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A narrative review on invasive brain stimulation for treatment-resistant depression

Manoj P. Dandekar Alexandre P. Diaz Ziaur Rahman Ritele H. Silva Ziad Nahas Scott Aaronson Sudhakar Selvaraj Albert J. Fenoy Marsal Sanches Jair C. Soares Patricio Riva-Posse Joao Quevedo About the authors

Abstract

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Treatment-resistant depression; deep brain stimulation; vagus nerve stimulation; epidural cortical stimulation subcallosal cingulate gyrus; medial forebrain bundle


Introduction

According to the World Health Organization, depression is the leading psychiatric cause of disability worldwide, with > 264 million people affected in 2017.11. World Health Organization (WHO). Depression [Internet]. 2020 Jan 30 [cited 2021 Jun 15]. https://www.who.int/news-room/fact-sheets/detail/depression
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,22. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789-858. In addition to critical functional impairment, depression is associated with a significant economic burden and premature mortality.33. Smith K. Trillion-dollar brain drain. Nature. 2011;478:15.,44. Weye N, Momen NC, Christensen MK, Iburg KM, Dalsgaard S, Laursen TM, et al. Association of specific mental disorders with premature mortality in the Danish population using alternative measurement methods. JAMA Netw Open. 2020;3:e206646. While pharmacotherapy and psychotherapy are effective in reducing depressive symptoms,55. Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17:111-26.,66. Dupuy JM, Ostacher MJ, Huffman J, Perlis RH, Nierenberg AA. A critical review of pharmacotherapy for major depressive disorder. Int J Neuropsychopharmacol. 2011;14:1417-31. a considerable number of patients (about 30%) do not achieve remission even after multiple trials.77. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR* D report. Am J Psychiatry. 2006;163:1905-17. 8. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR* D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.-99. A. Riva-Posse P. Why is deep brain stimulation for treatment-resistant depression a needed treatment option? Braz J Psychiatry. 2020;42:344-6. Although there is no consensus regarding the concept of treatment-resistant depression (TRD), it is usually defined as the lack of clinical response to at least two antidepressant trials employed in adequate doses and periods.1010. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-88. 11. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-59. 12. Hauptman JS, DeSalles AA, Espinoza R, Sedrak M, Ishida W. Potential surgical targets for deep brain stimulation in treatment-resistant depression. Neurosurg Focus. 2008;25:E3. 13. Rush A, George MS, Sackeim HA, Marangell LB, Husain M, Nahas Z. Continuing benefit of VNS therapy over 2 years for treatment-resistant depression. In: 43rd Annual NCDEU Meeting. Miami: NCDEU; 2003. 14. Souery D, Papakostas GI, Trivedi MH. Treatment-resistant depression. J Clin Psychiatry. 2006;67 Suppl 6:16-22.-1515. Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999;9:83-91. For these patients, neurostimulation therapies (NTs) may be required to manage their symptoms.

NTs are categorized into two types according to the clinical procedure. Non-invasive methods include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation, and transcranial direct current stimulation.1616. B. Borrione L, Bellini H, Razza LB, Avila AG, Baeken C, Brem A-K, et al. Precision non-implantable neuromodulation therapies: a perspective for the depressed brain. Braz J Psychiatry. 2020;42:403-19. As depicted in Figure 1, invasive techniques include vagus nerve stimulation (VNS), deep brain stimulation (DBS), and epidural cortical stimulation (ECS).1717. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology. 2012;37:102-16. While the efficacy of ECT has been demonstrated since its early days, some patients still do not achieve remission and may present cognitive complaints, despite the refinement of the technique in terms of effectiveness and safety.1818. Chu CW, Chien WC, Chung CH, Chao PC, Chang HA, Kao YC, et al. Electroconvulsive therapy and risk of dementia--a nationwide cohort study in Taiwan. Front Psychiatry. 2018;9:397. 19. McDonald WM, Weiner RD, Fochtmann LJ, McCall WV. The FDA and ECT. J ECT. 2016;32:75-7. 20. Narang P, Glowacki A, Lippmann S. Electroconvulsive therapy intervention for Parkinson’s disease. Innov Clin Neurosci. 2015;12:25-8. 21. Nordenskjöld A, von Knorring L, Engström I. Predictors of time to relapse/recurrence after electroconvulsive therapy in patients with major depressive disorder: a population-based cohort study. Depress Res Treat. 2011;2011:470985. 22. Sackeim HA, Prudic J, Fuller R, Keilp J, Lavori PW, Olfson M. The cognitive effects of electroconvulsive therapy in community settings. Neuropsychopharmacology. 2007;32:244-54.-2323. Zwil AS, PelchatRJ. ECT in the treatment of patients with neurological and somatic disease. Int J Psychiatry Med. 1994;24:1-29. Repetitive transcranial magnetic stimulation is another effective non-invasive technique that has also received U.S. Food and Drug Administration (FDA) approval as a treatment for major depressive disorder.2424. McClintock SM, Reti IM, Carpenter LL, McDonald WM, Dubin M, Taylor SF, et al. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry. 2017;79:16cs10905.,2525. Bennabi D, Haffen E. Transcranial direct current stimulation (tDCS): a promising treatment for major depressive disorder? Brain Sci. 2018;8:81.

Figure 1
Schematic representation of invasive brain stimulation techniques DBS, VNS, and ECS. Amygd = amygdala; DBS = deep brain stimulation; DL-PFC = dorsolateral prefrontal cortex; ECS = epidural cortical stimulation; FPC= frontopolar cortex; Hyp = hypothalamus; ITP = inferior thalamic peduncle; LHb = lateral habenula; MFB = medial forebrain bundle; NAc = nucleus accumbens; SCG = subgenual cingulate gyrus; VC/VS = ventral capsule/ventral striatum; VNS = vagus nerve stimulation.

Invasive NTs, such as VNS and DBS, have been increasingly investigated as treatments for TRD.1717. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology. 2012;37:102-16.,2626. Kosel M, Schlaepfer TE. Beyond the treatment of epilepsy: new applications of vagus nerve stimulation in psychiatry. CNS Spectr. 2003;8:515-21. 27. Schlaepfer TE, Fins JJ. Deep brain stimulation and the neuroethics of responsible publishing: when one is not enough. JAMA. 2010;303:775-6. 28. Schlaepfer TE, Bewernick BH, Kayser S, Mädler B, Coenen VA. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry. 2013;73:1204-12. 29. Smith DF. Exploratory meta-analysis on deep brain stimulation in treatment-resistant depression. Acta Neuropsychiatr. 2014;26:382-4.-3030. McGirr A, Berlim MT. Clinical usefulness of therapeutic neuromodulation for major depression: a systematic meta-review of recent meta-analyses. Psychiatr Clin North Am. 2018;41:485-503. VNS electrodes deliver a continuous low-frequency electrical signal to the left cervical vagus nerve from an implantable generator.3131. Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR, et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology. 2006;31:1345-55. The procedure received FDA approval in 2005 for TRD. DBS electrodes are stereotactically implanted in a specific brain region and connected to a subcutaneous pulse generator that supplies power and controls stimulation.3232. Gardner J. A history of deep brain stimulation: technological innovation and the role of clinical assessment tools. Soc Stud Sci. 2013;43:707-28. The FDA approved this intervention as a treatment for essential tremor in 1997, Parkinson disease in 2002, dystonia in 2003, and obsessive-compulsive disorder (as a humanitarian device exemption) in 2009.3232. Gardner J. A history of deep brain stimulation: technological innovation and the role of clinical assessment tools. Soc Stud Sci. 2013;43:707-28.,3333. Cook IA, Espinoza R, Leuchter AF. Neuromodulation for depression: invasive and noninvasive (deep brain stimulation, transcranial magnetic stimulation, trigeminal nerve stimulation). Neurosurg Clin N Am. 2014;25:103-16. It is being investigated as a treatment for TRD,3434. Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2018;23:843-9.,3535. Raymaekers S, Luyten L, Bervoets C, Gabriëls L, Nuttin B. Deep brain stimulation for treatment-resistant major depressive disorder: a comparison of two targets and long-term follow-up. Transl Psychiatry. 2017;7:e1251. addiction,3636. Rachid F. Neurostimulation techniques in the treatment of cocaine dependence: a review of the literature. Addict Behav. 2018;76:145-55. anorexia nervosa,3737. Martínez GV, Justicia A, Salgado P, Ginés JM, Guardiola R, Cedrón C, et al. A randomized trial of deep brain stimulation to the subcallosal cingulate and nucleus accumbens in patients with treatment-refractory, chronic, and severe anorexia nervosa: initial results at 6 months of follow up. J Clin Med. 2020;9:1946. Alzheimer’s disease,3838. Laxton AW, Tang‐Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol. 2010;68:521-34.,3939. Sankar T, Chakravarty MM, Bescos A, Lara M, Obuchi T, Laxton AW, et al. Deep brain stimulation influences brain structure in Alzheimer’s disease. Brain Stimul. 2015;8:645-54. and anxiety.4040. van Dijk A, Klanker M, van Oorschot N, Post R, Hamelink R, Feenstra MG, et al. Deep brain stimulation affects conditioned and unconditioned anxiety in different brain areas. Transl Psychiatry. 2013;3:e289. ECS, another brain stimulation technique that has been tested as a TRD treatment,4141. Nahas Z, Anderson BS, Borckardt J, Arana AB, George MS, Reeves ST, et al. Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Biol Psychiatry. 2010;67:101-9. delivers electrical stimulation to the cortex without penetrating the brain tissue. ECS appears to have fewer complications than DBS,4242. Canavero S, Bonicalzi V. Therapeutic extradural cortical stimulation for central and neuropathic pain: a review. Clin J Pain. 2002;18:48-55. and studies on this intervention have reported encouraging results.4141. Nahas Z, Anderson BS, Borckardt J, Arana AB, George MS, Reeves ST, et al. Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Biol Psychiatry. 2010;67:101-9.,4343. Williams NR, Short EB, Hopkins T, Bentzley BS, Sahlem GL, Pannu J, et al. Five-year follow-up of bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Brain Stimul. 2016;9:897-904. In this review, we will briefly discuss clinical invasive NTs and data supporting their potential as a treatment for TRD.

Vagus nerve stimulation

The vagus nerve, the 10th cranial nerve, has a long path extending from the brainstem to the abdomen. It is one of the main communication pathways between the brain and peripheral organs.4444. Breit S, Kupferberg A, Rogler G, Hasler G. Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front Psychiatry. 2018;9:44. The vagus nerve plays a pivotal role in modulating metabolic homeostasis and the neuroendocrine-immune axis through efferent and afferent pathways.4545. Ruffoli R, Giorgi FS, Pizzanelli C, Murri L, Paparelli A, Fornai F. The chemical neuroanatomy of vagus nerve stimulation. J Chem Neuroanat. 2011;42:288-96. Glutamatergic transmission through afferent pathways sends information from the internal organs to the brain, which may influence emotion and cognition, while the efferent pathways participate in the regulation of digestive, respiratory, and circulatory systems through parasympathetic cholinergic transmission.4646. Okonogi T, Sasaki T. Optogenetic manipulation of the vagus nerve. Adv Exp Med Biol. 2021;1293:459-70. Findings that treatment with anticonvulsants4747. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:79-88.,4848. Fatemi SH, Rapport DJ, Calabrese JR, Thuras P. Lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 1997;58:522-7. and VNS reduces seizures and is associated with mood improvement suggest that VNS has potential as a depression treatment. For instance, Harden et al.4949. Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR. A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav. 2000;1:93-9. investigated whether using VNS to treat epilepsy was associated with mood changes. The authors evaluated depressive symptoms before and after VNS and compared the results to those of a group of patients on stable antiepileptic drugs, such as gabapentin and lamotrigine. There was a significant decrease in depressive symptoms in the VNS group but only a trend toward significance in the antiepileptic group. In addition, patients who did and did not respond to VNS therapy for seizures did not differ in terms of depressive symptoms, suggesting that the mood improvement was not due to a decrease in seizure frequency.4949. Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR. A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav. 2000;1:93-9. Elger et al.5050. Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000;42:203-10. found similar results in 11 patients treated with VNS, whose depressive symptoms improved 3 and 6 months after implantation, independently of the therapy’s effect on seizure activity. In VNS, the left cervical vagus nerve is stimulated with an implantable electrical device,3131. Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR, et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology. 2006;31:1345-55.,5151. Chae JH, Nahas Z, Lomarev M, Denslow S, Lorberbaum JP, Bohning DE, et al. A review of functional neuroimaging studies of vagus nerve stimulation (VNS). J Psychiatr Res. 2003;37:443-55. which delivers electrical signals via bipolar leads tunneled under the skin. The stimulation parameters can be programmed externally according to patient demand. VNS received FDA approval as a treatment for resistant epilepsy and depression in 1997 and 2005, respectively.5252. Marangell LB, Rush AJ, George MS, Sackeim HA, Johnson CR, Husain MM, et al. Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes. Biol Psychiatry. 2002;51:280-7.

53. Cristancho P, Cristancho MA, Baltuch GH, Thase ME, O’Reardon JP. Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. J Clin Psychiatry. 2011;72:1376-82.
-5454. Morris GL 3rd, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;81:1453-9. Since then, as summarized in Table 1, several clinical studies have found that chronic VNS is efficacious for TRD.5555. Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry. 2017;174:640-8.-56. Aaronson ST, Conway CR. Vagus nerve stimulation: changing the paradigm for chronic severe depression? Psychiatr Clin North Am. 2018;41:409-18. 57. Burke MJ, Husain MM. Concomitant use of vagus nerve stimulation and electroconvulsive therapy for treatment-resistant depression. J ECT. 2006;22:218-22. 58. Conway CR, Chibnall JT, Gangwani S, Mintun MA, Price JL, Hershey T, et al. Pretreatment cerebral metabolic activity correlates with antidepressant efficacy of vagus nerve stimulation in treatment-resistant major depression: a potential marker for response? J Affect Disord. 2012;139:283-90. 59. Conway CR, Chibnall JT, Gebara MA, Price JL, Snyder AZ, Mintun MA, et al. Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression. Brain Stimul. 2013;6:788-97. 60. Conway CR, Kumar A, Xiong W, Bunker M, Aaronson ST, Rush AJ. Chronic vagus nerve stimulation significantly improves quality of life in treatment-resistant major depression. J Clin Psychiatry. 2018;79:18m12178. 6161. Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58:355-63.

Table 1
Summary of clinical trials and case reports on epidural cortical stimulation and vagus nerve stimulation for treatment-resistant depression

In a multi-site, open-label pilot study of VNS in 30 TRD patients, Rush et al.8181. Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry. 2000;47:276-86. reported that 40% of the participants achieved at least 50% symptom reduction after 10 weeks of treatment. Afterwards, Sackeim et al.8080. Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al. Vagus nerve stimulation (VNS™) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology. 2001;25:713-28. added data from 30 additional patients and reported a 30.5% response rate following 10 weeks of VNS treatment, with findings that suggested long-term therapeutic utility and good tolerability. Rush et al.1313. Rush A, George MS, Sackeim HA, Marangell LB, Husain M, Nahas Z. Continuing benefit of VNS therapy over 2 years for treatment-resistant depression. In: 43rd Annual NCDEU Meeting. Miami: NCDEU; 2003. continued observing this sample and reported 44% response and 27% remission rates after 1 year of stimulation, and 44% response and 22% remission rates after 2 years of stimulation. In the last observation carried forward analyses, Nahas et al.7777. Nahas Z, Marangell LB, Husain MM, Rush AJ, Sackeim HA, Lisanby SH, et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry. 2005;66:1097-104. found the response and remission rates of 44 and 27%, respectively, after 1 year and 42 and 22%, respectively, after 2 years of adjunctive VNS. Furthermore, response rates of 43% (in 15 patients), 35.7% (in 28 patients), 20% (in 27 patients), and 55% (in 11 patients) were reported following 12-month of VNS in four other studies with TRD patients.5353. Cristancho P, Cristancho MA, Baltuch GH, Thase ME, O’Reardon JP. Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. J Clin Psychiatry. 2011;72:1376-82.,7171. Tisi G, Franzini A, Messina G, Savino M, Gambini O. Vagus nerve stimulation therapy in treatment‐resistant depression: a series report. Psychiatry Clin Neurosci. 2014;68:606-11.,7272. Christmas D, Steele JD, Tolomeo S, Eljamel MS, Matthews K. Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients. J Affect Disord. 2013;150:1221-5.,7575. Corcoran CD, Thomas P, Phillips J, O’Keane V. Vagus nerve stimulation in chronic treatment-resistant depression: preliminary findings of an open-label study. Br J Psychiatry. 2006;189:282-3. However, few studies have reported a poor response to VNS treatment for depression. For instance, Rush et al.7979. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58:347-54. found a modest response to VNS in a 10-week randomized comparison of adjunctive VNS vs. sham in 222 TRD outpatients (VNS group = 112; sham group = 110). They suggested that VNS may be ineffective depending on the study sample and design and the length of treatment. The authors later reported a significant reduction in depressive symptoms, with a response rate of 27.2% after 1 year follow-up.6161. Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58:355-63. Importantly, in a non-randomized comparison study, George et al.7676. George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58:364-73. found a better response rate in patients who received concomitant pharmacotherapy + VNS than in those who received conventional treatment.

Bajbouj et al.7474. Bajbouj M, Merkl A, Schlaepfer TE, Frick C, Zobel A, Maier W, et al. Two-year outcome of vagus nerve stimulation in treatment-resistant depression. J Clin Psychopharmacol. 2010;30:273-81. conducted a naturalistic analysis of 74 European TRD patients after 2 years of VNS, finding a significant decrease in depression symptoms at all three-time points (3, 12, and 24 months). After 2 years of treatment, there was a 38.9% (19/49) remission rate and 53.1% (29/49) response rate. In a naturalistic 5-year follow-up study of five patients, the response and remission rates were both 40% (2/5) after 1 year and 5 years.7070. Albert U, Maina G, Aguglia A, Vitalucci A, Bogetto F, Fronda C, et al. Vagus nerve stimulation for treatment-resistant mood disorders: a long-term naturalistic study. BMC Psychiatry. 2015;15:64. The high symptom remittance levels over more extended periods (> 5 years) suggest that long-term VNS treatment is beneficial.6868. Müller HH, Lücke C, Moeller S, Philipsen A, Sperling W. Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients. J Clin Neurosci. 2017;44:340-1.,8282. Müller HH, Kornhuber J, Maler JM, Sperling W. The effects of stimulation parameters on clinical outcomes in patients with vagus nerve stimulation implants with major depression. J ECT. 2013;29:e40-2. Aaronson et al.5555. Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry. 2017;174:640-8. reported higher cumulative response (from 40.9 to 67.6%) and remission (from 25.7 to 43.3%) rates in a 5-year trial of 795 patients with depression. They also found a better response rate in patients treated with ECT plus VNS (71.3%) than ECT alone (56.9%), as well as decreased suicidal ideation. In open-label VNS therapy in six patients with TRD, Kucia et al.6565. Kucia K, Merk W, Zapalowicz K, Medrala T. Vagus nerve stimulation for treatment resistant depression: case series of six patients-retrospective efficacy and safety observation after one year follow up. Neuropsychiatr Dis Treat. 2019;15:3247-54. reported 53 and 40% response and remission rates, respectively, after 3 months of treatment. After 1 year of stimulation, they found a significant increase in the response rate (83%). These reports indicate that longer VNS treatment enhances the response/remission rate.

In an observational study of 124 patients, Dunner et al.8383. Dunner DL, Rush AJ, Russell JM, Burke M, Woodard S, Wingard P, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry. 2006;67:688-95. reported remission rates of 3.6 (4/112) and 7.8% (8/103) after 12 and 24 months of treatment-as-usual (TAU), respectively. A recent study found that antidepressant TAU plus VNS over 5 years resulted in a 63% (61/97) response rate vs. 39% (23/59) in the TAU-only group,6363. McAllister-Williams RH, Sousa S, Kumar A, Greco T, Bunker MT, Aaronson ST, et al. The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: a 5-year prospective registry. Int J bipolar Disord. 2020;8:13. in addition to lower suicidality. Kumar et al.6464. Kumar A, Bunker MT, Aaronson ST, Conway CR, Rothschild AJ, Mordenti G, et al. Durability of symptomatic responses obtained with adjunctive vagus nerve stimulation in treatment-resistant depression. Neuropsychiatr Dis Treat. 2019;15:457-68. also observed similar responses in their VNS + TAU cohort. According to Montgomery Asberg Depression Rating Scale (MADRS) scores, they found a 62.5% (205/328) response rate over 5 years, compared with 39.9% (108/271) in the TAU group. A meta-analysis comparing VNS + TAU (n=1,035) vs. TAU only (n=425) revealed that participants in the combined treatment group had greater response (12, 18, 28, and 32% at 12, 24, 48, and 96 weeks, respectively) and remission rates (3, 5, 10, and 14% at 12, 24, 48, and 96 weeks, respectively). Furthermore, patients who responded to VNS + TAU by the 24th week were more likely to have a sustained response at 48 weeks (odds ratio [OR] = 1.98, 95% confidence interval [95%CI] 1.34-3.01) and 96 weeks (OR = 3.42, 95%CI 1.78-7.31).8484. Berry SM, Broglio K, Bunker M, Jayewardene A, Olin B, Rush AJ. A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckland, NZ). 2013;6:17-35. Thus, adjunctive VNS could contribute to long-term response (1-5 years) in patients with TRD. VNS also resulted in clinically and statistically significant improvement in mental quality of life (QoL), physical QoL, and anxiety symptoms even if depression symptoms were not reduced.6060. Conway CR, Kumar A, Xiong W, Bunker M, Aaronson ST, Rush AJ. Chronic vagus nerve stimulation significantly improves quality of life in treatment-resistant major depression. J Clin Psychiatry. 2018;79:18m12178.,6767. Trottier-Duclos F, Jodoin VD, Fournier-Gosselin MP, Richer F, Desjardins N, Tieu S, et al. A 6-year follow-up study of vagus nerve stimulation effect on quality of life in treatment-resistant depression: a pilot study. J ECT. 2018;34:e58-60. In two TRD patients, chronic VNS stimulation after manic symptoms had been managed with standard treatments (mood stabilizers and ECT) resulted in no further mania/hypomania for up to 5 years.8585. Salloum NC, Walker MC, Gangwani S, Conway CR. Emergence of mania in two middle‐aged patients with a history of unipolar treatment‐refractory depression receiving vagus nerve stimulation. Bipolar Disord. 2017;19:60-4. As an adjunctive therapy for TRD patients with cognitive deficits, VNS improved learning and memory function after 2 years of treatment.6666. Jodoin VD, Richer F, Miron JP, Fournier-Gosselin MP, Lespérance P. Long-term sustained cognitive benefits of vagus nerve stimulation in refractory depression. J ECT. 2018;34:283-90.

VNS intensity could be associated with clinical effects. Aaronson et al.7373. Aaronson ST, Carpenter LL, Conway CR, Reimherr FW, Lisanby SH, Schwartz TL, et al. Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects. Brain Stimul. 2013;6:631-40. tested three doses of VNS (low [0.25 mA current, 130 μs pulse width], medium [0.5-1.0 mA, 250 μs], and high [1.25-1.5 mA, 250 μs]) in 331 patients with TRD over 22 weeks plus an additional 28 weeks to assess durability of response. They found a positive association between higher electrical doses and clinical response duration. VNS modulates the functional activity of cortical and subcortical brain regions,8686. Henry TR, Bakay RA, Votaw JR, Pennell PB, Epstein CM, Faber TL, et al. Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: I. Acute effects at high and low levels of stimulation. Epilepsia. 1998;39:983-90.,8787. George MS, Sackeim HA, Marangell LB, Husain MM, Nahas Z, Lisanby SH, et al. Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr Clin North Am. 2000;23:757-83. but few studies have addressed its mechanism of action. Few open-label trials of VNS have corroborated its utility in treatment-resistant anxiety disorders, bipolar depression, chronic refractory headaches, Alzheimer disease, or obesity.8888. Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014;1:64-73. Acute VNS treatment has been shown to normalize increased adrenocorticotropic hormone levels in patients who underwent a CRH challenge.7878. O’Keane V, Dinan TG, Scott L, Corcoran C. Changes in hypothalamic-pituitary-adrenal axis measures after vagus nerve stimulation therapy in chronic depression. Biol Psychiatry. 2005;58:963-8. Increased hippocampal gray matter volume following VNS treatment indicates that hippocampal remodeling is a response marker in TRD.6969. Perini GI, Toffanin T, Pigato G, Ferri G, Follador H, Zonta F, et al. Hippocampal gray volumes increase in treatment-resistant depression responding to vagus nerve stimulation. J ECT. 2017;33:160-6. While the precise mechanism of action of VNS is not fully known, pre-clinical and clinical studies suggest that it may act by modulating levels of crucial neurotransmitters and their metabolites such as dopamine, norepinephrine, gamma-aminobutyric acid (GABA), homovanillic acid, and 5-hydroxy indole acetic acid.6161. Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58:355-63.,8181. Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry. 2000;47:276-86.,8989. Carpenter LL, Moreno FA, Kling MA, Anderson GM, Regenold WT, Labiner DM, et al. Effect of vagus nerve stimulation on cerebrospinal fluid monoamine metabolites, norepinephrine, and gamma-aminobutyric acid concentrations in depressed patients. Biol Psychiatry. 2004;56:418-26.,9090. Takigawa M, Mogenson GJ. A study of inputs to antidromically identified neurons of the locus coeruleus. Brain Res. 1977;135:217-30. Pre-clinical and human research on VNS has corroborated the importance of norepinephrine and GABAergic neurotransmission.9191. Ben-Menachem E, Hamberger A, Hedner T, Hammond EJ, Uthman BM, Slater J, et al. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res. 1995;20:221-7. 92. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure‐attenuating effects of vagus nerve stimulation. Epilepsia. 1998;39:709-14.-9393. Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia. 1999;40:1051-7. VNS also stimulates the expression of c-fos, a nuclear protein that indicates excessive neuronal activation.9494. Cunningham JT, Mifflin SW, Gould GG, Frazer A. Induction of c-Fos and ΔFosB immunoreactivity in rat brain by vagal nerve stimulation. Neuropsychopharmacology. 2008;33:1884-95. Short-term VNS treatment modulates the functional activity of cortical and subcortical brain regions, such as the orbitofrontal cortex, entorhinal cortex, inferior parietal lobule, hypothalamus, thalamus, amygdala, and cingulate gyrus.8686. Henry TR, Bakay RA, Votaw JR, Pennell PB, Epstein CM, Faber TL, et al. Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: I. Acute effects at high and low levels of stimulation. Epilepsia. 1998;39:983-90.,8787. George MS, Sackeim HA, Marangell LB, Husain MM, Nahas Z, Lisanby SH, et al. Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr Clin North Am. 2000;23:757-83.,9595. Henry TR, Bakay RA, Pennell PB, Epstein CM, Votaw JR. Brain blood‐flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: II. prolonged effects at high and low levels of stimulation. Epilepsia. 2004;45:1064-70.-96. Wennberg R. Short term benefit of battery depletion in vagus nerve stimulation for epilepsy. J Neurol Neurosurg Psychiatry. 2004;75:939. 97. Lai J, David SV. Short-term effects of vagus nerve stimulation on learning and evoked activity in auditory cortex. eNeuro. 2021 Jun 2;ENEURO.0522-20.2021. doi: 10.1523/ENEURO.0522-20.2021. Online ahead of print.
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9898. Ravan M, Begnaud J. Investigating the effect of short term responsive VNS therapy on sleep quality using automatic sleep staging. IEEE Trans Biomed Eng. 2019;66:3301-9. In pre-clinical studies with models of depression, VNS treatment has also been associated with increased neuroplasticity markers, such as brain-derived neurotrophic factor (BDNF) and essential fibroblast growth factor expression, as well as mood improvement.9999. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15:7539-47.,100100. Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, et al. Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res. 2007;1179:28-34. Although Wu et al.101101. Wu CK, Tseng PT, Chen YW, Tu KY, Lin PY. Significantly higher peripheral fibroblast growth factor-2 levels in patients with major depressive disorder: a preliminary meta-analysis under MOOSE guidelines. Medicine (Baltimore). 2016;95:e4563. reported elevated levels of systemic fibroblast growth factor-2 protein and central FGFR1 RNA in major depressive disorder patients, another clinical study found unchanged plasma levels of fibroblast growth factor-2 in depressive patients.102102. Wu HE, Teixeira AL, Barroso L, Silva AP, Nicolau MS, Ferreira JD, et al. Epidermal growth factor and fibroblast growth factor-2 circulating levels in elderly with major depressive disorder. Psychiatry Res. 2019;272:141-3.

Strengths of VNS

VNS treatment plus citalopram and bupropion were found to be safe in patients with TRD, including pregnant women.8080. Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al. Vagus nerve stimulation (VNS™) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology. 2001;25:713-28. Long-term treatment with VNS resulted in depressive symptom remission in two-thirds of highly depressive patients.103103. Moeller S, Lücke C, Heinen C, Bewernick BH, Aydin M, Lam AP, et al. Vagus nerve stimulation as an adjunctive neurostimulation tool in treatment-resistant depression. J Vis Exp. 2019 Jan 7;(143). doi: 10.3791/58264.
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The incremental benefits of adjunctive VNS therapy have also been documented,6161. Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58:355-63.,6363. McAllister-Williams RH, Sousa S, Kumar A, Greco T, Bunker MT, Aaronson ST, et al. The effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: a 5-year prospective registry. Int J bipolar Disord. 2020;8:13. including detectable anti-suicidal effects and remission when applied alone or in combination with other antidepressant agents.104104. Müller HH, Moeller S, Lücke C, Lam AP, Braun N, Philipsen A. Vagus nerve stimulation (VNS) and other augmentation strategies for therapy-resistant depression (TRD): review of the evidence and clinical advice for use. Front Neurosci. 2018;12:239. VNS functioning is not affected by exposure to metal detectors, microwave ovens, mobile phones, or other electrical or electronic devices.8888. Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014;1:64-73. Although it is an invasive treatment, it is less invasive and risky than DBS or ECS, since the procedure can be performed on an outpatient basis. Significantly, no evidence of negative effects on cognition has been associated with VNS. Actually, improvement in some cognitive domains was observed, as well as reversal of depressive symptoms.8080. Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al. Vagus nerve stimulation (VNS™) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology. 2001;25:713-28.

Limitations of VNS

Since VNS may require a longer time to be effective (up to several months), it may not be an adequate option for patients in acute depressive crises, although it could be a reasonable option for patients with chronic depression.104104. Müller HH, Moeller S, Lücke C, Lam AP, Braun N, Philipsen A. Vagus nerve stimulation (VNS) and other augmentation strategies for therapy-resistant depression (TRD): review of the evidence and clinical advice for use. Front Neurosci. 2018;12:239. Implanting a stimulation device requires a surgical procedure, which can cause infection (3-6% of patients), nausea (40%), pain (33%), and anxiety (20%). While devices implanted on the vagus nerve are related to hoarseness (73%), dyspnea (47%), voice alteration, and vocal cord paresis (< 1% of patients), these potential side effects are not associated with meaningful treatment withdrawal.5353. Cristancho P, Cristancho MA, Baltuch GH, Thase ME, O’Reardon JP. Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year. J Clin Psychiatry. 2011;72:1376-82.,105105. Češková E. [Vagus nerve stimulation]. Ceska Slov Psychiatr. 2002;98:283-6.,106106. Sackeim HA, Brannan SK, Rush AJ, George MS, Marangell LB, Allen J. Durability of antidepressant response to vagus nerve stimulation (VNS™). Int J Neuropsychopharmacol. 2007;10:817-26. Horner’s syndrome, sore throat, shortness of breath, and coughing in > 10% of patients have also been reported in VNS.107107. Ben-Menachem E. Vagus nerve stimulation, side effects, and long-term safety. J Clin Neurophysiol. 2001;18:415-8. Moreover, 0.1% of patients had bradycardia and short-lived systole during initial stimulation and surgery.

Deep brain stimulation (DBS)

DBS is an invasive electrical stimulation technique approved by the FDA for treating essential tremors, Parkinson disease, dystonia, and obsessive-compulsive disorder.3232. Gardner J. A history of deep brain stimulation: technological innovation and the role of clinical assessment tools. Soc Stud Sci. 2013;43:707-28.,3333. Cook IA, Espinoza R, Leuchter AF. Neuromodulation for depression: invasive and noninvasive (deep brain stimulation, transcranial magnetic stimulation, trigeminal nerve stimulation). Neurosurg Clin N Am. 2014;25:103-16. As an experimental treatment, it is also being tested for many CNS disorders, including TRD.3434. Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2018;23:843-9.,3535. Raymaekers S, Luyten L, Bervoets C, Gabriëls L, Nuttin B. Deep brain stimulation for treatment-resistant major depressive disorder: a comparison of two targets and long-term follow-up. Transl Psychiatry. 2017;7:e1251. In this method, DBS electrodes are implanted in a target node of the brain, such as the subgenual cingulate region (SCG), ventral capsule/ventral striatum (VC/VS), nucleus accumbens (NAc), lateral habenula (LHb), inferior thalamic peduncle (ITP), or medial forebrain bundle (MFB). Structural and functional dysfunctions involving these regions have been reported in patients with depression.108108. Dandekar MP, Fenoy AJ, Carvalho AF, Soares JC, Quevedo J. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry. 2018;23:1094-112. Thus, based on clinical studies summarized in Table 2, we can say they are potential targets for interventions.

Table 2
Summary of clinical trials and case reports on DBS applied to various brain targets in TRD management

The proposed mechanism of action of DBS is to correct connectivity dysfunctions associated with clinical impairment, including those in patients with depression.133133. Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010;167:1305-20. DBS not only modulates the brain activity of the stimulated area, but distant regions through connected circuitry.115115. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651-60.,118118. Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology. 2008;33:368-77. For instance, stimulating the SCG decreases local metabolic activity while up- and downregulating remote regions through corticolimbic networks.134134. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9:471-81.-135. Hamani C, Mayberg H, Stone S, Laxton A, Haber S, Lozano AM. The subcallosal cingulate gyrus in the context of major depression. Biol Psychiatry. 2011;69:301-8. 136136. Etiévant A, Oosterhof C, Bétry C, Abrial E, Novo-Perez M, Rovera R, et al. Astroglial control of the antidepressant-like effects of prefrontal cortex deep brain stimulation. EBioMedicine. 2015;2:898-908. Stimulating the NAc regulates depression-related hypermetabolism in the SCG and prefrontal areas, which indicates functional connectivity between these two brain structures.117117. Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010;67:110-6. Meng et al.137137. Meng H, Wang Y, Huang M, Lin W, Wang S, Zhang B. Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression. Brain Res. 2011;1422:32-8. reported that DBS of the LHb region of rat brains increases the level of monoamines, including norepinephrine, dopamine, and 5-hydroxytryptamine (5-HT), in blood serum and brain tissues. Beyond metabolic and neurotransmitter changes, there are indications that DBS also modulates BDNF levels in the nervous system. However, the evidence is contradictory since both increased and decreased BDNF levels have been reported after DBS.138138. Hartmann M, Heumann R, Lessmann V. Synaptic secretion of BDNF after high‐frequency stimulation of glutamatergic synapses. EMBO J. 2001;20:5887-97.-139. Hoyer C, Kranaster L, Sartorius A, Hellweg R, Gass P. Long-term course of brain-derived neurotrophic factor serum levels in a patient treated with deep brain stimulation of the lateral habenula. Neuropsychobiology. 2012;65:147-52. 140140. Ramasubbu R, Vecchiarelli HA, Hill MN, Kiss ZH. Brain-derived neurotrophic factor and subcallosal deep brain stimulation for refractory depression. World J Biol Psychiatry. 2015;16:135-8.

DBS of the subcallosal cingulate gyrus

Pre-clinical studies involving DBS of the ventral medial prefrontal cortex (vmPFC) have shown antidepressant-like effects.137137. Meng H, Wang Y, Huang M, Lin W, Wang S, Zhang B. Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression. Brain Res. 2011;1422:32-8.,141141. Jiménez-Sánchez L, Linge R, Campa L, Valdizán EM, Pazos Á, Díaz Á, et al. Behavioral, neurochemical and molecular changes after acute deep brain stimulation of the infralimbic prefrontal cortex. Neuropharmacology. 2016;108:91-102. The rodent infralimbic cortex is assumed to be homologous to the human SCG.142142. Wallis JD. Cross-species studies of orbitofrontal cortex and value-based decision-making. Nat Neurosci. 2012;15:13-9. Hamani et al.143143. Hamani C, Diwan M, Isabella S, Lozano AM, Nobrega JN. Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats. J Psychiatr Res. 2010;44:683-7. reported that DBS of rat vmPFC or infralimbic cortex is associated with antidepressant-like effects. In addition, vmPFC stimulation has been shown to have antidepressant, anxiolytic and hedonic effects by modulating the dorsal raphe nucleus circuitry in a rodent depression model.144144. Lim LW, Janssen ML, Kocabicak E, Temel Y. The antidepressant effects of ventromedial prefrontal cortex stimulation is associated with neural activation in the medial part of the subthalamic nucleus. Behav Brain Res. 2015;279:17-21.-145. Lim LW, Prickaerts J, Huguet G, Kadar E, Hartung H, Sharp T, et al. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms. Transl Psychiatry. 2015;5:e535. 146146. Srejic LR, Hamani C, Hutchison WD. High-frequency stimulation of the medial prefrontal cortex decreases cellular firing in the dorsal raphe. Eur J Neurosci. 2015;41:1219-26. The antidepressant effect of vmPFC-DBS may be related to the modulation of prefrontal dorsal raphe nucleus projections, which are involved in serotonin synthesis and release.147147. Torres-Sanchez S, Perez-Caballero L, Mico JA, Celada P, Berrocoso E. Effect of deep brain stimulation of the ventromedial prefrontal cortex on the noradrenergic system in rats. Brain Stimul. 2018;11:222-30.

The first pioneering study of SCG-DBS in depression was conducted by Mayberg et al.115115. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651-60. In an open-label study, they reported a dramatic antidepressant response in four out of six TRD patients after 6 months. In a subsequent open-label study, Lozano et al.114114. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64:461-7. reported that SCG-DBS had an antidepressant effect in 40% of TRD patients 1-week post-stimulation (n=20), while 55-60% of patients reached the response threshold at 6 and 12 months. In their long-term (3-6 years) follow-up study, Kennedy et al.113113. Kennedy SH, Giacobbe P, Rizvi SJ, Placenza FM, Nishikawa Y, Mayberg HS, et al. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am J Psychiatry. 2011;168:502-10. reported depression score improvement of 62.5% in the1st year, 46.2% in the 2nd year, 75% in the 3rd year, and 64.3% in the 6th year. Crowell et al.109109. Crowell AL, Riva-Posse P, Holtzheimer PE, Garlow SJ, Kelley ME, Gross RE, et al. Long-term outcomes of subcallosal cingulate deep brain stimulation for treatment-resistant depression. Am J Psychiatry. 2019;176:949-56. reported that a majority of the 28 participants at their single-center experienced a robust and sustained antidepressant response in over 8 years of continuous observation after SCG-DBS. Additionally, they observed that once patients responded to DBS, they tended to stay well for 8 years, which is unusual in this degree of treatment resistance.109109. Crowell AL, Riva-Posse P, Holtzheimer PE, Garlow SJ, Kelley ME, Gross RE, et al. Long-term outcomes of subcallosal cingulate deep brain stimulation for treatment-resistant depression. Am J Psychiatry. 2019;176:949-56. In a randomized, double-blind, sham-controlled crossover study, Puigdemont et al.112112. Puigdemont D, Portella MJ, Pérez-Egea R, Molet J, Gironell A, de Diego-Adeliño J, et al. A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J Psychiatry Neurosci. 2015;40:224-31. observed improved depression scores in four out of five patients with TRD. Another double-blind, multisite, randomized, sham-controlled trial failed to find differences between active and sham stimulation after 6 months (20% response in the stimulation group vs. 17% response in the sham group).110110. Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry. 2017;4:839-49. These authors suggested that the antidepressant response to SCG-DBS may be improved by person-specific electrode implantation through brain mapping techniques such as diffusion tensor imaging tractography. Merkl et al.111111. Merkl A, Aust S, Schneider GH, Visser-Vandewalle V, Horn A, Kühn AA, et al. Deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a double-blinded randomized controlled study and long-term follow-up in eight patients. J Affect Disord. 2018;227:521-9. found no significant differences in depressive symptoms in eight patients randomized to a delayed-onset SCG-DBS group (4 weeks of sham-DBS) or non-delayed group. A meta-analysis of four retrospective trials of SCG-DBS showed response and remission levels of 36.6% (95%CI 25.8-48.9) and 16.7% (95%CI 6.3-37.5), 53.9% (95%CI 38.1-69) and 24.1% (95%CI 12.9-40.5), and 39.9% (95%CI 28.4-52.8) and 26.3% (95%CI 13-45.9) at 3, 6 and 12 months of follow-up, respectively.148148. Berlim MT, McGirr A, Van den Eynde F, Fleck MP, Giacobbe P. Effectiveness and acceptability of deep brain stimulation (DBS) of the subgenual cingulate cortex for treatment-resistant depression: a systematic review and exploratory meta-analysis. J Affect Disord. 2014;159:31-8. In recent years, advances in targeting through neuroimaging have resulted in even more positive antidepressant outcomes.3434. Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2018;23:843-9. It remains to be seen whether a new clinical trial could reproduce these findings.149149. Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008;13:663-81.-150. Riva-Posse P, Holtzheimer PE, Garlow SJ, Mayberg HS. Practical considerations in the development and refinement of subcallosal cingulate white matter deep brain stimulation for treatment-resistant depression. World Neurosurg. 2013;80:S27.e25-34. 151151. Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2018;23:843-9. Despite the fact that open-label trials have consistently demonstrated that DBS has a therapeutic effect on TRD, randomized controlled trials have not found similar results, which suggests that studies with greater power, refined techniques, and better participant selection could be necessary to achieve positive clinical outcomes.

DBS of the ventral capsule/ventral striatum

The VS is anatomically and functionally connected to brain regions such as the PFC, amygdala, and hippocampus, which are involved in regulating mood disorders, including depression.152152. Hwang JW, Xin SC, Ou YM, Zhang WY, Liang YL, Chen J, et al. Enhanced default mode network connectivity with ventral striatum in subthreshold depression individuals. J Psychiatr Res. 2016;76:111-20.,153153. Quevedo K, Ng R, Scott H, Kodavaganti S, Smyda G, Diwadkar V, et al. Ventral striatum functional connectivity during rewards and losses and symptomatology in depressed patients. Biol Psychol. 2017;123:62-73. DBS of the VC/VS has been associated with symptom improvement in patients with TRD.129129. Cassimjee N, van Coller R, Slabbert P, Fletcher L, Vaidyanathan J. Longitudinal neuropsychological outcomes in treatment-resistant depression following bed nucleus of the stria terminalis-area deep brain stimulation: a case review. Neurocase. 2018;24:231-7.,154154. Aouizerate B, Cuny E, Martin-Guehl C, Guehl D, Amieva H, Benazzouz A, et al. Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive-compulsive disorder and major depression. Case report. J Neurosurg. 2004;101:682-6. However, in a randomized sham-controlled trial of DBS of the VC/VS, Dougherty et al.120120. Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Reardon JP, et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry. 2015;78:240-8. observed 20, 26.7, and 23.3% response rates at 12, 18, and 24 months, respectively, with no significant differences between the active and sham groups.

Bergfeld et al.123123. Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhé HG, Notten P, van Laarhoven J, et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2016;73:456-64. published DBS data on 25 TRD patients who were implanted in the anterior limb of the internal capsule (ALIC), which is the caudoventral part of the VC/VS. Depressive symptoms significantly decreased after the first phase of the study, a 52-week open-label trial, and 40% of the participants were classified as responders. Sixteen patients participated in a subsequent randomized crossover phase, in which the active group benefitted more than the sham group, suggesting that chronic stimulation may be necessary for DBS therapy to be effective.123123. Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhé HG, Notten P, van Laarhoven J, et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2016;73:456-64. Two years of follow-up showed that ALIC-DBS had continued antidepressant efficacy, with the symptoms remaining stable or decreasing depending on the psychometric scale used.119119. van der Wal JM, Bergfeld IO, Lok A, Mantione M, Figee M, Notten P, et al. Long-term deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression. J Neurol Neurosurg Psychiatry. 2020;91:189-95.

DBS of the nucleus accumbens

Anhedonia, a core symptom of major depression, is associated with reduced NAc volume and reduced reward response.155155. Wacker J, Dillon DG, Pizzagalli DA. The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques. Neuroimage. 2009;46:327-37. It has been suggested that the therapeutic effect of NAc-DBS is achieved by modulating hot zones in the NAc rather than by modulating network circuitry.156156. Eggers AE. Treatment of depression with deep brain stimulation works by altering in specific ways the conscious perception of the core symptoms of sadness or anhedonia, not by modulating network circuitry. Med Hypotheses. 2014;83:62-4. Bewernick et al.116116. 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;37:1975-85. conducted a long-term open-label study on 11 patients with TRD, reporting that NAc-DBS produced a sustained antidepressant effect (45.5% response rate at 48 months follow-up). Millet et al.157157. Millet B, Jaafari N, Polosan M, Baup N, Giordana B, Haegelen C, et al. Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate. Eur Neuropsychopharmacol. 2014;24:1229-39. conducted an open-label study of six patients, three of whom presented a clinical response with no negative impact on cognitive function. While unilateral high-frequency stimulation of the NAc shell in rats did not change the depression-like phenotype compared to non-stimulated individuals,158158. Schumacher A, Haegele M, Spyth J, Moser A. Electrical high frequency stimulation of the nucleus accumbens shell does not modulate depressive-like behavior in rats. Behav Brain Res. 2020;378:112277. a number of preclinical studies have shown that depression remitted following NAc-DBS. 122122. Malone DA Jr, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65:267-75.,144144. Lim LW, Janssen ML, Kocabicak E, Temel Y. The antidepressant effects of ventromedial prefrontal cortex stimulation is associated with neural activation in the medial part of the subthalamic nucleus. Behav Brain Res. 2015;279:17-21.,145145. Lim LW, Prickaerts J, Huguet G, Kadar E, Hartung H, Sharp T, et al. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms. Transl Psychiatry. 2015;5:e535.,152152. Hwang JW, Xin SC, Ou YM, Zhang WY, Liang YL, Chen J, et al. Enhanced default mode network connectivity with ventral striatum in subthreshold depression individuals. J Psychiatr Res. 2016;76:111-20. In rodent studies, although NAc-DBS had an antidepressant effect, it impacted 5-HT and dopamine levels in the brain differently.159159. Sesia T, Bulthuis V, Tan S, Lim LW, Vlamings R, Blokland A, et al. Deep brain stimulation of the nucleus accumbens shell increases impulsive behavior and tissue levels of dopamine and serotonin. Exp Neurol. 2010;225:302-9.,160160. van Dijk A, Mason O, Klompmakers AA, Feenstra MG, Denys D. Unilateral deep brain stimulation in the nucleus accumbens core does not affect local monoamine release. J Neurosci Methods. 2011;202:113-8. Sesia et al.159159. Sesia T, Bulthuis V, Tan S, Lim LW, Vlamings R, Blokland A, et al. Deep brain stimulation of the nucleus accumbens shell increases impulsive behavior and tissue levels of dopamine and serotonin. Exp Neurol. 2010;225:302-9. reported that the effects of DBS are region-specific. They observed that stimulation of NAc increases dopamine and 5-HT levels in the NAc shell compared to its core. However, Van Dijk et al.160160. van Dijk A, Mason O, Klompmakers AA, Feenstra MG, Denys D. Unilateral deep brain stimulation in the nucleus accumbens core does not affect local monoamine release. J Neurosci Methods. 2011;202:113-8. found no change in dopamine or 5-HT levels after NAc-DBS. In a subsequent follow-up study, Van Dijk et al.161161. van Dijk A, Klompmakers AA, Feenstra MG, Denys D. Deep brain stimulation of the accumbens increases dopamine, serotonin, and noradrenaline in the prefrontal cortex. J Neurochem. 2012;123:897-903. reported that stimulating the mPFC or orbital-PFC parts of the NAc had differential effects on dopamine, 5-HT, and norepinephrine levels.

DBS of the medial forebrain bundle

DBS of the superolateral branch of the MFB has been associated with considerable improvement of depressive symptoms in patients with TRD.125125. Coenen VA, Bewernick BH, Kayser S, Kilian H, Boström J, Greschus S, et al. Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial. Neuropsychopharmacology. 2019;44:1224-32.-126. Fenoy AJ, Schulz PE, Selvaraj S, Burrows CL, Zunta-Soares G, Durkin K, et al. A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression. Transl Psychiatry. 2018;8:111. 127127. Bewernick BH, Kayser S, Gippert SM, Switala C, Coenen VA, Schlaepfer TE. Deep brain stimulation to the medial forebrain bundle for depression-long-term outcomes and a novel data analysis strategy. Brain Stimul. 2017;10:664-71. Schlaepfer et al.2828. Schlaepfer TE, Bewernick BH, Kayser S, Mädler B, Coenen VA. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry. 2013;73:1204-12. found the first clinical evidence that MFB-DBS had a rapid antidepressant effect. Their short-term study found a rapid decrease in depression severity in six out of seven patients within 2 days of bilateral MFB stimulation, and four out of seven participants had a therapeutic response 1-week post-stimulation. They continued observing all six responders for 12 to 33 weeks, and four of them recovered completely.2828. Schlaepfer TE, Bewernick BH, Kayser S, Mädler B, Coenen VA. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry. 2013;73:1204-12. Fenoy et al.126126. Fenoy AJ, Schulz PE, Selvaraj S, Burrows CL, Zunta-Soares G, Durkin K, et al. A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression. Transl Psychiatry. 2018;8:111. reported a clinical response 7 days after MFB-DBS in four out of six participants with TRD. In their follow-up publication, the same group had a > 70% decrease in MADRS scores relative to baseline at 52 weeks. In fiber tracts analysis, they observed significant common orbitofrontal connectivity to the seed region in all responders. Modulation of cortical activity following MFB-DBS, particularly in Brodmann area 10, may be critical for antidepressant effects. In another long-term MFB-DBS study by the Schlaepfer group, a stable (for 4 years) 75% decrease in depressive symptoms was found in six of eight TRD patients.127127. Bewernick BH, Kayser S, Gippert SM, Switala C, Coenen VA, Schlaepfer TE. Deep brain stimulation to the medial forebrain bundle for depression-long-term outcomes and a novel data analysis strategy. Brain Stimul. 2017;10:664-71. While the MFB-DBS results from two groups in Germany and the United States indicate that there is a rapid, robust, and impressive antidepressant effect in the majority of patients, another recent study reported that two patients had no antidepressant effects 32 weeks after stimulation.124124. Davidson B, Li DZ, Meng Y, Hamani C, Lipsman N. Psychiatric neuromodulation: the underappreciated importance of pre-and post-treatment care. Mol Psychiatry. 2020;26:366-9. The methodology used in this small sample, however, was not well described and could have contributed to the poor outcome. To date, data has been published on 22 patients who received MFB stimulation to manage depressive symptoms. Nevertheless, other clinical trials are underway (clinicaltrials.org: NCT03653858, NCT04009928, and NCT02046330),162162. Schlaepfer TE. Efficacy study of deep brain stimulation in patients with treatment resistant major depression (FORESEE III) [Internet]. 2020 Nov 2 [cited 2021 Jun 8]. clinicaltrials.gov/ct2/show/NCT03653858
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and their results are awaited with interest. To summarize, single-center open-label non-randomized studies with long-term acute application of MFB-DBS have shown clinical benefits and persistent antidepressant effects.

Some pre-clinical studies have commented on the underlying mechanisms of MFB-DBS, suggesting that it effects are significant because the MFB lies at the core of the reward pathway, connecting dopaminergic inputs from the midbrain ventral tegmental region to the PFC. In this context, Dandekar et al.163163. Dandekar MP, Luse D, Hoffmann C, Cotton P, Peery T, Ruiz C, et al. Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle. J Affect Disord. 2017;217:80-8. showed that activation of dopamine receptors in the PFC underlie antidepressant phenotypes following MFB stimulation. Similarly, increased mRNA expression of dopamine receptors D1 and D2 was reported following chronic and continuous MFB-DBS.164164. Thiele S, Sörensen A, Weis J, Braun F, Meyer PT, Coenen VA, et al. Deep brain stimulation of the medial forebrain bundle in a rodent model of depression: exploring dopaminergic mechanisms with raclopride and micro-PET. Stereotact Funct Neurosurg. 2020;98:8-20. MFB-DBS also triggered dopamine release in the distant NAc region in a rodent model of depression.165165. Vajari DA, Ramanathan C, Tong Y, Stieglitz T, Coenen VA, Döbrössy MD. Medial forebrain bundle DBS differentially modulates dopamine release in the nucleus accumbens in a rodent model of depression. Exp Neurol. 2020;327:113224. Moreover, the importance of BDNF and neuroimmune cytokines in a stress-driven chronic depression model has been described, as well as their restoration following chronic MFB-DBS treatment.166166. Dandekar MP, Saxena A, Scaini G, Shin JH, Migut A, Giridharan VV, et al. Medial forebrain bundle deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: importance of BDNF and inflammatory cytokines. Mol Neurobiol. 2019;56:4364-80.

Deep brain stimulation of the lateral habenula

The LHb region plays a key role in regulating mood, reward, motivation, and stress responses.167167. Lecourtier L, Kelly PH. A conductor hidden in the orchestra? A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition. Neurosci Biobehav Rev. 2007;31:658-72.

168. Gass N, Cleppien D, Zheng L, Schwarz AJ, Meyer-Lindenberg A, Vollmayr B, et al. Functionally altered neurocircuits in a rat model of treatment-resistant depression show prominent role of the habenula. Eur Neuropsychopharmacol. 2014;24:381-90.
-169169. Belzung C, Willner P, Philippot P. Depression: from psychopathology to pathophysiology. Curr Opin Neurobiol. 2015;30:24-30. It has been observed that electrical stimulation of the LHb is associated with improvement of depressive-like behavior in rats.170170. Friedman A, Lax E, Dikshtein Y, Abraham L, Flaumenhaft Y, Sudai E, et al. Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior. Neuropharmacology. 2010;59:452-9. In a preclinical study of LHb-DBS, acute 5 Hz stimulation resulted in significant depressive-like behavior, while high frequency (100 Hz) stimulation reduced despair and anxiety responses, was well as increased hedonic-like effects.171171. Jakobs M, Pitzer C, Sartorius A, Unterberg A, Kiening K. Acute 5 Hz deep brain stimulation of the lateral habenula is associated with depressive-like behavior in male wild-type Wistar rats. Brain Res. 2019;1721:146283. Sartorius et al.131131. Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry. 2010;67:e9-11. reported persistent remission of depressive symptoms following LHb-DBS for 4 months in one TRD patient. In a pre-clinical study, Meng et al.137137. Meng H, Wang Y, Huang M, Lin W, Wang S, Zhang B. Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression. Brain Res. 2011;1422:32-8. reported that LHb-DBS significantly improved norepinephrine, dopamine, and 5-HT levels in peripheral and brain regions after 28 days of therapy, which partially explains its therapeutic mechanism of action.

DBS of the inferior thalamic peduncle

The ITP is a collection of fibers that connects the non-specific thalamic system to the orbitofrontal cortex. This system induces electrocortical activation and helps suppress input from irrelevant stimuli.172172. Velasco F, Velasco M, Jiménez F, Velasco AL, Salin-Pascual R. Neurobiological background for performing surgical intervention in the inferior thalamic peduncle for treatment of major depression disorders. Neurosurgery. 2005;57:439-48.,173173. Velasco M, Velasco F, Jiménez F, Carrillo-Ruiz JD, Velasco AL, Salín-Pascual R. Electrocortical and behavioral responses elicited by acute electrical stimulation of inferior thalamic peduncle and nucleus reticularis thalami in a patient with major depression disorders. Clin Neurophysiol. 2006;117:320-7. The ITP is an emerging therapeutic target in the treatment of TRD and other neuropsychiatric disorders. Jiménez et al.132132. Jiménez F, Nicolini H, Lozano AM, Piedimonte F, Salín R, Velasco F. Electrical stimulation of the inferior thalamic peduncle in the treatment of major depression and obsessive compulsive disorders. World Neurosurg. 2013;80:S30.e17-25. reported a decrease in Hamilton Depression Rating Scale (HAM-D) scores (from 42 to 6) in one TRD patient following ITP-DBS.

DBS of the bed nucleus of the stria terminalis

The BNST is a complex brain region spreading from the NAc to the amygdala. Some recent studies have reported using BNST-DBS to treat TRD. In an open-label case series on TRD patients, Fitzgerald et al.128128. Fitzgerald PB, Segrave R, Richardson KE, Knox LA, Herring S, Daskalakis ZJ, et al. A pilot study of bed nucleus of the stria terminalis deep brain stimulation in treatment-resistant depression. Brain Stimul. 2018;11:921-8. found 20 and 60% response rates at 6 and 12 months, respectively, after treatment with BNST-DBS. Another case study found a marked reduction in psychiatric distress and improved cognition after 1 year of BNST-DBS.129129. Cassimjee N, van Coller R, Slabbert P, Fletcher L, Vaidyanathan J. Longitudinal neuropsychological outcomes in treatment-resistant depression following bed nucleus of the stria terminalis-area deep brain stimulation: a case review. Neurocase. 2018;24:231-7. In another case study, one patient with anorexia nervosa and depression was first treated with MFB-DBS for 2 years and was then shifted to BNST stimulation.130130. Blomstedt P, Naesström M, Bodlund O. Deep brain stimulation in the bed nucleus of the stria terminalis and medial forebrain bundle in a patient with major depressive disorder and anorexia nervosa. Clin Case Rep. 2017;5:679-84. After 12 months of BNST-DBS, the patient presented marked improvement in depressive scores (MADRS = 13 from 43 and HAM-D = 6 from 22). In a double-blind crossover study, the effects of BNST and ITP-DBS were assessed in seven TRD patients.3535. Raymaekers S, Luyten L, Bervoets C, Gabriëls L, Nuttin B. Deep brain stimulation for treatment-resistant major depressive disorder: a comparison of two targets and long-term follow-up. Transl Psychiatry. 2017;7:e1251. The outcomes during the two crossover periods in the first 16 months after surgery suggested that the effects of BNST stimulation were better than those of ITP stimulation. Three years after implanting the DBS device, all patients were stimulated in the BNST. Five of seven patients responded, and two were in remission. The improvement after BNST-DBS was more gradual but substantial. Due to the limited number of investigations, the efficacy of DBS at the two targets was not compared. The authors concluded that both BNST and ITP stimulation may alleviate depressive symptoms in patients with TRD.

Strengths of DBS

DBS has an advantage over non-invasive techniques in that it can precisely target critical nodes of brain circuitry.108108. Dandekar MP, Fenoy AJ, Carvalho AF, Soares JC, Quevedo J. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry. 2018;23:1094-112.,174174. Mehdorn HM, Goebel S, Falk D, Volkmann J, Leplow B, Pinsker MO. Deep brain stimulation for movement disorders and its neuropsychological implications. Acta Neurochir Suppl. 2008;101:9-12. A meta-analysis found a significant reduction of depression scores in DBS studies that targeted the SCG (-3.02; 95%CI -4.28 to -1.77, p < 0.00001), ALIC (-1.64; 95%CI -2.80 to -0.49, p = 0.005), NAc (-1.30; 95%CI -2.16 to -0.44, p = 0.003), and MFB (-2.43; 95%CI -3.66 to -1.19, p = 0.0001).175175. Zhou C, Zhang H, Qin Y, Tian T, Xu B, Chen J, et al. A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 2018;82:224-32. Many clinical trials have confirmed the long-term safety and efficacy of the DBS. As with VNS, when weighing the cost and potential complications of implanting hardware, it should be pointed out that in patients who receive continuous stimulation (with either VNS or DBS) the response is maintained for years. This is particularly important in TRD patients, who have very high rates of relapse even if they respond to non-invasive treatments. Around 160,000 patients worldwide have received DBS treatment for various neurological and psychiatric disorders, including TRD. Given the heterogeneity of depression, the optimal node may vary according to the patient’s clinical and neurobiological characteristics. Yu et al.176176 174. Yu M, Cullen N, Linn KA, Oathes DJ, Seok D, Cook PA, et al. Structural brain measures linked to clinical phenotypes in major depression replicate across clinical centres. Mol Psychiatry. 2021 Feb 15. doi: 10.1038/s41380-021-01039-8. Online ahead of print.
10.1038/s41380-021-01039-8...
investigated the structural brain measures associated with clinical phenotypes in depression. A total of 213 clinical items were assessed in patients with major depression, which yielded four groups: anxious misery, positive personality traits, reported history of emotional and physical abuse/neglect and reported history of sexual abuse. These clusters were associated with particular cortical thickness/subcortical volumes. For example, the authors found that while the anxious misery cluster was negatively associated with a cortical thickness/subcortical volume in the middle cingulate gyrus and posterior cingulate gyrus, the positive trait cluster was positively correlated with a cortical thickness/subcortical volume in the same regions. Whether these findings can help determine specific neuromodulation targets for different depression phenotypes is still unknown and worth investigation.176176 174. Yu M, Cullen N, Linn KA, Oathes DJ, Seok D, Cook PA, et al. Structural brain measures linked to clinical phenotypes in major depression replicate across clinical centres. Mol Psychiatry. 2021 Feb 15. doi: 10.1038/s41380-021-01039-8. Online ahead of print.
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A proof-of-concept study on personalized DBS to treat depression found different emotional responses depending on the target region in a severe TRD patient who was implanted multisite intracranial electrodes across corticolimbic circuits.177177. Scangos KW, Makhoul GS, Sugrue LP, Chang EF, Krystal AD. State-dependent responses to intracranial brain stimulation in a patient with depression. Nat Med. 2021;27:229-31.

Limitations of DBS

DBS is highly invasive and expensive, and its implantation and follow-up require a multidisciplinary team. Some potential side effects include bleeding, infection, paresthesia, muscle contraction, dysarthria, diplopia, hypomania, and anxiety.116116. 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;37:1975-85.,178178. Grubert C, Hurlemann R, Bewernick BH, Kayser S, Hadrysiewicz B, Axmacher N, et al. Neuropsychological safety of nucleus accumbens deep brain stimulation for major depression: effects of 12-month stimulation. World J Biol Psychiatry. 2011;12:516-27. Most studies are open-label, have small samples, and do not have a sham-control group. Of note, this technique has been tested in two clinical trials, and both failed to demonstrate its efficacy. A Dutch study on DBS of the VC/VS found that depression returned when stimulation was discontinued.123123. Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhé HG, Notten P, van Laarhoven J, et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2016;73:456-64. However, this is not the same as conducting a double-blind placebo-controlled trial, such as that of Reclaim & Broaden, which failed.120120. Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Reardon JP, et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry. 2015;78:240-8. MFB-DBS has not yet been tested in this manner.

Epidural cortical stimulation

ECS has been employed to selectively activate the dorsolateral prefrontal cortex (DL-PFC) and frontopolar cortex regions of TRD patients.4141. Nahas Z, Anderson BS, Borckardt J, Arana AB, George MS, Reeves ST, et al. Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Biol Psychiatry. 2010;67:101-9.,4343. Williams NR, Short EB, Hopkins T, Bentzley BS, Sahlem GL, Pannu J, et al. Five-year follow-up of bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Brain Stimul. 2016;9:897-904.,6262. Kopell BH, Halverson J, Butson CR, Dickinson M, Bobholz J, Harsch H, et al. Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery. 2011;69:1015-29. In this NT modality, the stimulating electrodes are directly positioned over these cortical areas. In a open-label study of ECS, Nahas et al.4141. Nahas Z, Anderson BS, Borckardt J, Arana AB, George MS, Reeves ST, et al. Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Biol Psychiatry. 2010;67:101-9. reported a 60% (3 of 5 patients) response rate after 7 months of follow-up (Table 1). Kopell et al.6262. Kopell BH, Halverson J, Butson CR, Dickinson M, Bobholz J, Harsch H, et al. Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery. 2011;69:1015-29. recruited 12 patients for a randomized, single-blind, sham-controlled open-label trial and reported ≥ 40% improvement in 6 of 12 patients, ≥ 50% improvement in 5 of 12 patients, and < 10% improvement in 4 of 12 patients 104 weeks after left dorsolateral PFC stimulation. Williams et al.4343. Williams NR, Short EB, Hopkins T, Bentzley BS, Sahlem GL, Pannu J, et al. Five-year follow-up of bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Brain Stimul. 2016;9:897-904. published 5 years of data on five TRD patients treated with frontopolar cortex ECS and DL-PFC stimulation. They reported uniform response rates (41.2-54.9) between 7 months and 5 years of ECS. These results suggest that ECS has long-term efficacy as a TRD treatment. Williams et al.4343. Williams NR, Short EB, Hopkins T, Bentzley BS, Sahlem GL, Pannu J, et al. Five-year follow-up of bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Brain Stimul. 2016;9:897-904. also reported some adverse events, such as infection in one patient and device malfunction in four patients. These data indicate that chronic bilateral ECS over the frontopolar cortex and DL-PFC could be a promising technique for TRD treatment. Taken together, evidence from 2 groups with a total of 19 patients appears to indicate that ECS may be beneficial in TRD treatment, although large trials are necessary to confirm this.

Strengths of ECS

Electrical stimulation with this method is a unique therapeutic approach, which selectively triggers the cortex without interference from the scalp and skull. This method is probably safer and is less invasive than DBS since it does not require penetration of the dura.179179. Williams NR, Sudheimer KD, Bentzley BS, Pannu J, Stimpson KH, Duvio D, et al. High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain. 2018;141:e18.

Limitations of ECS

Device implantation may lead to infection at the wound site (3-6% of patients). Stimulating the left DL-PFC with ECS is still ambiguous due to the broad area it covers. Moreover, the precise site of electrode implantation during ECS has not been fully standardized in order to maximize the efficacy of the treatment.180180. Pathak Y, Kopell BH, Szabo A, Rainey C, Harsch H, Butson CR. The role of electrode location and stimulation polarity in patient response to cortical stimulation for major depressive disorder. Brain Stimul. 2013;6:254-60.

Conclusions

There is growing therapeutic potential for invasive neuromodulation that targets mood neurocircuitry. Given that ∼ 30% of depressive patients fail to fully respond to interventions, such as pharmacotherapy and psychotherapy, or to non-invasive neuromodulation approaches, such as ECT or repetitive transcranial magnetic stimulation, alternative treatment options, such as ECS, VNS, and DBS, have been considered.4141. Nahas Z, Anderson BS, Borckardt J, Arana AB, George MS, Reeves ST, et al. Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression. Biol Psychiatry. 2010;67:101-9.,8787. George MS, Sackeim HA, Marangell LB, Husain MM, Nahas Z, Lisanby SH, et al. Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr Clin North Am. 2000;23:757-83.,114114. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64:461-7. While the clinical results of invasive NTs trials related to TRD management are still inconclusive, several clinical brain stimulation studies have documented rapid and robust antidepressant effects. Importantly, no major side effects have been reported in long-term invasive NTs trials.181181. Marangell LB, Martinez M, Jurdi RA, Zboyan H. Neurostimulation therapies in depression: a review of new modalities. Acta Psychiatr Scand. 2007;116:174-81.,182182. Taghva AS, Malone DA, Rezai AR. Deep brain stimulation for treatment-resistant depression. World Neurosurg. 2013;80:S27.e17-24. Long-term VNS treatment resulted in a dramatic remission of depressive symptoms in two-thirds of depressive patients. For DBS, targets such as the SCG, NAc, VC/VS or ALIC, MFB, LHb, ITP, and BNST have been identified as critical nodes for TRD management. Although ECS is an alternative invasive treatment option, only a few cases have been reported and larger trials are needed to confirm its potential for TRD. Based on current data, invasive NTs may be considered a promising therapy for TRD. However, additional randomized and double-blind clinical trials with a greater number of patients will provide more meaningful information on the safety and efficacy of each stimulation method. It is likely that an in-depth understanding of the neurobiology of TRD may lead to precise and personalized treatments, improving the safety and efficacy of invasive NTS.

Acknowledgements

MPD and ZR authors would like to thank the Department of Pharmaceuticals, the Ministry of Chemicals and Fertilizers, the Government of India, and the National Institute of Pharmaceutical Education and Research of Hyderabad for financial support. The Translational Psychiatry Program (United States) is funded by a grant from the National Institute of Health/National Institute of Mental Health (1R21MH117636-01A1, to JQ). The Center of Excellence on Mood Disorders (United States) is funded by the Pat Rutherford Jr. Chair in Psychiatry, the John S. Dunn Foundation, and the Anne and Don Fizer Foundation Endowment for Depression Research. The Translational Psychiatry Laboratory (Brazil) is funded by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), and the Instituto Cérebro e Mente.

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Publication Dates

  • Publication in this collection
    30 Aug 2021
  • Date of issue
    May-Jun 2022

History

  • Received
    13 Mar 2021
  • Accepted
    22 Apr 2021
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