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MedGenMed. 2007; 9(4): 62.
Published online Dec 20, 2007.
PMCID: PMC2234325

Improved Mood and Remission of Symptoms in Long-term Major Depression Using Vagus Nerve Stimulation

Amita R. Patel, MD, CMD, MHA, CPE, Clinical Associate Professor and Shannon M. Wozniak, NP, Adjunct Clinical Instructor

Abstract

This is a case study of a 68-year-old woman with previously unremitting depression. The patient came to our care in 1994 following a series of treatment interventions that did not alter the course of chronic depression. We report our treatment approach and results seen with this patient, including her tepid response to traditional antidepressants and the positive results seen in the past year using vagus nerve stimulation (VNS) therapy. The patient experienced broad gains in measures of depression severity and well-being under her current treatment regimen. She has had no serious adverse events associated with the regimen, which includes VNS therapy and decreased doses of common antidepressant medications.

Introduction

Major depressive disorder (MDD) affects about 18 million people in the United States,[1] and most patients who have one major depressive episode are likely to have another within 5 years.[2] Overall, as many as 20% of patients with major depression do not respond to 2 or more adequate treatment regimens for depression.[3,4] The treatment options for these patients have traditionally been limited. Treatment typically entails trials of different antidepressants, and in severe cases, use of electroconvulsive therapy (ECT). But this type of “treatment as usual” often fails to bring about remission. One prospective study looked at the long-term outcomes of patients with treatment-resistant depression (TRD) who continued with ongoing “treatment as usual.” After 2 years, more than 90% of the 124 patients continued to experience substantial levels of depressive symptoms; 65% showed no response at any point and 81% showed no remission at any point.[5]

These findings suggest that the vast majority of patients with TRD do not experience long-term benefits from traditional therapeutic strategies. These patients continue to have decreased quality of life and the debilitating symptoms associated with major depression.

A relatively little-known treatment for TRD, vagus nerve stimulation (VNS Therapy™, Cyberonics, Houston, Texas), was approved by the US Food and Drug Administration for this indication in July 2005.[6] The therapy consists of an implanted, disk-shaped generator that provides timed and measured pulses via electrodes to the left vagus nerve. The stimulation dose is set by using an external telemetric wand and software to stimulate the vagus nerve at regular intervals. During routine office visits, physicians can adjust the timing and amount of stimulation the patient receives (Figure). Because of its nature, the therapy assures patient adherence.

Figure
Diagram of vagus nerve stimulation device. (A) A small pacemaker-like pulse generator is implanted under the skin in the left chest area. Timed and measured pulses are generated and pass through a thin, flexible wire to electrodes that stimulate the left ...

VNS therapy is indicated for patients 18 years of age or older who are unable to achieve sustained remission after 4 or more adequate trials of antidepressants. A 10-week randomized, controlled study of 235 outpatients with long-term unresponsive MDD (n = 210) or bipolar disorder (n = 25) reported a higher response among patients receiving VNS therapy than among those receiving sham therapy on the 24-item Hamilton Rating Scale for Depression (HRSD24), the patients receiving VNS also had a statistically significant response on the Inventory of Depressive Symptomatology-Self-Report (IDS-SR30).[7] A 12-month naturalistic follow-up study compared the effect of a full year of adjunct VNS therapy in all 205 evaluable patients, with those previously receiving sham therapy switched to active therapy. The primary analysis revealed a significant reduction in HRSD24 scores over time and at exit (mean monthly improvement 0.45; P < .001) as well as significant reductions over time in IDS-SR30 scores (mean monthly improvement, 0.52; P < .001).[8] These findings suggest that the benefit of VNS therapy may not be realized until several months into therapy.

Patients in this pivotal trial of VNS therapy were a mean 46.5 years of age and had a mean duration of illness of 25.5 years.[8] Could the therapy be effective for a considerably older woman with a duration of illness longer than most of the study sample? We report the case of a postmenopausal woman with long-standing MDD and a history of poor response to antidepressants and ECT. Her condition was further complicated by comorbid conditions, including obesity, hypertension, hypercholesterolemia, gastroesophageal reflux disease, hypothyroidism, and osteoarthritis.

Case Report

J.F. is a 68-year-old married white woman with a 32-year history of treatment-resistant MDD. Her early treatment included ineffectual trials of tricyclic antidepressants, serotonin reuptake inhibitors, and dual-action antidepressants as well as adjunctive treatments with antipsychotic agents and anxiolytics. By November 1988, J.F. had been hospitalized 5 times. She was recommended for and received ECT. Although her suicidality initially remitted, she remained depressed and required further ECT in January 1989.

By the time she was referred to our office in September 1994, J.F had had MDD with chronic dysthymic symptoms, characterized by feelings of worthlessness, low self-esteem, and a daily lack of energy and motivation, for 20 years. During a major depressive episode in January 1995, she was treated aggressively with maximum doses of dual-action antidepressants in combination with serotonergic agents. She showed a partial response and was augmented with methylphenidate (Ritalin).

J.F.'s low-grade depressive symptoms did not fully remit. Over the next 10 years, she was prescribed alternative medications, which frequently were ineffective or caused unacceptable side effects. Her primary maintenance drug regimen consisted of high doses of venlafaxine hydrochloride (Effexor XR) (up to 375 mg SID), trazodone hydrochloride (Desyrel) 150 mg QHS, clonazepam (Klonopin) 0.5 mg TID, and Ritalin 20 mg TID. She had episodes of major depression for 3 to 6 months every year, during which doses were adjusted and alternative medications tried. During February 2001, ECT was again administered, but improvements in mood were transient and did not result in a meaningful decrease in antidepressant medications.

The patient's long course of treatment-resistant major depressive episodes made her a strong candidate for VNS therapy. She and her family were counseled and expressed a desire to proceed with the new treatment. In February 2006, J.F. underwent VNS therapy device implantation; stimulation was activated during an office visit later that month. At the time, J.F. was receiving Ritalin 20 mg TID, Klonopin 0.5 mg QID, bupropion (Wellbutrin SR) 100 mg TID, duloxetine hydrochloride (Cymbalta) 60 mg QAM, and zolpidem tartrate (Ambien CR) 12.5 mg QHS. Within 4 months, the patient noted substantial improvements in mood. By July 2006, the current had been titrated up to an output of 1.25 mA, standard signal frequency of 30 Hz, pulse width of 500 microseconds, and signal time of 30 seconds on and 5 minutes off.

Improvements in J.F.'s mood and quality of life were measured by physician observation, clinical signs and symptoms, changes in daily functioning, and the patient's own account. Twelve months since initiation of VNS therapy, J.F. seems to be in complete remission and she no longer meets criteria for major depression nor shows evidence of chronic dysthymic disorder. J.F. demonstrates a significant increase in energy and motivation without the use of stimulant medication, and she notes a higher activity level in her daily life and “around the house.” At age 68, she describes a fullness of mood and energy levels not experienced since her mid-30s. In conversation she is more spontaneous and verbalizes her feelings better. Although voice alteration is the most commonly reported side effect with VNS therapy, J.F. has experienced no adverse events.

Perhaps the most significant improvement since device activation has been the reduction from 5 to 3 medications. The patient is now maintained on antidepressant monotherapy. Augmentation with Wellbutrin and Ritalin has been discontinued, which reduces her risk for serious cardiovascular side effects in light of her comorbid conditions. Frequency of Klonopin 0.5 mg has been reduced to 3 times a day. The patient had been experiencing frequent falls, but these have decreased in conjunction with the reduction in medication. The profound improvements experienced by J.F. appear to signal the utility of VNS therapy for major depression in older women with a longstanding history of treatment failure.

Discussion

Treatment-resistant depression occurs in a substantial proportion of people with MDD. The negative effects of chronic depression on daily activities are well documented. In addition, chronic depression is associated with a lower quality of life, a history of suicide attempts, and generalized anxiety disorder.[9] Despite the predominance of several classes and types of antidepressants to treat depression, evidence-based treatment options for patients with TRD are limited. In the case reported here, J.F. had had chronic depression for more than 3 decades despite aggressive treatment. She had been hospitalized on numerous occasions to gain control of her symptoms. Treatment was further complicated by comorbid conditions, which were managed with various medications.

Depression can present differently in geriatric patients with TRD, with predominant symptoms of irritability and anxiety as well as multiple somatic complaints. As is the case with J.F., older patients also commonly have a higher incidence of medical conditions that puts them at risk for potential medication interaction and side effects. J.F. experienced frequent falls and other side effects associated with her complex antidepressant regimen. Any therapy that could reduce the number of medications, and by extension any side effects from these medications, is especially welcome in the geriatric population.

VNS therapy has been approved by the FDA for use in cases like J.F.'s. It is certainly not for everyone – indeed, the prospective patient should have experienced 4 or more unsuccessful adequate trials of antidepressants before consideration. Our experience has shown that immense strides in patient well-being may be achieved using VNS therapy for unremitting depression. Yet, despite its very good tolerability profile, VNS therapy remains relatively unknown compared with commonly prescribed antidepressants, such as selective serotonin reuptake inhibitors. Given the data we are now seeing that point toward decreasing chances of response in successive (failed) trials of antidepressants, psychiatrists and other health care providers who treat patients with chronic depression need to be aware of every treatment option available.

Acknowledgments

The authors thank IntraMed Educational Group for providing editorial support on behalf of Cyberonics.

Footnotes

Reader Comments on: Improved Mood and Remission of Symptoms in Long-term Major Depression Using Vagus Nerve Stimulation See reader comments on this article and provide your own.

Readers are encouraged to respond to the authors at moc.oohay@dmletapatima and moc.oohay@kainzownonnahs or to Paul Blumenthal, MD, Deputy Editor of MedGenMed, for the editor's eyes only or for possible publication as an actual Letter in MedGenMed via email: ude.drofnats@nemulbp

Contributor Information

Amita R. Patel, Wright State University, Boonshoft School of Medicine, Dayton, Ohio. Author's email: moc.oohay@dmletapatima.

Shannon M. Wozniak, Wright State University, Miami Valley College of Nursing and Health, Dayton, Ohio. Author's email: moc.oohay@kainzownonnahs.

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6. US Food and Drug Administration. Centers for Devices and Radiological Health. New Device Approval. VNS Therapy System - P970003s050. Available at: www.fda.gov/cdrh/mda/docs/p970003s050.html Accessed December 4, 2007.
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