Support for using VNS for TRD came from a multitude of investigations and observations. Harden et al23 and Elger et al24 prospectively evaluated epileptic patients with standard depression symptom severity rating scales. They found that VNS was associated with statistically significant improvements in mood that were not related to reductions in seizures.23,24
The mechanism of action of VNS is not clear. Earlier researchers had found evidence that VNS affected brain regions associated with norepinephrine25 and serotonin systems26; both of these neurotransmitters have been implicated in the pathophysiology of depression. Positron emission tomography studies conducted during VNS treatment of epilepsy showed metabolic changes in cortical and subcortical areas of the brain, including the amygdala, hippocampus, and cingulate gyrus, all structures implicated in the pathophysiology of mood disorders.27
Most studies conducted to evaluate the efficacy of VNS have been observational, looking at depression ratings before and after treatment with VNS. The short-term studies measured the difference in depression rating scales at baseline and after 10 weeks of treatment. In most of these studies, treatment with VNS resulted in a statistically significant drop in depression rating scales scores, such as on the Hamilton Depression Rating Scale (HAM-D). Based on the study design and number of study participants, response rates have varied from 13%28 to 40%,29 whereas remission rates have varied from 15.3%30 to 28%.31 More than one-half of the reduction in symptoms occurred after 6 weeks of treatment.30 In longer-term follow-up studies, the antidepressant effect generally was sustained over time. Response rates remained essentially unchanged, but the remission rates increased to approximately 29%.29 Only 1 RCT has compared patients with controls; it found no significant differences in the response or remission rates between active VNS and sham VNS.32 In this study, all patients had VNS implanted, but in the control group, the VNS was never turned on.32 In a meta-analysis conducted by Martin and Martín-Sánchez,33 31.8% (95% confidence interval [CI], 23.2% to 41.8%; P < .001) of patients treated with VNS had a significant reduction in HAM-D scores. The response rate in patients with TRD ranged from 27% to 37% and the remission rate was approximately 13%. In studies that followed patients over longer periods, both the remission and response rates increased over time.34
Recent evidence suggests that the effectiveness of VNS may depend on the stimulation level. A multi-center double-blind study randomized patients to receive either a low (0.25 mA current, 130-millisecond pulse width), medium (0.5e1.0 mA, 250 millisecond), or high (1.25e1.5 mA, 250 millisecond) dose of VNS.35 Although all dose levels were associated with improvement in symptoms, a statistically significant durability in response was associated with the medium- and high-dose treatments.
Adverse effects. VNS has no major adverse effects on cognitive functioning, and some studies have found improvement in executive functioning that corresponded to improvement in depressive symptoms.30 VNS also may result in improved sleep patterns as evidenced by EEG changes.31 The most commonly reported adverse effects include pain in the incision site, hoarseness of voice, throat pain, and neck pain.36