13 Deep Brain Stimulation in Major Depression

13.1 Introduction

Major depressive disorder, herein referred to simply as depression, is a clinical syndrome defined in the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders as clinically significant distress or dysfunction lasting at least 2 weeks due to depressed mood or anhedonia combined with additional symptoms that may include feelings of worthlessness, impaired concentration, recurrent thoughts of death or suicide, or changes in baseline appetite, sleep, and motoric activity.1 Depression represents a considerable public health concern: the World Health Organization’s landmark 2010 Global Burden of Disease Study² as well as its 2013 update³ both reported depression to be the second leading cause of years lived with disability in the world. This is at least partially due to the epidemiology of depression, which is notable for a high lifetime prevalence (related to it chronicity), high recurrence rates, and a substantial lack of access to effective treatments worldwide.⁴

Standard first- and second-line treatments for depression include psychotherapy and/or a variety of antidepressant medications. While these treatments are effective for many, the therapeutic effect from pharmacotherapy is delayed and often requires the trial of multiple medications before achieving satisfactory response. Indeed, the National Institute of Mental Health (NIMH)-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that remission did not occur in 63% of patients treated with a first-line antidepressant,⁵ and only about half who received an adequate trial of two antidepressants remitted.⁶ While the terminology is not standardized,^7,8 treatment-resistant depression (TRD) is generally defined as a lack of clinically meaningful response with two antidepressant treatment trials of adequate dose and duration.^6,9 TRD has been reported to range from 10 to 40% of all depressed patients, translating into a prevalence of 1 to 3% in the United States.^10,11,12 TRD is consistently associated with worse clinical outcomes¹³ and exorbitant costs to society.¹⁴

This relatively high rate of TRD represents a major unmet clinical need and has motivated the ongoing use and trial of various interventional therapeutic approaches¹⁵ including electroconvulsive therapy (ECT), transcranial magnetic stimulation, transcranial direct current stimulation, magnetic seizure therapy, vagus nerve stimulation, and epidural cortical stimulation. Of these, ECT has been the most extensively studied approach that continues to offer a relatively fast therapeutic response and remains the most effective antidepressant treatment available.¹⁶ Limits to its use include adverse effects, particularly cognitive,^17,18 relapse of depression after ECT is stopped (even when medications are restarted),¹⁹ and ongoing societal stigma.

Treatment for severe depression also has included ablative neurosurgical procedures.²⁰ Deep brain stimulation (DBS) emerged as a modern reversible descendant of these ablative interventions, and given the urgent need for more effective antidepressant therapies, DBS is actively being explored as an experimental treatment for TRD. In this chapter, we review the history leading to DBS as a potential treatment for depression, the brain regions that have been targeted based on an emerging understanding of depression as a disorder of neural circuitry, and the results of the associated clinical trials. We then discuss current limitations and elaborate on some of the issues and advances that are likely to play a crucial role in improving therapeutic outcomes of DBS for TRD. We conclude with a consideration of the ethical issues and risks inherent to this invasive and currently investigational intervention.

13.2 The Current State of DBS for Major Depression

In the 19th century, physicians began to describe closely the correlations between distinct brain lesions and behavioral changes, leading to the hypothesis that pathological mental states might be treated with the removal of a particular locus.20 The first therapeutic surgery for patients suffering from schizophrenia was described by Buckhardt in 1888.²¹ As a biological understanding of brain function grew, the putative importance of brain circuitry rather than distinct loci became increasingly hypothesized to be responsible for behavior, and neurosurgical treatments consequently began to shift toward disruption of white matter tracts.²² In 1936, Moniz described the first clinical trial of the now-infamous prefrontal leucotomy for psychiatric illness, including depression.²³ The popularity of this procedure soared over the next two decades, only to recede with the discovery of chlorpromazine and other psychotropic medications in tandem with growing ethical concerns over psychiatric neurosurgery.²⁴ Still, the development of more advanced stereotactic techniques for neurosurgery led to the trial of focal ablations for intractable conditions, as exemplified by the anterior cingulotomy for both depression and obsessive-compulsive disorder (OCD).25,26

Concurrent with this refinement in neurosurgical procedures was the advent of techniques for repetitive intracranial stimulation, which ultimately developed into modern DBS. Although the efficacy and safety of DBS were established by its systematic use in movement disorders,²⁰ the concept has been applied to psychiatric problems since its inception.²⁷ Nevertheless, the 1991 report that chronic stimulation could function as a “reversible lesion” and safely mimic the effect of thalamotomy in the treatment of tremor²⁸ marked the major turning point in the widespread emergence of DBS. Eight years later Nuttin and colleagues reported chronic stimulation of the anterior limb of the internal capsule (ALIC) led to symptomatic improvement in three out of four patients with intractable OCD,²⁹ setting the stage for the application of DBS to TRD.

We now will review the major results of this application by target. Please see Table 13.1 for a listing of all DBS trials described in this chapter and additional case reports of one or two subjects that are not discussed in the main text.

13.2.1 Initial DBS Application to Depression: Targeting the Subcallosal Cingulate

Utilizing results obtained from the rapidly advancing field of neuroimaging, especially positron emission tomography (PET), Mayberg in 1997 proposed a hypothesis linking depression to cortical, subcortical, and limbic dysregulation.30 Her hypothesis synthesized imaging results from patients with depression after a traumatic brain injury, induction of transient sadness in healthy subjects, and changes in brain metabolism following successful pharmacological antidepressant treatment. Specifically, the subcallosal cingulate (SCC) (also known as the subgenual cingulate or Brodmann area 25) is metabolically hyperactive in depression, and decreased metabolism in the same region correlates with clinical response to a variety of antidepressant treatments. Based on this hypothesis, Mayberg and colleagues first initiated a trial of high-frequency DBS of the SCC white matter in six subjects with severe TRD, using the standard approach for DBS used in movement disorders.³¹ In this initial cohort described in 2005, acute postimplantation antidepressant effects were reported by all subjects in conjunction with stimulation. Examples included decreased feelings of emptiness, heightened sense of awareness, and brightening of the room with sharpened visual details.³¹ After 6 months of chronic stimulation, four of the subjects met criteria for treatment response, with three demonstrating full or near full remission.

Subsequent open-label and small controlled studies

Given the success in this small open-label trial and the absence of major adverse effects linked to acute or chronic DBS, the study was expanded to a total of 20 subjects in 2008. Clinical benefits were observed in the first few months and were progressive until reaching a stable plateau after 6 months. After 1 year of stimulation, 55% of subjects were responders and 35% achieved full remission or near full remission.³² PET scans of eight responders demonstrated widespread changes in limbic and cortical metabolism providing plausible biological correlates to the treatment response. Specific metabolic changes included decreased activity in orbital cortex, medial frontal cortex, and insula as well as increased activity in lateral prefrontal and parietal cortex, anterior midcingulate, and posterior cingulate areas.³² Longer-term follow-up of the same subjects in 2011 revealed average response and remission rates of 55% and 35%, respectively at the final follow-up visit 3 to 6 years after the procedure.³³ Serious adverse events included two suicides that occurred after some degree of response had been achieved, although analysis suggested both cases were secondary to an acute relapse of a depressive episode and not an adverse effect of any stimulation parameter change or chronic DBS itself.

To expand beyond the open-label design, in 2012 the next trial of DBS of the SCC white matter included an initial 4-week, single-blind, sham stimulation phase. This was followed by 24 weeks of open-label active stimulation and then a single-blind discontinuation phase before resuming active treatment for 2 years. Notably, this study also included subjects with bipolar II disorder.³⁴ The first three subjects who underwent the discontinuation phase experienced complete relapse within 2 weeks with significant distress and suicidal ideation. Out of concern for subject safety, this phase was removed for remainder of the subjects. Results were notable for a significant but mild antidepressant effect of initial sham treatment, followed by a progressively more robust effect of chronic DBS over the course of multiple months. After 2 years, the clinical remission rate was 58% without distinction between subjects with unipolar or bipolar depression, and no episodes of hypomania or mania emerged.³⁴

With this continued success, investigators sought, in 2012, to replicate these results across three different medical centers in Canada with a prospective, open-label trial of 21 subjects for 12 months.³⁵ Improvement was again progressive over the first few months, with clinical gains observed at 3 months generally maintained at 1 year. However, outcomes were less impressive with a response rate of 29%, though if the definition of treatment response had been liberalized from a 50% reduction in symptom burden to a 40% improvement, then the response rate would have increased to 62%. While all prior studies had delivered stimulation using voltage-controlled pulse generators, this study utilized a constant-current mode of delivery based on the theory that such stimulation would be independent of the variable impedance of the electrode–tissue interface. As such, less adjustment of stimulation parameters might be required, though it was unclear if that was indeed the case.

The promise of DBS targeting the SCC for TRD as reported by the initial studies described above led additional investigators to pursue their own trials. In 2012, a group in Spain first reported clinically meaningful improvement after 3 to 6 months of stimulation with a 12-month remission rate of 50% in an open-label study of eight subjects.³⁶ This group reported that using bipolar stimulation (two contacts on the electrode are activated—one as the cathode and one as the anode) improved clinical efficacy, whereas previous studies of DBS at this target had utilized monopolar stimulation (one of the contacts on the electrode is programmed to be cathode to the implanted pulse generator case). Monopolar stimulation leads to radial current diffusion out from the stimulating electrode in a spherical manner, whereas bipolar stimulation creates a narrower and more focused field with maximal effect near the cathode.⁶²

To further their analysis, the Barcelona group followed these initial results with a double-blind, randomized, sham-controlled crossover study in 2015 to confirm efficacy and measure the effects of discontinuation in a subset of the same subjects.43 Subjects who had been implanted and had achieved at least 3 months of sustained clinical remission were randomized to receive either 3 months of sham stimulation followed by 3 months of active stimulation or vice versa. During active stimulation, four out of five subjects maintained response scores and none relapsed. During sham stimulation, only two subjects remained in remission, and one subject was withdrawn from the trial due to a serious relapse during the sham phase. Statistical analysis revealed a statistically significant effect of active stimulation. Limitations of this important step forward included small sample size and the sampling bias inherent to the study design.

A German group published their initial results in 2013, soon after the first report from the Spanish group. They studied both acute and chronic stimulation in a group of six subjects with TRD. High-intensity stimulation for 24 hours with rotating homologous contact pairs over 5 consecutive days after surgery was found to have modest antidepressant effects at best, but chronic stimulation over approximately 6 months did lead to remission in two subjects.³⁹ Of note, subsequent imaging revealed that the stimulating contacts in one of the responders were actually located in the posterior gyrus rectus bilaterally.⁴⁰

Contemporaneously, a Canadian group sought to address ongoing questions regarding optimal stimulation parameters by adjusting the frequency and pulse width in four subjects in a double-blind, random manner over the first 3 months following electrode implantation and then monitoring symptoms for another 6 months.⁴¹ In 2013, they reported that after stimulation with the optimized parameters, two subjects met criteria for treatment response. The authors also noted that increased pulse width seemed to be associated with clinical improvement.

Multisite-controlled study powered for efficacy testing

These relatively consistent reports of clinical efficacy in a significant number of subjects led to the initiation of a multicenter, prospective, randomized controlled trial (RCT) for TRD. Known as the BROdmann Area 25 DEep brain Neuromodulation (BROADEN) study and sponsored by industry (St. Jude Medical), the randomized phase of the trial lasted 6 months and compared active versus sham conditions in a double-blind paradigm. The trial was halted early in 2013 by the study sponsor because it failed a short-term futility analysis.⁶³ The complete results were published in 2017.⁴⁶ Ninety subjects were implanted across 13 investigational sites, with 60 subjects randomized to active treatment and the remaining 30 received sham stimulation. Both groups demonstrated a statistically significant and mild improvement in depressive symptoms after 6 months, but there was no statistical difference between treatment groups in response or remission rates (20 and 5% for stimulation versus 17 and 7% in sham, respectively).

After 6 months, all subjects eligible and willing to continue entered an open-label phase of stimulation lasting 6 more months. Subjects and investigators remained blinded as to whether each participant had received active or sham stimulation during the randomized phase, and blinding was successful based on subjects’ inability to correctly guess their treatment condition beyond random chance. At the end of this additional period, in comparison to symptom burden at the end of the randomized phase, both groups demonstrated a mild and progressive improvement that did not reach statistical significance. Seventy-seven subjects continued in an ongoing follow-up study for up to 4 years. Data from up to 30 months was reported because not all subjects reached the final time point prior to study termination. With longer-term treatment, response/remission rates at 12, 18, and 24 months were 29%/14%, 53%/18%, and 49%/26%, respectively. Overall, chronic DBS was well tolerated and most serious adverse events were attributed to the primary mood disorder. Two deaths by suicide occurred, both during the 6-month open-label phase in subjects who had received sham stimulation during the randomized phase. The 18 and 24-month follow-up response rates of approximately 50% support the cumulative clinical effect of chronic stimulation and suggest that confirmatory efficacy testing be delayed until after at least 1 year of DBS for TRD.

13.2.2 Targeting the Nucleus Accumbens

The nucleus accumbens (NAcc) plays a critical role in reward-seeking, motivation, and addiction.64,65 Schlaeffer and others hypothesized that DBS of this region might be efficacious in TRD via modulation of the apathy and anhedonia that is frequently part of the depression syndrome. Their brief first report in 2008 included three subjects (two were monozygotic twins), who were alternated between bilateral stimulation or no stimulation in a double-blind manner over the course of several weeks.⁴⁷ A mean improvement of 42% in depressive ratings was noted after the first week, and improvement in depressive symptoms correlated with stimulation but not control. In fact, symptomatic worsening during the control phase was severe enough to require resumption of stimulation prior to the end of the 4-week blinded placebo period in two of the subjects. Although improvement was rapid—noted on a scale of days to weeks—the study lasted only a few months and accordingly was unable to assess for stability of response.

Based on this preliminary success, in 2010, the authors expanded the study to an open-label trial of 10 subjects who were followed for 1 year.⁴⁸ The study had initially been planned to be sham-controlled, but this design was abandoned after enrolling the first three subjects due to acute worsening of symptoms during the sham phase. Responses were seen at 1 month and were progressive throughout the trial. At 1 year, 50% of subjects were responders and 30% met criteria for remission. A secondary measure of anxiety also demonstrated significant improvement and subjects engaged in increased levels of activity (e.g., returning to work part-time, starting a new hobby, establishing a daily structure, making new acquaintances). Interestingly, PET after 6 months of stimulation demonstrated significantly decreased metabolism in the amygdala of responders as compared to that of nonresponders, similar to successful antidepressant medication treatment studies of amygdala activity.66 Notable adverse events following parameter adjustment included one subject with psychosis and two subjects with hypomania. One subject committed suicide, though this did not appear to be attributable to DBS itself. A subsequent report in 2012 followed up some of these subjects for upto 4 years and found that the antidepressant effect (or lack of treatment response) remained stable.⁴⁹

13.2.3 Targeting the Ventral Capsule/Ventral Striatum

The rationale for extending the NAcc target (ventral striatum) for TRD to include the adjacent white matter (ventral anterior limb of internal capsule), a region collectively referred to as the ventral capsule/ventral striatum (VC/VS), came from trials of DBS for refractory OCD that reported concomitant improvement in depressive symptoms.67,68 Accordingly, Malone and colleagues proceeded with an initial open-label trial spread across three clinical sites targeting the VC/VS in 15 subjects with TRD (1 with bipolar depression) in 2009. Maximal response was seen after 3 months of stimulation, and a 40% response rate was recorded after 6 months. By the end of the study (mean of 23.5 months), the response rate was 53% and the remission rate was 40%.⁵¹ In a non-peer-reviewed article the next year, the lead author reported that addition of two more subjects and extended follow-up to 67 months (mean 37.4 months) had improved the results to 71% response rate and 35% remission rate.⁶⁹

Multi-site, randomized double-blind sham-controlled trial

These promising results led to the first RCT of DBS of the VC/VS for TRD in 2015. In what was to be a study adequately powered to test efficacy (n = 208), the RECLAIM RCT was designed as a randomized, double-blind sham-controlled study for 16 weeks followed by an open-label continuation phase for at least 2 years. The trial was halted early due to disappointing results from the first 30 subjects.⁵² During the controlled phase, only 3 out of 15 subjects receiving active stimulation responded, compared to 2 out of 14 control subjects. The continuation phase resulted in only a meager improvement in the response rate (23%). One subject committed suicide during the study. Importantly, since monopolar stimulation is more likely to lead to noticeable physical effects (i.e., paresthesia at the pulse generator site) which could break the blind, bipolar stimulation was used exclusively during the blinded phase. Interestingly, only subjects undergoing active treatment experienced an increased frequency of mood-related adverse events, including three subjects who experienced hypomanic or manic episodes despite no prior history of bipolar disorder.

Randomized sham-controlled trial after open-label optimization

Despite this setback, a Dutch group that had previously described significant antidepressant response during their experiences with VC/VS DBS for treatment-refractory OCD proceeded with a separate trial of this target for TRD in 2016. Referring to the DBS target as ventral ALIC (vALIC), they studied 25 subjects with an open-label design for 1 year during which setting optimization was attempted, followed by a double-blind, randomized crossover phase for two blocks of 6 weeks.⁵³ First responses were noted after approximately 2 months, and at the end of the open-label phase 40% of subjects were responders and 20% were in clinical remission. Sixteen subjects remained in the study and proceeded to the crossover phase. Tellingly, all responders from the open-label phase had to be prematurely crossed over to active from sham phase due to an increase in depressive symptoms. Active DBS led to a statistically significant improvement in depression severity with a mean improvement of 9.5 points on the Hamilton Depression Rating Scale (HDRS).⁷⁰ Significance was not lost with post-hoc inclusion of the nine subjects who did not proceed to the crossover phase, arguing against the result being attributable to potential bias. Notable adverse events included five suicide attempts (none clearly linked to stimulation itself), mania in two subjects, and hypomania in one subject. Two subjects who withdrew from the study and whose DBS accordingly had been stopped died shortly afterward, one via suicide and one via legal euthanasia in the Netherlands.

13.2.4 Targeting the Medial Forebrain Bundle

Building on prior results suggesting that stimulation of NAcc could modulate the brain’s intrinsic reward circuit and thereby produce antidepressant effects, other components of functionally connected reward circuitry have also been studied clinically as targets for DBS. The superolateral branch of the medial fore-brain bundle (slMFB) is a central component of the mesolimbic dopaminergic reward circuit and connects multiple brain regions involved in reward processing such as the ventral tegmental area (VTA), lateral and medial hypothalamus, VS, NAcc, and limbic prefrontal cortex.71 In 2013, the Bonn group published an initial open-label trial of DBS targeting the slMFB in a group of seven subjects with TRD.⁵⁴ Notably, the slMFB cannot be identified with conventional magnetic resonance imaging (MRI), and each subject underwent diffusion tensor imaging to identify the implantation target. Treatment response was noted quite quickly as compared to prior DBS trials: six subjects experienced improvement of symptoms within 2 days, and four met the criterion for treatment response after 1 week. Subjects were followed for up to 33 weeks (minimum of 12), and at the last observation 86% and 57% were responders and remitters, respectively. Secondary measures of anxiety and functioning also improved. All subjects experienced oculomotor adverse events with certain stimulation settings consistent with the target being located near oculomotor nerve fibers.

With these initial encouraging results, the group updated their experience in a 2017 publication, including one more subject and describing longer follow-up.⁵⁶ At 1 year follow-up, six of eight subjects were responders, four of whom were in remission also. Some subjects were followed for up to 4 years, and the response appeared stable and durable. Oculomotor effects continued to be a ubiquitous adverse event. Curiously, one subject who had experienced stable remission requested device explantation against medical advice without explanation after 27 months, but he remained stable in his remission for the next year.

To further examine the slMFB target, a group in Texas began a clinical trial to replicate the prior findings and in 2016 published a preliminary report with data from their first four subjects.55 One week following implantation, the subjects entered a single-blind sham stimulation phase lasting 4 weeks, after which they were unblinded for the subsequent 12 months of stimulation. Mean depression ratings improved considerably during the sham period but did not reach the level of statistical significance (p = 0.101). Within 1 week of active stimulation, however, the difference became statistically significant, and three of four subjects met criterion for response. Unfortunately, one of the responders was then lost to follow-up, but after 6 months the two responders had maintained the response and even continued to improve. All subjects experienced vertical diplopia, but such oculomotor adverse events were mostly transient. A potentially important additional finding was that structural connectivity between the stimulation sites and the medial prefrontal cortex was much stronger in the three responders than in the nonresponder.⁵⁵

Of note, all slMFB trials utilized the Montgomery–Åsberg Depression Rating Scale (MADRS)⁷² to calculate response and remission rates, whereas all the previous studies described in this review used the HDRS to assess the primary depression outcome. Comparison of MADRS with HDRS results in these studies indicates that use of the MADRS led to a higher proportion of subjects meeting criteria for treatment efficacy, raising several questions including: (1) whether the MADRS may be a more sensitive depression measure for use in future studies, and (2) whether the use of the MADRS in the slMFB studies artificially inflated the response rates compared to studies of other targets which used the HDRS.

13.2.5 DBS for Bipolar Depression

The depressive episodes encountered in bipolar disorder represent another treatment challenge for modern psychiatry with only a few medications available with the Food and Drug Administration (FDA) approval for this condition. TRD in bipolar disorder is a common clinical dilemma.73 Although modern neuroscience has revealed clear differences in the pathophysiology of unipolar depression and bipolar disorder, there is also evidence for involvement of similar neural networks during depressive episodes, and mania and hypomania have been rare reported side effects of DBS for TRD and movement disorders.⁷³ Accordingly, DBS has been considered in severe cases of bipolar TRD.⁷⁴ Indeed, several of the trials already described in this chapter targeting the SCC,^32,34 VC/VS,⁵¹ and slMFB⁵⁴ have included individuals experiencing bipolar depression, and overall efficacy and tolerability have been indistinguishable from subjects with unipolar TRD in this small sample size. Additional successful treatment of bipolar TRD with DBS is also described in several case reports (see Table 13.1), but overall this area of study remains very much in its infancy.

13.2.6 Ongoing DBS trials

Various trials of DBS for TRD are in planning, ongoing, or awaiting reporting of results. A search of clinicaltrials.gov on October 18, 2017, was performed using the query terms “deep brain stimulation” and “depression” without filtering by country. Results were then sorted to reflect only studies testing for treatment efficacy in a primary mood disorder (unipolar or bipolar depression). Finally, studies that were classified as withdrawn or completed with results available were also excluded. Targeted brain regions include SCC, VC/VS, NAcc, and slMFB as discussed above in addition to the inferior thalamic peduncle and the capsula interna/bed nucleus of the stria terminalis; see Table 13.2 for results of this search. Of note, some trials identified had not updated their status in some time and may reflect studies that have already been completed and reported or were never launched.

13.3 The Future of DBS for Major Depression

A careful review of the published evidence demonstrates that DBS may be an effective treatment for TRD. While there has been considerable variability, response rates in the 30 to 50% range (sometimes higher, see Table 13.1), along with cases of sustained remission and cases of re-emergence of severe symptoms when crossing from active to sham stimulation, are quite impressive results, particularly in the context of a severely ill patient population that has already been failed by scores of pharmacological, psychotherapeutic, and noninvasive stimulation interventions. Although mania, hypomania, psychosis, motor effects, and suicides have been reported during these trials, in general DBS for TRD is well tolerated, and there are at least five distinct but promising brain targets currently in study. Like treatment with antidepressant medications, meaningful and sustained antidepressant effects of DBS appear to be delayed in onset by weeks to months. However, unlike antidepressant medications, relapse when DBS is abruptly ceased (i.e., consequent to battery depletion or crossover from active stimulation to sham stimulation) is much swifter.

Despite the promise, many limitations and questions remain. Although some subjects plainly respond to DBS, the factors that underlie response remain obscure, and expectation bias must always be considered as a source of response variability. Clinical presentation does not predict response, and currently there is no validated rational means to link a unique patient with the most promising DBS target for that patient. Further, the most appropriate measurements of treatment response remain debatable, and ongoing diagnostic challenges and ethical concerns remain at the collective forefront of the field. These limitations are underscored by the early termination of two of the three RCTs that have occurred to date (the BROADEN and the RECLAIM trials).

While the challenges are great, the need for effective treatments for TRD is greater. Results thus far strongly suggest that DBS has the potential not only to help meet that need, but also to contribute to the understanding of affective neural networks such that highly effective but less invasive antidepressant treatments might be developed. In the remainder of this chapter, we elaborate on some of these challenges, discuss putative explanations for discordant results obtained, and suggest guidance for future trials with an emphasis on confirming target engagement.

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