VNS in the treatment of major depression VNS was recently demonstrated to have an antidepressant effect in a rat model, significantly better than sham treatment, and similar to other antidepressant treatments (desipramine or ECS).190 During the past 5 years, Sackeim, Rush, and colleagues have published results of open and randomized controlled studies of VNS in the treatment of major depression. A preliminary open study of VNS in 60 patients with treatment-resistant

Inhibitors,research,lifescience,medical nonpsychotic major depressive episode revealed a response rate of 30% to 38% by 10 weeks of treatment.191 A 2-year Gefitinib chemical structure follow-up of this open study found a response rate of 40% to 44% after 1 year and 42% after 2 years, and Inhibitors,research,lifescience,medical a remission rate of 27% after 1 year and 22% after 2 years.192,193 A randomized controlled study of VNS in over 200 patients with treatment-resistant, nonpsychotic, major depressive episode showed that acute treatment (10 weeks) yielded a response rate of 15% that was similar to the response rate with sham treatment (10%). 194 After the acute treatment, all patients (VNS and sham groups) received

long-term treatment with VNS for another 12 months. This was associated with a response rate of 27% and a remission rate of 16%. 195 The response rate in the group of patients who were receiving VNS plus medication or ECT for a year (27%) was significantly Inhibitors,research,lifescience,medical better than the response rate of a similar Inhibitors,research,lifescience,medical but nonrandomized group of patients with treatment-resistant

depression who were receiving only medication or ECT for a year (response rate was only 13 %).196 Adverse effects The most common side effects of VNS are voice alteration or hoarseness (55%), coughing (17%), shortness of breath (15%), headache Inhibitors,research,lifescience,medical (22%), neck pain (17%), dysphagia (20%), and pain (15%). Although most side effects usually resolve within a few weeks, voice alteration and dyspnea might persist for long periods. Reduction in current intensity decreases the severity of these symptoms.191 Mechanism of action VNS most probably alters synaptic activities at vagal afferent terminations, stimulates deep brain areas, and thus modulates antidepressant neuronal circuits in multiple limbic system structures. Brain imaging studies reveal some of these suspected brain changes. Metalloexopeptidase PET measurements of cerebral blood flow in 10 patients with epilepsy before and during acute VNS treatment (both low- and high- stimulation VNS) demonstrated increased blood flow in the rostral, dorsal-central medulla, the right postcentral gyrus, bilaterally in the hypothalami, thalami, and insular cortices, and in the cerebellar hemispheres inferiorly Decreased blood flow was demonstrated bilaterally in hippocampus, amygdala, and posterior cingulate gyri.184 Similar changes in cerebral blood flow were also demonstrated during prolonged VNS treatment.