortex. NAcc DBS also has sustained and durable antidepressant effects, with the same open-label cohort describing response rates of 45% (5 of 11) at 48 months ( ). A different group in France implanted four subjects with the intention of doing a pilot multicenter prospective, noncomparative, and open trial. Patients initially received caudate stimulation, and after lack of antidepressant response, accumbens stimulation. This change in the DBS stimulation target caused that three of the four subjects had positive changes in mood ( ). No cognitive or other major adverse effects were reported in either trial ( ). The literature provides promising evidence of NAcc DBS being a treatment for TRD; however, small samples have prevented definitive conclusions regarding its antidepressant efficacy.

Clinical studies

The surgical technique of DBS in MFB invariably requires of deterministic tractography to individually map the target area. The MFB is not visible in standard neuroimaging, instead requiring the acquisition of special tractography sequences. This apparent disadvantage in the target selection resulted, in the end, in avoiding the pitfalls that both SCC and VC/VS had, when the initial clinical trials were guided by less precise implantations.

The original pilot study in Germany assessed safety and efficacy of DBS in MFB in seven patients with TRD ( ). Strikingly, the antidepressant effects were very rapid in their onset, even faster than NAcc previously described. The authors described instant intraoperative antidepressant-like effects such as appetitive motivation. In the acute intraoperative reports, MFB stimulation usually causes increased vigilance, eye contact, and engagement in conversation, as well as self-reported feelings of energy and motivation concordant with mood improvement ( ). Within the first week of stimulation, patients already had significant responses, and response and remission rates of 86% and 57.1%, respectively. Not only the antidepressant effects were evident early on, but they were sustained in time. Half of those patients continued to have sustained remission at 1-year which continued until the 4-year follow-up ( ). A separate group in the United States replicated the early effects. Three of six patients had > 50% decrease in depression scores after a week poststimulation initiation relative to baseline ( ). An interesting fact in these two case-series is that the response to DBS relies on the preservation of the anatomical target. In the original cohort, the patient who did not respond to DBS had a minor intracranial hemorrhage in the trajectory of the lead, therefore irreversibly lesioning the intended target of stimulation. In the second cohort, the patient that did not respond to DBS had reduced frontal connectivity to the MFB when the DTI was analyzed. Both centers have published their long-term results, and the antidepressant effectiveness is sustained, and the neurocognitive tests did not find changes in cognition or impulsivity ( ; ). Due to its proximity to oculomotor control areas in the midbrain, strabismus and double vision are the most significant stimulation related adverse effects of DBS in this target were blurred vision and strabismus. Similarly to the rapid onset of antidepressant effects, there seems to be an abrupt return of depressive symptomatology if stimulation is discontinued ( ).

More recently, a clinical study with a randomized-controlled onset of stimulation was reported ( ). Sixteen patients were implanted in a double-blind randomized-control (DBS active vs sham) condition for the initial 8 weeks after surgery, at which point blinding was lifted and all patients received active stimulation. Similar to the first study, all 16 patients reached the response criterion, and most patients ( n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation (MADRS < 10). Both groups (active/sham) demonstrated an antidepressant effect. Thus, it appeared that the sham-stimulation phase of 2 months was not long enough to separate treatment from other effects. The study reached its primary outcome at 12 months of stimulation, with all participants responding to DBS and a 56% mean decline in MADRS (50% of patients in remission). This lack of difference at this endpoint highlights the difficulties in trial design for DBS. It would be hard to justify that a trial with the sustained antidepressant results as these have reported would be due to placebo effects. Patients with TRD usually have little response to antidepressant interventions, and these are usually short lived. But any regulatory agency who would have asked for a sham versus active trial as the primary efficacy outcome would have deemed this study inconclusive. The authors of this trial rightfully comment that slow, careful, and adaptive study development in DBS for depression is appropriate.

Clinical studies

Despite its promising neurobiological support, there have only been two case reports in the literature ( ). In one case, the authors reported remission of depressive symptoms after 4 months of habenular stimulation. Interestingly, cessation of DBS current resulted in the return of depressive symptoms ( ). Further clinical trials, case series, and studies of comparison between targets are under way to further examine the feasibility as a DBS target.