Elsevier

Brain, Behavior, and Immunity

Volume 87, July 2020, Pages 910-920
Brain, Behavior, and Immunity

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

https://doi.org/10.1016/j.bbi.2020.02.016Get rights and content

Highlights

  • Non-convulsive neurostimulation is an alternative depression treatment.

  • Systematic review of endocrine and immune effects of non-convulsive neurostimulation in depression.

  • Non-convulsive neurostimulation reverted HPA axis and cytokines changes found in depression.

  • Promise shown for non-convulsive neurostimulation in treating multiple facets of depression.

  • Further research, including blinded, sham-controlled comparator designs required.

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Introduction

How non-convulsive neurostimulation impacts the Hypothalamic-pituitary-adrenal (HPA) axis and its main output cortisol in depression is an open question. Similarly, the alterations in immune function that may accompany such treatments are largely unknown. Two systematic reviews examined the response of the HPA axis to repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS) in depression in bids to identify biological markers that associate with symptom response in clinical trials (Fidalgo et al., 2014, Sampaio et al., 2012). A pattern of mixed effects on HPA axis function and cortisol levels was detected: while Sampaio et al. (2012) concluded that rTMS treatment may play a role in restitution of normal HPA axis function during treatment, Fidalgo et al. (2014) noted that such restitution did not occur in all studies examined, even when a reduction in depressive symptoms co-occurred. As these works both focussed on biological markers used in previously published clinical trials, neither examined non-convulsive neuro-stimulatory modalities beyond rTMS and tDCS, nor did they report on immune parameters that changed in response to rTMS or tDCS.

In addition to rTMS and tDCS, Vagal Nerve Stimulation (VNS), Deep Brain Stimulation (DBS) and electroacupuncture are all interventions that mediate their effect on depressive symptoms without inducing an electroencephalographic seizure. Lower risk for side effects compared with Electro-convulsive Therapy (ECT) - the gold-standard neuro-stimulatory intervention (Milev et al., 2016) - and increasing accessibility of non-convulsive neurostimulation treatments means that understanding how non-convulsive treatments impact the endocrine and immune aberrations present in depression is important. Such knowledge could be used to generate greater pathophysiological understanding of depression and perhaps identify neural circuits that impact endocrine and immune function in both health and disease.

The increased pace of investigation into the use of non-convulsive neurostimulation as a treatment for depression, combined with the lack of a comprehensive review of the multiple impacts that these treatments have on the HPA axis and the immune system, motivated our systematic review of all studies that quantified HPA axis activity and/or immune activity (in the form of cytokine production) in depression and how these systems responded to rTMS, tDCS, VNS, DBS or electroacupuncture. Since many of these techniques are not widely used in clinical practice, we also review studies that used animals to investigate these interventions and their impact on HPA signaling and immune activation in depression. We highlight this developing area of study and identify how non-convulsive neurostimulation contributes to restitution of normal HPA axis and immune function in depression.

Section snippets

Methods

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009, Liberati et al., 2009).

Search results

128 articles were retrieved by our search. Full-text review revealed that 94 of these articles used ECT exclusively. These articles were excluded from further analysis (Fig. 1). After removal of duplicates, we identified 34 articles for further detailed review, 22 that reported data from humans and 12 that reported data from animal models (Fig. 1). 15 human rTMS studies were retrieved. 6 of these studies were subsequently excluded, 2 because they measured neither the HPA axis nor cytokine

Discussion

True to our supposition that the scope of the literature on our research question would be limited, a small number of studies was identified (Fig. 1). This contrasts with the relative wealth of literature examining the impact of ECT on endocrine and immune function in depression (Yrondi et al., 2018, Guloksuz et al., 2014). The majority of human studies retrieved in our work tested the impact of rTMS. This is perhaps not surprising as rTMS has gained significant traction as a low-barrier

Conflicts

AJP: None.

CMP: research funding from Janssen Pharmaceutical NV/Janssen Pharmaceutical Companies of Johnson & Johnson; speaker’s fees from Lundbeck and consultation fees from Eleusis Benefit Corporation.

Acknowledgements

We thank Dr. Cai Song for clarifying data presented in one of the included articles.

Funding

AJP is the recipient of career development funding from the Province of British Columbia through the Clinician Investigator Program at the University of British Columbia (UBC), the Detweiler Travelling Fellowship from the Royal College of Physicians and Surgeons of Canada, and the Friedman Award for Scholars in Health from UBC. CMP is supported by grants from Immunopsychiatry: a Consortium to Test the Opportunity for Immunotherapeutics in Psychiatry (MR/L014815/1) and the Medical Research

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