VNS for treatment-resistant depression

History

Interest in the effects of vagus nerve stimulation (VNS) on the central nervous system began in the early 20th century, with Bailey and Bremer demonstrating in 1938 that electrical stimulation of the vagus nerve of cats resulted in increased electrographical activity of cortical structures ( ). Dell and Olson discovered a suggestive link between the vagus nerve and affective disorders in 1951 in their own study of cats, demonstrating an evoked response in the amygdala in response to vagal stimulation ( ). As a clinical intervention, VNS was first investigated for its potential role in treating epilepsy. Beginning in the 1980s, began animal experiments that demonstrated VNS’s ability to both terminate acute seizure activity and prevent seizures chronically with continuous stimulation. The first human implanted VNS device occurred in 1988 by Penry and Dean in four patients with intractable partial seizures, of whom two obtained complete seizure control ( ). VNS for medication refractory epilepsy received approval in Europe in 1994 and in the United States in 1997 ( ).

These epilepsy trials suggested a potential role for VNS in the treatment of depression. Reports of improved mood and cognition in patients receiving VNS for epilepsy came out of the trials used to gain VNS’s initial United States Food and Drug Administration (FDA) approval ( ). The role of anticonvulsant medications, including carbamazepine, lamotrigine, and valproate, in the treatment of mood disorders further hinted at a common mechanism underlying treatments for epilepsy and depression. Perhaps, researchers suspected, VNS would provide the same shared benefit.

Initially, this hypothesis gained strength through undercontrolled clinical observations in patients whose mood improved after receiving VNS for epilepsy ( ; ). These observations developed into more rigorously designed interventions exploring mood in epilepsy patients who had received VNS—several of which supported VNS’s mood-improving effects ( ; ; ).

The first VNS device was implanted specifically for depression in 1998 at the Medical University of South Carolina as part of a multicenter pilot trial which further established VNS’s antidepressant effects ( ). On the basis of four clinical trials in patients who had failed two to six treatments for their unipolar or bipolar depression (considered to be treatment-resistant depression (TRD)) which included a feasibility trial ( ); a randomized, sham-controlled 3 month-clinical trial ( ); a long-term open-label extension of the 3-month randomized trial ( ); and a long-term observational study comparing subjects receiving standard-of-care treatments with subjects receiving VNS ( ), the United States Federal Drug Administration (FDA) granted approval for the use VNS in treatment-resistant depression in 2005 even though the 3-month randomized controlled trial did not show significance in the primary depression outcome measure. This unusual determination was largely due to the absence of proven effective alternatives for this treatment-resistant population.

Subsequently, in 2007, the United States Center for Medicare and Medicaid Services (CMS) decided against coverage of VNS for TRD. This decision was based on the failure of the initial randomized controlled trial (RCT) to demonstrate separation in response between the active VNS group and the sham VNS group during the first 12 weeks of treatment. Subsequent years of research would reveal that the length of stimulation time required for VNS to achieve clinical efficacy is far longer than this 12-week endpoint—closer, in fact, to 6 months to 1 year ( ; ). Nevertheless, the adoption of vagus nerve stimulation since its initial approval for depression has been impeded by this early trial as well as by a later dose-finding trial in which subjects were randomized to low-, medium-, or high-dose stimulation ( ). While this study built on the results of the earlier RCT and made the primary end point 6 months after implantation, the efficacy of even modest, low-dose stimulation hampered demonstration of significantly improved efficacy of higher doses, though each group showed remarkable improvement. Most private insurers have followed the CMS decision and also do not cover the significant costs associated with the VNS device and surgical implantation. Costs of the device and implantation have been estimated at about $28,000; however, further economic analysis has suggested that, 8 years after device implantation, savings associated with VNS for TRD may be in the range of $23,000–$41,000 ( ). Despite these potential savings, the noncoverage determination placed VNS largely out of reach of the typical patient suffering from treatment-resistant depression during the first decade of its FDA approval ( ).

Researchers have continued investigating VNS’s efficacy for TRD in intervening years. To date, some 5000 patients have been implanted with VNS devices for treatment of depression in various clinical trials ( ). Notable among this body of literature is the VNS for TRD registry, which was established by LivaNova, the manufacturer of the VNS device, as part of the FDA’s initial approval in 2005 ( ). This registry followed 500 patients who had received VNS for TRD and 300 who received treatment as usual for over 5 years. report on these patients suggested improvements in depression in those with VNS compared to those receiving treatment as usual. As a result of these findings, CMS reopened its noncoverage decision in 2018. Currently, VNS for TRD falls under the “coverage with evidence development” category, indicating CMS’s participation in funding a new randomized controlled trial to further development of the VNS for TRD’s evidence base ( ).

The VNS device and its mechanism of action

The vagus nerve comprises a complex web of efferent and afferent fibers involved in diverse bodily functions, including autonomic control, motor action, and various sensory modalities. VNS targets the afferent fibers of the left cervical vagus nerve, which carry visceral, somatic, and gustatory sensation to the brainstem ( ). While the precise mechanism of action of VNS in depression is not entirely understood, there are several anatomical and neurobiological theories that help elucidate its antidepressant effects.

The VNS device

VNS entails surgical placement of electrode coils around the left vagus nerve. The device itself includes the stimulating electrodes, a pulse generator which serves as a battery and provides current to the electrodes, and electrode extenders which connect the electrodes to the pulse generator ( ; ; ) ( Fig. 21.1 ).