Krahl et al.[17] showed that lesioning the locus ceruleus in rats eliminates the ability of VNS to suppress seizures. It was also demonstrated that after chronically either depleting the norepinephrine in the locus ceruleus by infusing 6-hydroxydopamine into the structure bilaterally, the acute anti-seizure effects of VNS was reversed. Ben-Menachem et al.[18] reported increase in cerebrospinal fluid (CSF) concentration of Gamma-amino-butyric acid (GABA), and 5-hydroxy-indole-acetic acid, as well as simultaneous decrease in the concentrations of glutamate and aspartate in 16 patients following VNS. These seem to advocate a neurotransmitter mechanism of the ability of VNS to suppress seizures. Cerebral blood flow theory Henry et al.

,[19] in 1998, showed that cervical vagus nerve stimulation caused bilateral alteration in blood flow to the cortex, thalamus, hippocampus, amygdala, and posterior cingulate gyri, and may activate inhibitory structures in the brain. Depression It is predicted that by the year 2030, depression would become one of the major disease burdens to humanity, second only to human immunodeficiency virus (HIV).[20] The major challenge here is that the etiopathogenesis of depression is not clearly understood; being multi-factorial and as such developing effective treatment has been a challenge to both the research and pharmacology community. Interestingly, it has been shown that depressed patient, who received vagus nerve stimulation for epilepsy, showed clinical improvement with depression unrelated to the effect of the VNS on their seizures. Rush et al.

,[21] in a multi center trial, reported 40-50% improvement in patients with non-psychotic major depression. VNS has been approved by the Food and Drug Administration, USA for treatment-resistant depression July 2005. Bajbouj et al.,[22] 2010, in a two-year outcome review involving 74 patients, reported a 53.1% response and 38.9% remission with VNS treatment in major depression. In an Editorial by Ashton A.K. 2010,[23] it was duly pointed out that patients relapsed into clinical depression after explantation of vagus nerve stimulator. Hence, it is evident that VNS for treatment-resistant depression has been proven to be beneficial as an adjunct therapy. Mechanism of action of vagus nerve stimulator for depression Alterations in several neurotransmitters have been noted in depression, particularly serotonin, norepinephrine, and dopamine. However, there is inadequate understanding of the exact pathophysiology of clinical depression. In the same light, the exact mode of action Entinostat of VNS for depression is not clearly understood. The possible hypotheses are explained.