Clinical effectiveness of non-TMS neurostimulation in depression: Clinical trials from 2010 to 2020
Introduction
Major depressive disorder (MDD) is an incapacitating illness associated with significant personal, social, and economic impairment that affects over 300 million people worldwide (Leigh et al., 2018). Patients with MDD present lower quality of life and higher prevalence of medical conditions (Kessler et al., 2003). About half of these patients undergo a new depression episode later in life, and one-third are treatment-resistant (Weel-Baumgarten et al., 2000). Many patients do not tolerate the side effects and end up discontinuing pharmacological treatments (McIntyre et al., 2013). The development of alternative non-pharmacological methods of treatment for MDD is essential as this disorder is a recurrent condition. As a result of the increased understanding of the neural circuitry and neurobiology of major psychiatric disorders, investigators have developed new treatments that directly stimulate the brain with the goal of symptom improvement.
The use of “neuromodulation” for depressive disorders can be traced back to late 1938 with the advent of the use of electroconvulsive therapy (ECT), which involves the electrical induction of a generalized seizure (Kopell et al., 2011). The terms neuromodulation and neurostimulation have been used to describe procedures that use magnetic or electrical stimulation on the brain to treat psychiatric or neurological disorders through cortical activity modulation (Freire et al., 2018). The term neurostimulation is more adequate for those treatments, since neuromodulation is also applied to neurobiological changes from chemicals and drugs (Freire et al., 2018). Although the word stimulation is used it does not necessarily connote increasing neuronal firing rates within a functional circuit. Depending on the brain region, nature and depolarization state of the neurons targeted and stimulus characteristics such as frequency and train pattern, the external stimulation may result in excitation or inhibition of a functional circuit (Pandurangi et al., 2012).
All forms of neurostimulation have acute effects, which occur during the stimulation, and aftereffects, which occur in a period ranging from a few minutes to several months. In treatments administered in sessions, such as ECT, magnetic seizure therapy (MST), and transcranial direct current stimulation (tDCS), for instance, the acute effects and the aftereffects are unambiguous (Freire and Nardi, 2018). In methods with continuous stimulation, such as deep brain stimulation (DBS) and vagus nerve stimulation (VNS), it is hard to distinguish between acute effects and aftereffects (Freire and Nardi, 2018). Evidence indicates that the therapeutic benefits of neurostimulation are due to these lasting effects, which include changes in neuronal excitability, neurogenesis, changes in glial function, gene activation/regulation, de novo protein synthesis, morphological changes, homeostatic processes, neuroendocrine changes, and changes in neurotransmitters (Freire and Nardi, 2018). Without a doubt, neurostimulation is not a one size-fits-all approach. The heterogeneity of structure, synapses, and excitability throughout the nervous system necessitates customization of stimulation location, amplitude, duration, mode, and frequency (Pancrazio, 2018). Neurostimulation methods may be noninvasive, such as transcranial direct/alternating current stimulation (tDCS/tACS), repetitive transcranial magnetic stimulation (TMS), ECT, MST and trigeminal nerve stimulation (TNS), or invasive, VNS, deep DBS and epidural cortical stimulation (EpCS).
ECT and TMS are approved by the United States Food and Drug Administration (FDA) and are an evidence-based treatment for MDD (Grunhaus et al., 2002; Medda et al., 2009; McClintock et al., 2017; O'Reardon et al., 2008). Recent findings on TMS have already been extensively reviewed (Brunoni et al., 2017; Sonmez et al., 2018; Hung et al., 2019; Gellersen and De Santis, 2019; Voigt et al., 2019) and therefore, TMS was not included in the current review. MST, tDCS, DBS, EpCS and VNS are mainly experimental treatments for depressive disorders; clinical trials with these techniques are scarce. The FDA has approved VNS only for adult patients with severe or recurrent treatment-resistant depression (TRD); the other treatment modalities have not received FDA approval (Freire et al., 2018).
Neurostimulation is an active area of clinical research with extensive literature surrounding this subject. This article focuses on summarizing and discussing recent evidence regarding the therapeutic aspects of non-TMS neurostimulation in MDD patients, based on clinical trials available from 2010 to 2020.
Section snippets
Search strategy and selection criteria
This systematic review was conducted in accordance with the reporting guidelines of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (Moher et al., 2009). Articles were identified by a search of electronic records, including the databases from MEDLINE/PubMed, the Cochrane Library, PsycINFO and Thomson Reuters's Web of Science. The search terms used were: (“major depressive disorder” OR “major depression” OR “depressive disorder”) NOT (“bipolar disorder” OR
Results
The database searches were conducted in March of 2020 and yielded 250 articles in CENTRAL, 449 articles in PsycINFO, 407 in MEDLINE/PubMed and 691 in Web of Science. The sum of articles after removing the duplicates was 1152; after screening, 293 articles remained. Reviewers examined the full-texts and only 20 articles met the inclusion criteria. The inter-rater agreement was substantial, with a free marginal kappa coefficient of 0.74. The process of study identification and selection is shown
Discussion
This systematic review aimed to identify the efficacy of antidepressant effects of neurostimulation in major depressive disorder. This study brought together a total of 20 studies, including 10 studies with tDCS, 3 studies with DBS, 2 studies with TNS, 2 studies with MST, 1 study with VNS, 1 study with EpCS and 1 study with tACS.
Conclusion
Technological advances and new knowledge about the dysfunction of the brain circuits has led to the development of various neurostimulation techniques. Evidence from research done in the last 10 years has shown promising results with regards to non-TMS neurostimulation treatments for MDD and TRD patients, although there are still few studies of head-to-head comparisons. The studies published in the past decade had many limitations as most clinical trials had a small sample size and were open
Author contributions
MMZ and RF are responsible for the conception and design of the study. MMZ and MF were responsible for data acquisition. All authors contributed to the analysis and interpretation of results. All authors reviewed the final draft of the manuscript.
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declaration of competing interest
The authors declare no competing interests.
Acknowledgments
None.
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