Severe depression may lead, in many cases, to life threatening suicidal behavior and / or  treatment-resistant depression (TRD).

Activation of the central nervous system via electrical stimulation of peripheral nerves has become known as the “bottom-up” mechanism, which is a hypothesis based on the neurobiology of the vagus nerve and its effects on neural activity.

The  FDA approved VNS treatment for chronic depression and TRD (Kucia et al., 2019), as  tVNS has been found to be particularly effective in patients  who have not responded well to other forms of antidepressant treatment,  such as selective serotonin reuptake inhibitors (SSRIs). It has also been found to be effective for people with atypical depression, which is a subtype of depression characterized by weight gain, sleepiness, and sensitivity to rejection.

VNS affects many of the same brain areas, neurotransmitters (serotonin, norepinephrine) and signal transduction mechanisms (brain-derived neurotrophic factor–tropomyosin receptor kinase B) as those found with traditional antidepressants (Carreno and Frazer, 2017).

In terms of efficacy, tVNS has shown promising results in the treatment of depression;  a number of studies have demonstrated that tVNS can reduce the symptoms of depression and improve overall mood.

VNS modulates the concentrations of neurotransmitters (especially serotonin, norepinephrine, GABA and glutamate) and their metabolites associated with the pathophysiology of depression,  while producing changes in the functional activity of CNS regions. This  mode of action of VNS is similar to that of most antidepressants, such as SSRIs. (Müller et al., 2018).

The vagus nerve is involved in the regulation of mood and stimulation thereof  has  shown to have antidepressant effects in some people. Interestingly, changes in regional cerebral blood flow induced by VNS are similar to those found in depressed patients treated with selective serotonin reuptake inhibitors (fluoxetine) either in the amygdala, hippocampus, or parahippocampus (Yap et al., 2020).

In the hippocampal plasticity hypothesis of depression, chronic stress leads to atrophy and synaptic changes in the limbic brain. VNS increases the expression of neurotrophic and growth factors – brain derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) which promote the neuroplasticity, ie, the formation and differentiation of neurons, decreased in mood disorders (Müller etal., 2018).