Endocrine and immune effects of non-convulsive neurostimulation in depression: A systematic review

Non-convulsive neurostimulation is a rapidly-developing alternative to traditional treatment approaches in depression. Modalities such as repetitive Transcranial Magnetic Stimulation (rTMS), transcranial Direct Current Stimulation (tDCS), Vagal Nerve Stimulation (VNS) and Deep Brain Stimulation (DBS) are now recognized as potential treatments. How non-convulsive neurostimulation interventions impact the neurohormonal and neuroimmune changes that accompany depression remains relatively unknown. If this type of intervention can drive endocrine, immune, as well symptom changes in depression, non-convulsive neurostimulation may represent a viable, multi-faceted treatment approach in depression. We were therefore interested to understand the state of the literature in this developing area. A systematic review of all studies that examined the impact of non-convulsive neurostimulation interventions on the hypothalamic-pituitary-adrenal (HPA) axis and immune function in the form of cytokine production in depression. We identified 15 human studies, 9 that examined rTMS, 2 that examined tDCS, 2 that examined VNS and 2 that examined electroacupuncture. 11 animal studies were also identified, 3 that examined rTMS, 2 that examined DBS and 6 that examined electroacupuncture. All types of non-convulsive neurostimulation were able to revert the increases in cortisol, ACTH and other components of the HPA axis that are seen in depressed patients, as well as to modulate the levels of key cytokines known to be up-regulated in depression, such as IL-1β, IL-6 and TNF-α. Changes in the HPA axis and levels of cytokines in response to non-convulsive neurostimulation often did not correlate with change in depressive symptoms. Most studies were not controlled trials and thus, significant methodologic variability existed. Furthermore, many human studies lacked a sham stimulation comparator arm. We were unable to conduct relevant meta-analyses due to the design heterogeneities, heterogeneity in the reported outcome measures and the limited number of studies retrieved. Animal studies generally supported the findings of those in human, but again, significant variability in methodology and study design were evident. Non-convulsive neurostimulation interventions show promise in their ability to alter the endocrine and immune disturbances that accompany depression. Further research, which includes blinded, sham-controlled comparator designs is required.