Brain Stimulation 10 (2017) 997e1000
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Sustained remission in patients with treatment-resistant depression receiving vagal nerve stimulation: A case series VNS implantation, experienced an average of over nine years of sustained antidepressant remission. Keywords: Vagus nerve stimulation Treatment-resistant depression Major depressive disorder
Dear Editor, One third of patients suffering from major depression fail to respond to available standard treatments [1] and are considered treatment-resistant major depression (TRMD). TRMD is associated with reduced quality of life, disability, high rates of co-morbid illnesses, and substantially increased resource utilization [2]. Left cervical vagus nerve stimulation (VNS) via an implantable electrical pulse generator is a well-tolerated, FDA-approved treatment for TRMD. Although a subset of patients experience relatively rapid antidepressant response to VNS (within 1e2 months), most TRMD patients experience antidepressant benefit only after many months of stimulation (6e24 months) [3,4]. A critical challenge in the management of TRMD patients is to sustain antidepressant remission and minimize relapse. Results from the largest clinical depression trial to date, the Sequenced Treatment Alternatives to Relieve Depression or STAR*D, demonstrated that the likelihood of both remitting and maintaining remission for one year in patients at levels 3 and 4 of the trial was disappointingly low (5% and 3% respectively [5]). Existing data on the antidepressant effect of VNS supports that those responding to VNS maintain the response at one and two years [3,4]. A recently published observational study compared antidepressant outcomes in 795 patients with TRMD, including 494 patients receiving VNS for 60 months [6]. This study demonstrated -vis a 5-year cumulative remission rate of 43.3% with VNS (vis-a 25.7% in the treatment-as-usual group). Now that the FDA approval of VNS for TRMD is greater than a decade old (2005), we can begin to assess if VNS can sustain antidepressant effects beyond 5 years. We currently report a series of six TRMD patients with wellcharacterized pre-treatment histories of TRMD, who, following
http://dx.doi.org/10.1016/j.brs.2017.06.001 1935-861X/Published by Elsevier Inc.
Methods We recruited six subjects with DSM IV-diagnosed major depressive disorder and documented histories of TRMD, who have been receiving VNS with regular follow-up at Washington University. These subjects have previously participated in prospective studies conducted at Washington University and St. Louis University as part of multicenter VNS TRMD trials [6e8]. The study was approved by the Washington University Institutional Review Board, and all patients provided written informed consent. Data were extracted from chart review, archived data from the original studies, and a one-time in-person interview (last reported data) during which a battery of assessments and rating scales were performed including the Montgomery-Åsberg Depression Scale (MADRS, reported here) and a customized illness burden questionnaire. Analyses were limited to descriptive statistics, means and standard deviations. Results All subjects (four males, two females, mean age 60.3) were Caucasian, highly educated (mean: 4.2 years post secondary), with a primary diagnosis of MDD, mean age of onset of 29.3 and mean pre-implantation duration of illness of 20.5 years. On average, the sample had 0.8 previous psychiatric hospitalizations and 8.5 documented failed, adequate dose-duration antidepressant trials (50% failed electroconvulsive therapy [ECT] and 50% failed monoamine oxidase inhibitor [MAO-I] treatment). Psychiatric comorbidities were rare: one subject had alcohol use disorder (in remission) and another had an unspecified anxiety disorder. Of note, there was a strong family history of alcohol dependence (100% of the sample had a first-degree relative with alcohol dependence) and mood disorders (80% of the sample had a first-degree relative with a mood disorder). Table 1 presents the clinical course and characteristics of each subject; Fig. 1 graphically depicts depression symptomology (MADRS) scores at various time points. VNS electrical settings were as follows (Mean ± SD): Output current ¼ 0.83 ± 0.4 mA, signal frequency ¼ 20 ± 0 Hz, and pulse width ¼ 293 ± 169 ms.
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Table 1 Clinical course and characteristics by subject. Subject
Age
Gender
Pre-VNS Duration of Illness (years)
Longest Remission pre-VNS (years)
MDE pre-VNS (years)
Total time in remission post-VNS (years)
Post-VNS course
A
63
Male
33
0.5
5
6
B
66
Male
19
2.5
8
6.3
C
54
Male
15
0.5
0.4
6.5
D
54
Female
21
0.75
0.5
8.3
E
57
Male
16
0.25
2.4
14
F
68
Female
19
0.25
1.2
14.3
Subject remitted at 6 months and has been in full remission since. He started his own business and makes regular missionary trips to Africa. Subject remitted at 3 months and sustained remission for 3 years. In post-implantation year 3, he was diagnosed with prostate CA with re-emergence of depressive symptoms. His MDD symptoms resolved spontaneously after successful cancer treatment. He then regained full remission status for the following two years (until present), without adjunctive pharmacotherapy. Subject responded at 3 months followed by remission at 6 months. 3 years later, he relapsed after a VNS battery failure, which was replaced at month 44. He returned to remission 10 months later; has been in full remission for 6.5 years. Subject had a rapid remission within 3 months and remained in remission for the following 8 years. She currently is on one antidepressant medication-down from four different pre-VNS psychotropics. Subject gradually improved after 9 months of VNS; remission achieved at 12 months. He relapsed after 3.8 years, following a device lead break [10] not depicted in figure, as MADRS scoring was not taken during this interval. At 2 weeks post-surgical device replacement, he again achieved and has since sustained remission. Subject remitted at 3 months followed by a short relapse at 7 months and back into remission at 9 months. She has now been in full remission for more than 14 years.
The mean total time in remission post-VNS was 9.2 years with no reported suicidal ideation or attempts, and no post-implantation psychiatric hospitalizations, except one subject admitted overnight for severe anxiety after mirtazapine initiation (spontaneously resolved). Discussion To our knowledge, this is the first description of chronic and sustained antidepressant effects of VNS for TRMD beyond five years duration. The TRMD subjects in this case series experienced nearly a decade of full remission after VNS implantation, with some being symptom-free for more than 14 years. Several noteworthy observations emerge from these cases. First, all had a well-documented history of severe TRMD prior to VNS, with an average of more than twenty years of chronic symptoms, very short inter-episodic remissions, and multiple failed treatment trials. These sustained VNS-associated responses are quite unusual among TRMD patients, as STAR*D found that antidepressant resistance was associated with a very high rate of relapse following responses to treatments [5]. This persistent antidepressant efficacy may suggest that VNS is acting via different pathways than antidepressant medications. Second, the subjects have heavy family histories of depressive illness and alcoholism. The latter finding is particularly interesting as family history of alcohol use disorder has been previously associated with antidepressant response to ketamine in TRMD [9]. Third, VNS antidepressant efficacy appears to
be resilient: in three of the six cases (B, C, and E in Table and Fig. 1) device-related interruption of stimulation (C and E) or major medical illness (prostate cancer with chemotherapy) led to reemergence of depression. Once repaired/restored to health, all three patients regained full remission. One of these cases (E) has been previously described [10]. There are several limitations to this case series. We acknowledge the selection bias in this sample, i.e., we knowingly selected TRMD patients who had sustained VNS antidepressant response. We do not intend to suggest that all TRMD patients will have a similar response, but rather, to demonstrate that a subset of patients, with histories of well-characterized, severe, and prolonged TRMD can achieve protracted antidepressant remission with VNS. Additionally, the absence of formalized rating scales performed beyond the period of the clinical trials in which the subjects were enrolled poses another limitation. However, we did access regular clinic notes and interviews, as well as patient recall, to retrace the subjects' illness trajectory to date. In summary, this case series demonstrates a persistent and potentially “near permanent” antidepressant response to VNS in the treatment and maintenance of at least some patients with severe TRMD. Funding sources The registry studies were sponsored by Cyberonics, Inc., makers of the VNS device. Dr. Conway has received research support from
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Fig. 1. MADRS Scores Across Treatment Time Points By Patient. Graphic depiction of course of depressive illness over time for all six VNS-implanted TRMD patients. Patients C and E experienced interrupted VNS: C experienced battery expiration; E with a device lead break with subsequent replacement (return of depressive symptoms during lead break not depicted, as no MADRS data was available at this time). MADRS ¼ Montgomery Åsberg Depression Rating Scale.
Bristol-Myers Squibb, the Stanley Medical Research Institute (14T010), the National Institute of Mental Health (K08 Award 1K08MH078156-01A1 and R21 Award 1R21MH108901-01A1), NeoSync, Inc., Brain & Behavior Research Foundation, McDonnell Center for Systems Neuroscience, Cyberonics, Inc., (all not related
to the subject matter of the paper); The Taylor Family Institute for Innovative Psychiatric Research, The August Busch IV Foundation, and Barnes-Jewish Hospital Foundation. He has served as an unpaid consultant to Cyberonics, Inc. Other authors report no research funding.
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Acknowledgments We would like to thank Dr. John Chibnall for assisting us in the creation of the graphs, and the participants for sharing their histories and experiences. References [1] 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(11):1905e17. [2] Corey-Lisle PK, Birnbaum HG, Greenberg PE, Marynchenko MB, Claxton AJ. Identification of a claims data “signature” and economic consequences for treatment-resistant depression. J Clin Psychiatry 2002;63(8):717e26. [3] 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(6):817e26. [4] 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(9):1097e104. [5] Conway CR, George MS, Sackeim HA. Toward an evidence-based, operational definition of treatment-resistant depression: when enough is enough. JAMA Psychiatry 2017;74(1):9e10. [6] 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
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response, remission, and suicidality. Am J Psychiatry 2017 March 31. appiajp201716010034, http://dx.doi.org/10.1176/appi.ajp.2017.16010034. 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(5):355e63. 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(4):631e40. Niciu MJ, Luckenbaugh DA, Ionescu DF, Guevara S, Machado-Vieira R, Richards EM, et al. Clinical predictors of ketamine response in treatmentresistant major depression. J Clin Psychiatry 2014;75(5):e417e23. Conway CR, Chibnall JT, Tait RC. Vagus nerve stimulation for depression: a case of a broken lead, depression relapse, revision surgery, and restoration of patient response. Brain Stimul 2008;1(3):227e8.
Naji C. Salloum, Britt M. Gott, Charles R. Conway* Department of Psychiatry, Washington University in St. Louis, 660 S. Euclid Ave, Campus Box #8134, St. Louis, MO, USA *
Corresponding author. E-mail address:
[email protected] (C.R. Conway). 15 May 2017 Available online 8 June 2017
