Psychiatric Annals

CME 

Deep Brain Stimulation for Treatment-Resistant Depression

Navneet Kaur, BS; Tina Chou, BA; Andrew K. Corse, BA; Amanda R. Arulpragasam, BS, BA; Thilo Deckersbach, PhD; Karleyton C. Evans, MD, MSc

Abstract

CME Educational Objectives

1. Describe the role of deep brain stimulation (DBS) in treatment-resistant depression (TRD).

2.Identify the current primary brain targets used in DBS for TRD and describe the major clinical findings.

3. Explain the potential future direction of DBS for TRD.

Major depressive disorder (MDD) is a psychiatric disorder characterized by depressed mood, anhedonia, insomnia, weight loss or gain, agitation or psychomotor retardation, fatigue, feelings of worthlessness or excessive guilt, diminished concentration, and suicidal ideation/behavior (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision [DSM-IV-TR]). MDD is one of the leading causes of disability in the world, affecting approximately 14.8 million American adults with a lifetime prevalence rate of 19.2%.

Abstract

CME Educational Objectives

1. Describe the role of deep brain stimulation (DBS) in treatment-resistant depression (TRD).

2.Identify the current primary brain targets used in DBS for TRD and describe the major clinical findings.

3. Explain the potential future direction of DBS for TRD.

Major depressive disorder (MDD) is a psychiatric disorder characterized by depressed mood, anhedonia, insomnia, weight loss or gain, agitation or psychomotor retardation, fatigue, feelings of worthlessness or excessive guilt, diminished concentration, and suicidal ideation/behavior (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision [DSM-IV-TR]). MDD is one of the leading causes of disability in the world, affecting approximately 14.8 million American adults with a lifetime prevalence rate of 19.2%.

Major depressive disorder (MDD) is a psychiatric disorder characterized by depressed mood, anhedonia, insomnia, weight loss or gain, agitation or psychomotor retardation, fatigue, feelings of worthlessness or excessive guilt, diminished concentration, and suicidal ideation/behavior (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision [DSM-IV-TR]).1 MDD is one of the leading causes of disability in the world, affecting approximately 14.8 million American adults with a lifetime prevalence rate of 19.2%.2

Even though a substantial number of depressed patients receive considerable benefit from antidepressant treatments, Fava3 estimated that 50% to 60% of depressed patients fail to fully respond to an antidepressant trial in which adequate dosing and duration have occurred. A patient is classified as having treatment-resistant depression (TRD) if there is no acute or sustained remission of depressive symptoms after one adequate anti-depressant treatment. It is estimated that up to 15% of depressed patients eventually develop TRD.4 Even though only one failed treatment is required to meet the TRD classification, patients with TRD can remain symptomatic despite undergoing several psychotropic medication trials as well as trials of psychotherapy and electroconvulsive therapy (ECT).5 After exhaustive trials of failed conventional therapies, neurosurgical approaches are often considered to treat severe cases of TRD.

Deep brain stimulation (DBS) is a reversible neurosurgical intervention initially developed for treatment-refractory neuropsychiatric disorders. Notably, DBS has proven to be a viable treatment for epilepsy and movement disorders such as Parkinson’s disease, essential tremor, and extrapyramidal dyskinesia.6 Over the last decade, a growing number of clinical studies have used DBS to treat psychiatric conditions such as TRD and obsessive-compulsive disorder (OCD). (See review appearing in this issue of Psychiatric Annals by Corse et al, page 351).

The typical DBS system involves surgically implanted electrodes at specific brain locations. The electrodes are connected to lead extensions that exit the brain, course under the scalp, and are ultimately connected to implantable pulse generators (IPGs) that are surgically implanted under the pectoral muscle (like cardiac pacemakers). The IPGs are programmed transdermally via a handheld interface and can be set to deliver electrical impulses of variable magnitude, pulse width, and frequency to targeted brain regions.

Distinctive Features of DBS Studies

Clinical trials of DBS are quite different from the typical clinical trials of psychotropic medications for depression. Compared with pharmacologic trials, DBS trials have been conducted with small sample sizes (ie, < 25) and for longer periods of study (ie, 6–48 months). An additional and important contrast to pharmacologic trials is the practice of maintaining DBS patients on stable doses of their previous medications several weeks before and after the onset of DBS therapy.

Although TRD has not been a criterion for many pharmacologic trials, severe depressive illness has historically been an absolute requirement for entry into DBS trials. The severity of illness poses a significant impact on the conduct and interpretation of DBS studies. The inclusion and exclusion criteria for the majority of the DBS studies reviewed here were fairly similar, with common requirements of a 5-year history or longer of chronic or recurrent depression and four or more documented treatment failures. Common exclusions included comorbid neurologic or medical illness, substance abuse/dependence, and active suicidal behavior/ideation. Table 1 and Table 2 provide summaries of patient characteristics including baseline Hamilton Depression Rating Scale (HDRS)7 scores for the reviewed studies. The average HDRS score across the reviewed studies was 32.4 ± 7.3, reflecting severely depressed cohorts.8 Unless mentioned otherwise, most DBS authors have considered a treatment response as equal to a 50% change in the primary outcome measure (eg, HDRS) and MDD remission as an absolute HDRS or Montgomery-Åsberg Depression Rating Scale (MADRS)9 score of 10 or less.

Cohort Characteristics for Studies of Deep Brain Stimulation in Major Depressive Disorder

Table 1. Cohort Characteristics for Studies of Deep Brain Stimulation in Major Depressive Disorder

Cohort Characteristics for Studies of Deep Brain Stimulation in Major Depressive Disorder

Table 2. Cohort Characteristics for Studies of Deep Brain Stimulation in Major Depressive Disorder

This review focuses on the primary findings of recent DBS studies for TRD and the general commonalities and differences between stimulation targets. The studies reviewed are organized by DBS target location. Given this focus, an elaboration of specific details will be limited within the text; however, some details related to illness severity, stimulation parameters, and clinical rating scores are provided in Tables 1 and 2.

In contrast to conventional, first-line psychiatric treatments (eg, pharmacotherapy and psychotherapy) that are broad based, affect global brain function, and confer varying degrees of side-effect burden, DBS is an extremely focused treatment that directly affects a very small volume of brain tissue (indirect effects may be widespread). By precisely targeting brain regions, DBS facilitates the modulation of those regions and their distributed neuronal networks.10,11 Although the precise mechanism of action of DBS remains unclear, a number of different brain regions have served as DBS targets, most of which have shown a 50% response rate in TRD (see Figure 1).11–17 Particular attention is given to the DBS targets for which there are substantive data including the ventral capsule/ventral striatum (VC/VS), the subgenual cingulate gyrus (SCG)/Brodmann area 25 (BA25), and the nucleus accumbens (NAcc). Because some other DBS targets have only limited data available to support their use in TRD, they will be given less emphasis accordingly (eg, medial forebrain bundle [MFB), lateral habenula [LHb], and inferior thalamic peduncle [ITP]). We include coverage of the MFB, LHb, and ITP because they may certainly serve as candidate targets for larger DBS studies in the future.

The anatomic localizations of deep brain stimulation (DBS) targets for treatment-resistant depression. The sagittal and coronal sections of structural brain magnetic resonance imaging (deidentified file data from Massachusetts General Hospital) are shown with overlaid schematic representations of the approximate DBS target locations of (a) the subgenual cingulate gyrus (SCG), (b) the nucleus accumbens (NAcc) and the ventral capsule/ventral striatum (VC/VS), (c) the medial forebrain bundle (MFB), (d) the inferior thalamic peduncle (ITP), and (e) the lateral habenula (LHb). MDD = major depressive disorder.Image courtesy of Massachusetts General Hospital.

Figure 1. The anatomic localizations of deep brain stimulation (DBS) targets for treatment-resistant depression. The sagittal and coronal sections of structural brain magnetic resonance imaging (deidentified file data from Massachusetts General Hospital) are shown with overlaid schematic representations of the approximate DBS target locations of (a) the subgenual cingulate gyrus (SCG), (b) the nucleus accumbens (NAcc) and the ventral capsule/ventral striatum (VC/VS), (c) the medial forebrain bundle (MFB), (d) the inferior thalamic peduncle (ITP), and (e) the lateral habenula (LHb). MDD = major depressive disorder.Image courtesy of Massachusetts General Hospital.

The Ventral Capsule/Ventral Striatum (VC/VS)

The use of the VC/VS as a DBS target for depression stems from early lesion studies performed in the mid-20th century, which targeted the anterior limb of the internal capsule (ie, anterior capsulotomy) in patients with treatment-refractory OCD.18 A review of the lesion literature published in 1990 reported on 213 of 362 thermocapsulotomy cases; approximately 64% of patients obtained a benefit.19 More recently, significant benefits have been reported in approximately one-third to two-thirds of patient cohorts undergoing these procedures.5 Furthermore, a response rate of approximately 50% was noted in a sample of OCD patients undergoing gamma knife capsulotomy.20 As an alternative to ablative procedures in OCD, DBS was first used by Nuttin et al,21 who reported on a cohort of four patients with intractable OCD and comorbid depression. Their initial DBS target was based on anterior capsulotomy; however, the target was later modified to a more posterior location at the VC/VS junction (see Figure 2). With this new target, Greenberg et al22 reported that after 36 months of VC/VS DBS treatment in 26 patients with intractable OCD, the patients showed an average decrease in HDRS score of 43.2%. Moreover, more than 50% of the patient cohort met the criteria for remission from their depressive symptoms (HDRS score < 7) at their last follow-up.

The location of the ventral capsule/ventral striatum (VC/VS) deep brain stimulation (DBS) target for treatment-resistant depression. The left panel shows a coronal section of structural brain magnetic resonance imaging (deidentified file data from the Massachusetts General Hospital) with an overlaid schematic of bilateral VC/VS DBS electrodes. The right panel shows a detailed schematic cartoon of the VC/VS target (image used with permission by Medtronic). The four gray stripes on the electrode show four separate electrode contacts that enable flexibility in stimulation depth from ventral to dorsal regions of the VC/VS target. G.P. = globus pallidus.Image courtesy of Massachusetts General Hospital and Medtronic.

Figure 2. The location of the ventral capsule/ventral striatum (VC/VS) deep brain stimulation (DBS) target for treatment-resistant depression. The left panel shows a coronal section of structural brain magnetic resonance imaging (deidentified file data from the Massachusetts General Hospital) with an overlaid schematic of bilateral VC/VS DBS electrodes. The right panel shows a detailed schematic cartoon of the VC/VS target (image used with permission by Medtronic). The four gray stripes on the electrode show four separate electrode contacts that enable flexibility in stimulation depth from ventral to dorsal regions of the VC/VS target. G.P. = globus pallidus. Image courtesy of Massachusetts General Hospital and Medtronic.

Motivated by the high response rates in OCD trials, Malone et al23 conducted the first VC/VS DBS open-label, multi-center trial at three collaborating clinical sites: Cleveland Clinic, Butler Hospital/Brown Medical School, and Massachusetts General Hospital. Fifteen patients with chronic, severe TRD received bilateral DBS in the VC/VS over a period of 45 months. Symptomatic and functional improvements were observed in the patients despite the severity of their illness pre-DBS (40% remission rate). It is noteworthy that no adverse cognitive effects were reported (based on a pre/post-DBS comprehensive neuropsychological battery). There were two incidents of hypomania in one bipolar patient and an incident of worsening depression during stimulation, which were resolved after stimulation parameter modifications and medication alterations. Interestingly, there were several reported instances of worsening depression caused by battery depletion or inadvertent deactivation of the neurostimulator. Battery replacement and/or reactivation of the neurostimulator resulted in the prompt return of antidepressant efficacy in most of these cases. Although this study was limited by its open design, it provided compelling preliminary evidence for the sustained therapeutic effect of VC/VS DBS in patients with TRD.

In 2010, Malone24 reported on an expanded cohort of VC/VS DBS patients (the original 15 patients from his previous study plus two additional patients). The results were very similar to those of the original study. A 53% response rate was observed at 3 months, a 47% response rate at 6 months, and a 71% response rate at the last follow-up. We are aware that a multicenter, randomized, double-blind, clinical trial has been conducted to compare the efficacy of active versus sham VC/VS stimulation in patients with TRD. Results from the double-blind study await publication.

The Subgenual Cingulate Gyrus (SCG)

Based on a translational model developed from animal studies and human neuroimaging studies, the SCG, also referred to as BA25, has been identified as a critical region involved in emotional regulation. Functional neuroimaging studies have shown the SCG to exhibit exaggerated activity in healthy patients during induced sadness as well as in depressed patients with TRD.10,25 The disturbances in circadian regulation in depression have been implicated in SCG connections to the brainstem, hypothalamus, and insula. Furthermore, disturbances in learning, memory, motivation, and reward have been associated with SCG connections to the orbitofrontal and medial prefrontal cortices.11 Treatment with pharmacotherapy, ECT, transcranial magnetic stimulation, and DBS has shown a normalization of exaggerated SCG activity in patients with remitted depression.26

Mayberg et al11 conducted the first DBS study of the SCG as an open-label trial in six patients with MDD. Four of the six patients achieved a sustained clinical response or remission (≥50% change in HDRS) after 6 months of stimulation without changes in concurrent medications. No negative neuropsychological effects were reported. This same group of investigators expanded the original cohort11 to 20 patients (ie, 14 additional patients with TRD) and, subsequently, published their findings for SCG DBS after 1 year of stimulation in TRD patients.12 The baseline HDRS for the expanded cohort was 24.4 ± 3.5, which is indicative of severe depression. After 1 year of treatment, 55% of patients were responders, and nearly 35% were in remission. The 1-year trial of SCG DBS was generally well tolerated because seven patients were reported to be free of adverse events. However, the following adverse events common to neurosurgery were reported: perioperative infections (five patients), headache/pain (four patients), and seizures (one patient). Follow-up of these 20 patients was extended from 3 to 6 years post-DBS implantation.13 Based on the available data, response rates were 46.2% after 2 years, 75% after 3 years, and 64.3% at the last follow-up visit. Remission rates were reported as 15.4% after 2 years, 50% after 3 years, and 42.9% at the last follow-up visit. The HDRS score did not differ significantly from scores at years 1, 2, and 3 but were significantly lower at the last follow-up visit compared with HDRS scores at baseline.

In an effort to characterize the functional neuroanatomy modulated by DBS of the SCG, the pre-/post-treatment effects of SCG stimulation were assessed via positron emission tomography imaging. Specifically, oxygen-15 positron emission tomography measures of regional blood flow were conducted in the first six patients,11 and fluorodeoxyglucose positron emission tomography (FDG-PET) measures of regional glucose metabolism were conducted in 11 of the 14 patients in the expanded SCG DBS cohort.12 Collectively, the imaging data revealed decreased activity within the insular, orbital, and medial frontal cortices (inclusive of the SCG) and increased activity in the lateral prefrontal and parietal cortices as well as in the anterior, mid, and posterior cingulate. The medial and orbital frontal changes were initially observed at the 3-month post-treatment scan and persisted at the 6-month post-treatment scan. Taken together, these findings suggest that DBS of the SCG modulates dynamic change in brain regions associated with the emotional and cognitive/executive symptoms in depressed patients.11,12 Specifically, dorsal regions observed to have low activity at pretreatment were shown to have an increase in activity at post-treatment, and ventral regions observed to have high activity at pretreatment were shown to have a decrease in activity at post-treatment, consistent with the dorsal/ventral component model proposed by Mayberg.10

More recently, the group led by Dr. Mayberg conducted an additional trial of DBS of the SCG in 17 patients with TRD (n = 10) and bipolar disorder (BP; n = 7).14 Importantly, this trial included a single-blind sham lead-in phase to address the potential placebo effect. After SCG DBS implantation, the original protocol consisted of 1) a 4-week, single-blind, sham stimulation phase in which patients were told they would be randomized to receive either active stimulation or sham stimulation; however, all patients received sham stimulation; 2) a 24-week open active stimulation phase; and 3) a single-blind discontinuation phase in which patients were told they would be randomized to receive either active stimulation or sham stimulation; however, all patients received sham stimulation. The discontinuation phase was ultimately removed from the protocol because of concerns for patient safety after the first three consecutive patients developed significant worsening of their depressive symptoms.

There was no clinically meaningful difference in HDRS scores at the end of the 4-week sham period (20.5 ± 1.7) compared with the end of the first 4 weeks of active stimulation (17.9 ± 0.9), suggesting that stimulation was no better than sham (at least for the initial 4 weeks of treatment). However, compared with baseline, the average HDRS score decreased 43.6%, 43%, and 70.1% by the 24-week, 1-year, and 2-year time points, respectively. Furthermore, all patients who reached the 2-year time point (n = 12) entered remission or had only mild depressive symptoms. A significant improvement was observed in all other measures, and there were no significant differences in clinical measures between the MDD and BP group. It is also noteworthy that comparable antidepressant efficacy was shown in patients with BP without the provocation of manic or hypomanic episodes.

The Nucleus Accumbens (NAcc)

Evidence from studies of various animal model studies27 and human neuroimaging data28 implicates a prominent role of reward and pleasure processing within the NAcc. Given dense reciprocal connections of the NAcc to limbic and prefrontal regions, the NAcc is well situated to mediate reward-seeking motivational behavior via dopaminergic circuitry.27,29 An increase in NAcc neuronal activity has been observed during expectations and experience of rewards.25 Although the pathophysiological mechanisms for NAcc dysfunction in MDD are not fully understood, the NAcc appears to play a key role in MDD, particularly in depressive symptoms of anhedonia and impaired motivation.

Schlaepfer et al30 conducted the first study of DBS of the NAcc designed to investigate the potential clinical usefulness of NAcc DBS in TRD and its functional neuroanatomy via FDG-PET imaging. After an acute 2- to 6-week initial stimulation phase, the protocol incorporated a short (1–5 weeks) double-blind discontinuation phase followed by an active stimulation continuation phase. In all three patients studied, significant improvements on the HDRS occurred when the stimulator was turned on but not when the stimulator was turned off. No major DBS-related adverse events were reported. The FDG-PET findings after 1 week of stimulation compared with preimplantation showed bilateral increased metabolism in the VS (including the NAcc), the cingulated cortex, the amygdale, and dorsolateral/dorsomedial prefrontal cortices. Decreased metabolism was observed in the caudate, thalamus, and ventromedial/ventrolateral prefrontal cortices.

The group led by Schlaepfer later published another study of NAcc DBS effects on TRD in a larger sample (n = 10) for a longer duration of treatment (1 year).15 Relative to pretreatment, five of the patients had a 50% reduction in their HDRS score at 1 year. Furthermore, clinical anxiety scores (via the Hamilton Anxiety Scale) were significantly reduced in the entire sample and more pronounced in the responders. No permanent adverse effects were reported. FDG-PET findings (6 months post-treatment vs. pretreatment) in this sample revealed decreases in metabolism localized to the SGC, orbital prefrontal cortex, posterior cingulate cortex, thalamus, and caudate nucleus. In a subsequent article by Bewernick et al,16 the authors reported on the long-term effects of NAcc DBS for TRD. The sample (n = 11) included subjects from the authors’ earlier report.15 The mean total HDRS score for the whole sample was 32.2 ± 5.5 at baseline, 20.2 ± 7.5 after 1 year, 19.5 ± 9 after 2 years, and 22.1 ± 13.4 at the last follow-up (4 years). Five of the patients were categorized as responders (50% reduction in HDRS) at 1 year, showing a therapeutic response to NAcc DBS that was sustained through the last follow-up (4 years). Adverse events reported for this study were neither serious nor permanent; they were primarily related to the surgery (eg, pain and dysphagia) or transient/reversible DBS effects (eg, erythema, anxiety, and tension). Overall, DBS of the NAcc has shown sustained antidepressant efficacy in some patients with TRD with minimal side effects.

The Medial Forebrain Bundle (MFB)

The MFB is a white-matter tract that carries both ascending and descending fibers between the ventral tegmental area (VTA) and the NAcc, conferring a functional anatomy similar to the VC/VS and NAcc DBS target sites for TRD. Increased dopamine levels after stimulation of the MFB in an animal model suggests a reward/hedonic role for the MFB similar to that associated with the NAcc.31

Schlaepfer et al17 performed a pilot investigation of DBS of the MFB in six patients with TRD and one patient with BP in a sustained and severe depressive episode. Because the MFB cannot be identified by standard anatomic magnetic resonance imaging, deterministic diffusion tensor imaging is required to visualize the fiber tracts of the intended superolateral branch target of the MFB in surgical planning. Although the MADRS served as the primary outcome measure, we report the HDRS scores here for ease in comparing the MFB findings with the other studies presented in this review. The mean HDRS was 23 ± 1.5 at baseline, 12.4 ± 9.9 at week 1, and 14.7 ± 8.2 at week 12. At the last follow-up (12–33 weeks), six of seven patients were classified as responders; of these, four met remission criteria (based on changes in MADRS scores; Table 2, see page 360). In summary, this pilot study of DBS of the MFB showed clinically relevant antidepressant efficacy in an otherwise treatment-refractory sample and welcomes further investigation of the MFB in TRD. Adverse events were minimal, reversible, and of limited duration (eg, intraoperative intracranial bleed, IPG implant site infection, and strabismus at high stimulator voltage).

The Lateral Habenula (LHb)

The habenular complex, located in the medial to posterior thalamic regions, is known to exert influence over the following primary neurotransmitter systems implicated in depression: serotonergic neurons of the dorsal raphe nuclei, noradrenergic neurons of the locus coeruleus, and dopaminergic neurons of the ventral tegmental area.32,33 The consideration of the habenular complex as a DBS target is based on converging lines of evidence from animal models as well as structural and functional neuroimaging studies in depressed patients.32 Perhaps the strongest evidence has been derived from animal studies of the LHb in which stimulation has been shown to reduce learned helplessness behavior.33

To date, only one case study of LHb-DBS has been reported. Sartorius et al34 published findings from DBS of the major afferent bundle (ie, the stria medullaris thalami) of the LHb in a 64-year old woman who had lifelong TRD. Although no acute antidepressant effects were observed, DB of the LHb resulted in a sustained full remission of depressive symptoms after approximately 4 months of stimulation. The apparent therapeutic effect conferred by DBS of the LHb awaits replication and extension to larger samples.

The ITP

The ITP is a fiber bundle with connections between the mediodorsal thalamic nucleus and the insular, temporal, and orbitofrontal cortices. The ITP courses along the ventromedial side of the thalamus to the posterior limb off the internal capsule and has some regional proximity to the VC/VS DBS target.

Overall, the empirical basis for DBS of the ITP is scant. To our knowledge, only one case report has been published.35 Jimenez et al35 performed DBS of the ITP in a 49-year old woman with a history of MDD comorbid with borderline personality disorder and bulimia. The patient had a significant history of depression that spanned 20 years. Her monthly HDRS scores were greater than 30 for the 4 months that preceded surgery. After implantation, the patient received 8 months of continuous stimulation that were associated with HDRS scores below 10. At month 8, the patient entered a double-blind phase of the protocol in which the stimulator was switched off until month 20, when stimulation resumed. With the exception of a 2-month oscillation in the HDRS (scores of 12 and 20), HDRS scores remained below 10 during the double-blind trial with no stimulation. The authors considered several explanations for the sustained therapy in the absence of active stimulation (eg, DBS of the ITP afforded an induction of neurotransmitter regulatory processes like those proposed for ECT). However, because discontinuation of DBS at most of the other targets has been associated with dramatic worsening of depressive symptoms, the possibility of a placebo effect in this case study of ITP DBS cannot be excluded.

Conclusion and Future Directions

Mounting evidence strongly suggests that DBS may be a viable treatment option for patients suffering from TRD. Approximately 50% to 60% of patients who have received DBS therapy have achieved a significant response, defined as a 50% decrease on standard depression rating scales. A significant treatment response has been reported within 1 week34 although the most convincing response data have been derived from periods of stimulation of 6 to 12 months and longer. Even though the perioperative risks associated with neurosurgery must be carefully considered, data from the reviewed studies show intermediate to long-term safety for DBS. In most cases, DBS-related side effects were transient and resolved with the adjustment of stimulation parameters.

We have placed the greatest emphasis of our review of DBS for TRD on the VC/VS, NAcc, and SCG targets because studies of these targets included larger sample sizes and a longer course of treatment. Importantly, studies for each of these three targets have reported comparable positive response rates.12,15,16,18,23 Furthermore, pre-/post-treatment neuroimaging findings associated with the NAcc and SCG DBS12,15,18,30 have provided compelling insights into the pathophysiology of MDD and informed neural models for treatment response.

Although the data that support the safety and efficacy of the other DBS targets (eg, LHb, ITP, and MFB) are limited, we view these relatively new targets as important candidate regions for future, larger studies of DBS for TRD. Even though significant response rates have been reported in the DBS studies of VC/VS, NAcc, and SCG targets, the efficacy has been somewhat inconsistent; clinical outcomes vary from no response to complete remission. It is possible that the inconsistency relates to individual patient characteristics. Perhaps one target may be found superior to another in the treatment of an individual patient. For example, the NAcc target was associated with significant reductions in anxiety not observed in studies of the VC/VS and SCG targets.15 As our knowledge of DBS treatments deepens and we develop greater clinical insight into the neural network underlying TRD, it seems conceivable that DBS treatments may be tailored to symptom-specific individual profiles in the future. Yet, there remains an immediate and imperative unmet medical need for validation of DBS for TRD via large double-blind trials.

References

  1. First MB, Spitzer RL, Gibbon M, Williams JB. Structured Clinical Interview for DSMIV-TR Axis I Disorders. New York, NY: State New York Psychiatric Institute; 1995.
  2. Bromet E, Andrade LH, Hwang I, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9(90.
  3. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–659.
  4. Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52(1):46–54.
  5. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am. 2003;26(2):457–494.
  6. Krack P, Hariz MI, Baunez C, et al. Deep brain stimulation: from neurology to psychiatry?Trends Neurosci. 2010;33(10):474–484.
  7. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:5662.
  8. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31(9):1841–1853.
  9. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389.
  10. Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193–207.
  11. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651–660.
  12. Lozano AM, Mayberg HS, Giacobbe P, et al. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64(6):461–467.
  13. Kennedy SH, Giacobbe P, Rizvi SJ, et al. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am J Psychiatry. 2011;168(5):502–510.
  14. Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012;69(2):150–158.
  15. Bewernick BH, Hurlemann R, Matusch A, et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010;67(2):110–116.
  16. Bewernick BH, Kayser S, Sturm V, Schlaepfer TE. Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Neuropsychopharmacology. 2012;37(9):1975–1985.
  17. Schlaepfer TE, Bewernick BH, Kayser S, et al. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry. 2013;73(12):1204–1212.
  18. Talairach J, Hecaen H, David M. Lobotomie Préfrontal Limitée par Electrocoagulation des Fibres Thalamo-frontales a leur Émergence du Bras Anterieur de la Capsule Interne. Paris: Congres Neurologique International; 1949:141.
  19. Waziri R. Psychosurgery for Anxiety and Obsessive-Compulsive Disorders. In Noyes R., Roth M., Burrows G. (Eds), Handbook of Anxiety: The treatment of anxiety. Amsterdam: Elsevier; 1990;519–535.
  20. Ruck C, Karlsson A, Steele JD, et al. Capsulotomy for obsessive-compulsive disorder: long-term follow-up of 25 patients. Arch Gen Psychiatry. 2008;65(8):914–921.
  21. Nuttin B, Cosyns P, Demeulemeester H, et al. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet. 1999;354(9189):1526.
  22. Greenberg BD, Gabriels LA, Malone DA, et al. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry. 2010;15(10):64–79.
  23. Malone DA Jr, Dougherty DD, Rezai AR, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65(4):267–275.
  24. Malone DA Jr, . Use of deep brain stimulation in treatment-resistant depression. Cleve Clin J Med. 2010;77(Suppl 3):77–80.
  25. George MS, Ketter TA, Parekh PI, et al. Brain activity during transient sadness and happiness in healthy women. Am J Psychiatry. 1995;152(3):341–351.
  26. Mayberg HS. Targeted electrode-based modulation of neural circuits for depression. J Clin Invest. 2009;119(4):717–725.
  27. Ongur D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10(3):206–219.
  28. Knutson B, Adams CM, Fong GW, Hommer DC. Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci. 2001;21(16):RC159.
  29. Rodriguez PF, Aron AR, Poldrack RA. Ventral-striatal/nucleus-accumbens sensitivity to prediction errors during classification learning. Hum Brain Mapp. 2006;27(4):306–313.
  30. Schlaepfer TE, Cohen MX, Frick C, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology. 2008;33(2):368–377.
  31. Hernandez G, Hamdani S, Rajabi H, et al. Prolonged rewarding stimulation of the rat medial forebrain bundle: neurochemical and behavioral consequences. Behav Neurosci. 2006;120(4):888–904.
  32. Sartorius A, Henn FA. Deep brain stimulation of the lateral habenula in treatment resistant major depression. Med Hypotheses. 2007;69:1305–1308.
  33. Li B, Piriz J, Mirrione M, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470(7335):535–539.
  34. Sartorius A, Kiening KL, Kirsch P, et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry. 2010;67(2):e9–e11.
  35. Jimenez F, Velasco F, Salin-Pascual R, et al. A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery. 2005;57(3):585–593; discussion 585–593.

Cohort Characteristics for Studies of Deep Brain Stimulation in Major Depressive Disorder

Study Number of Patients Age of MDD Onset, Years (SD) Age at Implant, Years (SD) Number of Failed Medication Trials (SD)
VC/VS
Malone et al, 2009;23 Malone et al, 201024 17 25.3 (10.5) 46.3 (10.8) 6.1 (2.6)
SCG
  Mayberg et al, 200511 6 29.5 (12) 46.0 (8.0) ≥ 4
  Lozano et al, 2008;12 Kennedy et al, 201113 20 27.1 (8.3) 47.4 (10.4) 4.2 (4.1)
  Holtzheimer et al, 201214 17 19.9 (7.8) 42.0 (8.9) 6.2 (2.7)
NAcc
  Schlaepfer et al, 200830 3 13 (16.9) 46.7 (16.7) 3.3 (1.5)
  Bewernick et al, 201015 10 31.7 (13.2) 48.6 (11.7) 4.3 (1.3)
  Bewernick et al, 201216 11 32.6 (12.4) 48.6 (11.1) 4.36 (1.2)
MFB
  Schlaepfer et al, 201317 7 30.0 (10.1) 42.6 (9.8) 4.0 (3.9)
LHb
  Sartorius et al, 201034 1 18 64 > 2
ITP
  Jiménez et al, 200535 1 29 49 > 5

Cohort Characteristics for Studies of Deep Brain Stimulation in Major Depressive Disorder

Study Number of Patients Stimulation Parameters (Voltage, Pulse Width, Frequency) Follow-Up Period Baseline Last Follow-Up
HDRS MADRS GAF or CGI HDRS MADRS GAF or CGI
VC/VS
Malone et al, 200923 15 6.7 V, 113 mcs, 127 Hz 45 months 33.1 (5.5) 34.8 (7.3) GAF: 43.4 (2.8) 14.3 (9.3) 15.7 (11.0) GAF: 61.8 (13.1)
SCG
Mayberg et al, 200511 6 4.0 V, 60 mcs, 130 Hz 6 months 34.6 (1.9) 33.3 (4.5) CGI: 6.2 (0.4) 18.8 (10.6) 18.5 (10.4) CGI: 4.0 (1.7)
Lozano et al, 200812 20 3.5–5.0 V, 90 mcs, 130 Hz 12 months 24.4 (3.5) - CGI: 5.1 (0.7) 12.6 (6.3) - CGI: 3.2 (1.40
Holtzheimer et al, 201214 17 4.0–8.0 mA, 90 mcs, 130 Hz 24 months 23.9 (0.7) - GAF: 33.9 (1.7) 7.3 (0.7) - GAF: 78.7 (4.1)
NAcc
Schlaepfer et al, 200830 3 4.0 V, 90 mcs, 145 Hz 1 week 33.7 (3.8) 35.7 (2.9) - 19.7 ± 6.7 24.7 (6.7) -
Bewernick et al, 201015 10 2.0 V, 90 mcs, 130 Hz 12 months 32.5 (5.3) 30.6 - 20.8 20.3 -
Bewernick et al, 201216 11 5.0–8.0 V, 90 mcs, 130 Hz 48 months 32.2 (5.5) 32.3 (3.7) - 22.1 (13.4) 21.6 (10.7) -
MFB
Schlaepfer et al, 201317 7 2.86 mA, 60 mcs, 130 Hz 12 weeks 23.0 (1.5) 29.9 (8.0) GAF: 4.1 (1.1) 14.7 (8.2) 11.0 (9.7) GAF: 6.6 (1.3)
LHb
Sartorius et al, 201034 1 10.5 V N/A 45 - - 11 - -
ITP
Jiménez et al, 200535 1 2.5 V, 450 mcs, 130 Hz 8 months 42 - - 3 - -
Authors

Navneet Kaur, BS, is Clinical Research Coordinator, Division of Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital. Tina Chou, BA, is a graduate student within the Division of Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital, and Department of Psychology, Harvard University, Cambridge, MA. Andrew K. Corse, BA, is Clinical Research Coordinator, Division of Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital. Amanda R. Arulpragasam, BS, BA, is Clinical Research Coordinator, Division of Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital. Thilo Deckersbach, PhD, is Director of Research, Division of Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital, Associate Professor, Harvard Medical School. Karleyton C. Evans, MD, MSc, is Assistant Clinical Director, Division of Neurotherapeutics, Department of Psychiatry, Massachusetts General Hospital, Assistant Professor, Harvard Medical School.

Address correspondence to: Karleyton C. Evans, MD, MSc, Department of Psychiatry, Massachusetts General Hospital CNY2625, 149 13th Street, Charlestown, MA 02129; email: kcevans@partners.org. 

Disclosure: Dr. Evans receives research funding from NIMH (K23-MH086619). He has also participated in research funded by Cyberonics, Medtronic, Northstar Neuroscience, and Pfizer. The other authors report no relevant financial disclosures.

The authors thank Tian Yue Song for editorial assistance.

10.3928/00485713-20130806-04

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