Vagus Nerve Stimulation in HIV-Associated Depression

Depression is the top comorbidity in HIV-positive adults, with prevalence rates that are 3 to 4 times higher than those in the general population.^1,2 Although standard pharmacologic and psychotherapeutic interventions are effective in reducing symptoms in a substantial percentage of patients, up to 30% of patients are resistant to such treatments.

Both HIV and depression are associated with proinflammatory states, likely due to chronic activation of stress responses that impair the functioning of the central nervous system (CNS). Elevated proinflammatory cytokines and reduced brain-derived neurotrophic factor (BDNF) have been observed in both diseases.^,34 This leads to neuroendocrine and neuroimmunologic dysregulation marked by a collection of symptoms known as “sickness behavior” —  impaired sleep and appetite, fatigue, mood and cognitive disturbances, social withdrawal, pain, psychomotor disturbance, apathy, and anhedonia.⁵

These are the most common symptoms seen in patients with comorbid HIV and depression. This “sickness state” is believed to be induced by the production of cytokines as a result of chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathomedullary system — all of which are mediated by chronic disruption of the vagus nerve (VN) in response to ongoing stress.

“The VN is a major component of the autonomic nervous system, which influences neuronal, endocrine, and immune functions (neuroendocrine-immune axis) via its efferent (motor) and afferent (sensory) pathways,” as explained in a recent review published in Neuropsychiatric Disease and Treatment.⁶ “The vagal cholinergic anti-inflammatory pathway (CAP) interacts with the CNS, and is primarily responsible for sickness behavior.”

Stimulation of the VN evokes an anti-inflammatory response by regulating cytokine expression, which can reverse sickness behavior, suggesting that treatment approaches targeting the VN could prove useful in HIV-associated depression. Implantable vagus nerve stimulation (iVNS) received US Food and Drug Administration (FDA) approval in 2005 as an intervention for treatment-resistant depression. Research findings pertaining to iVNS and treatment-resistant depression have been promising but mixed overall; although combined findings from 21 studies on the topic support the effectiveness of the approach, there have been few randomized controlled trials, and further research is needed before firm conclusions can be drawn.

Transcutaneous VNS (tVNS) is a simpler, nonsurgical approach that does not require an implanted device; instead, bilateral electrodes are placed on the outer ear. This allows “researchers to bypass the limitations of traditional iVNS and enable more rigorous clinical trials,” the researchers wrote, and it may offer an effective and more convenient and cost-effective treatment in patients with HIV and treatment-resistant depression.

The review covered the results of studies that examined the effectiveness of tVNS in treating depression. In one single-blind trial, participants received active (n=18) or sham (n=16) tVNS twice daily for 5 days per week throughout a 1-month period.⁷ Changes in scores on the Hamilton Depression Rating Scale indicated a ≤50% reduction in depressive symptoms in the active group, which were corroborated by fMRI findings revealing improved functional connectivity in the default-mode brain network implicated in depression. Similar results were noted in a nonrandomized study published in 2012, and results of additional studies also supported the effectiveness of tVNS for depression, with no significant side effects.⁸

Psychiatry Advisor spoke with one of the meta-analysis investigators to learn more about the proposed mechanisms underlying the apparent depression-relieving effects of VNS, as well as the clinical implications of their findings and future research needs. Chance Nicholson, MSN, PMHNP-BC, is a PhD student at the University of Alabama at Birmingham, and an instructor at the school of nursing.