Vagus nerve stimulation for treatment resistant depression: Current status and future research directions

Mario Savino, Mario Miniati, Giuseppe Messina, Giovanni Broggi

Research output: Contribution to journalArticlepeer-review


Background and significance. Treatment-resistant depression (TRD) is common in clinical practice. At least 10-20% of all depressed patients do not have satisfactory sustained responses to pharmacotherapy, psychotherapy or both. Moreover, treatment resistance may increase with episodes recurrence or episode duration [1]. ECT for patients suffering for depression who did not previously respond to psychopharmacological treatments is widely utilized. Less common is the use of other treatments, such as deep brain stimulation (DBS), transcranial magnetic stimulation (rTMS) or vagal nerve stimulation (VNS). VNS has received the Food and Drug Administration (FDA) approval for treatment-resistant major depression. VNS has been also approved for a CE mark (indicating compliance with safety and environmental regulations) in the member countries of the European Union for treatment of adults with treatment-resistant or treatment-intolerant chronic or recurrent depression, including unipolar and bipolar depression. The rationale for considering vagus nerve stimulation (VNS) as potentially effective long-term treatment for patients with a chronic and highly recurrent resistant depression is based on the following observations: (a) patients with resistant epilepsy treated with VNS improve also in mood and cognition; (b) brain imaging studies demonstrate that the afferent part of vagus nerve is linked to limbic structures and to other neurological pathways, whose functions are altered in depressed patients; (c) neurochemical studies in animals and humans reveal that the concentrations of monoamines are changed by VNS. Aim of this review is to summarize current knowledge in VNS for treatment resistant unipolar and bipolar depression. Methods. This review report on two main topics of the clinical literature relating to VNS in treatment-resistant depression, namely: (1) to identify the antidepressant mechanisms of action of VNS; (2) to evaluate response, sustained response, remission, and safety of VNS in samples of patients with treatment-resistant depression. Results. (1) Studies on antidepressant mechanisms of VNS. The precise mechanism by which VNS influence depressive symptomatology has been extensively investigated, but it is not yet fully understood. Available studies are mainly based on three hypotheses: (a) VNS increase noradrenaline: VNS has been shown to result in a long-lasting increase in release of noradrenaline in the basolateral amygdala, the origin of which could be the locus coeruleus, in receipt of projections from the nucleus of the solitary tract. Alternatively, It is also possible that noradrenaline in the amygdala is increased by the direct projections of the noradrenergic neurons of the nucleus of the solitary tract, which project to the amygdala, as well as the locus coeruleus [2]. (b) VNS affect the firing rate of hippocampal neurons: It has been observed that both chronic treatment with antidepressant medication and ECT cause an increase in BDNF in the hippocampus of animal models. Furthermore, BDNF protects against stress-induced neuronal damage and affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders leading to a neurotrophin hypothesis of antidepressant action [3,4]. In a recent study, the question whether BDNF serum concentrations in therapy-resistant depressed patients change during a 4-week treatment with VNS has been addressed [5]. However, no changes on BDNF serum concentrations and no association of neurotrophin concentrations in serum with clinical parameters were found, suggesting that VNS, in contrast to several antidepressant medications, do not change BDNF serum concentrations. (c) Recently, It has been hypothesized also that the antidepressant action of VNS is related to a corrective influence on "negativity biases" the in memory of depressed patients, namely on the over-representation of negative thoughts and memories, underlying that VNS could modulate the activity within orbito-frontal, ventro-medial, polar pre-frontal, and mid-cingulate cortices [6]. (2) Studies on efficacy and safety of VNS in treatment-resistant depression. To our knowledge, of the original articles that have investigated the anti-depressant properties of VNS in human patients, five papers reported on the longitudinal effects of VNS in the same patient cohort. With one exception all the studies concluded that VNS improved mood. The only study that did not find any significant improvement of mood with VNS investigated the anti-depressant effects of VNS in a cohort of epileptic patients; whereas, in the other studies the patients were clinically depressed but without a history of epilepsy [7]. The first study of the effects of VNS in patients with depression was published in 2000 [8]. It was an open-label, multicenter pilot study, conducted on a sample of 30 patients with a DSM-IV diagnosis of major depressive disorder (MDE), or bipolar I/II disorders. Data obtained from this study, prompted the US FDA to approve the 1-year clinical trial to follow the same 30 patients over an additional 9 months. The response rate was defined as at least 50% reduction in baseline Hamilton rating score. The observed response rate was 40%, and the remission rate (Hamilton rating score

Original languageEnglish
Pages (from-to)23-24
Number of pages2
JournalInternational Journal of Psychiatry in Clinical Practice
Issue numberSUPPL. 1
Publication statusPublished - May 2007

ASJC Scopus subject areas

  • Psychiatry and Mental health


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