Clinical effectiveness of non-TMS neurostimulation in depression: Clinical trials from 2010 to 2020

https://doi.org/10.1016/j.pnpbp.2021.110287Get rights and content

Highlights

  • tDCS is well tolerated and likely effective in MDD.

  • tDCS with duration of 4 or more weeks may be effective in women diagnosed with MDD in the perinatal period.

  • 10 Hz-tACS was more effective in improving depressive symptoms after 2 weeks compared to 40 Hz-tACS and to sham.

  • DBS, EpCS, MST, TNS and taVNS are well tolerated and may improve the course of illness in patients with TRD.

Abstract

Objective

Treatment for major depressive disorder (MDD) have evolved, although there is still a strong unmet need for more effective and tolerable options. The present study summarizes and discusses recent evidence regarding the non-transcranial magnetic stimulation (non-TMS) neurostimulation treatment for MDD.

Methods

The authors reviewed non-TMS neurostimulation clinical trials for MDD between 2010 and 2020. Electroconvulsive therapy was not included in this review. A systematic review was performed in MEDLINE database through PubMed, the Cochrane Collaboration's Clinical Trials Register (CENTRAL), PsycINFO and Thomson Reuters's Web of Science.

Results

Only 20 articles met the inclusion criteria. Randomized controlled trials demonstrated efficacy of transcranial direct current stimulation (tDCS) in five of seven trials. tDCS augmented with sertraline, fluoxetine, citalopram and escitalopram was superior to placebo and to tDCS only. A comparative trial demonstrated that the duration of tDCS sessions can modulate the effectiveness of this treatment. Open trials indicated that deep brain stimulation, epidural cortical stimulation, trigeminal nerve stimulation, magnetic seizure therapy and vagus nerve stimulation may be effective in treatment-resistant depression.

Conclusion

This review confirmed the efficacy of tDCS in MDD. Despite new evidence showing effectiveness for other non-TMS neurostimulation, their effectiveness is still unclear. Non-TMS neurostimulation RCTs with large samples and head-to-head studies comparing non-TMS neurostimulation and gold standard pharmacological treatments are still lacking.

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.

References (88)

  • D.M. Martin

    Clinical pilot study of transcranial direct current stimulation combined with cognitive emotional training for medication resistant depression

    J. Affect. Disord.

    (2018)
  • P. Medda et al.

    Response to ECT in bipolar I, bipolar II and unipolar depression

    J. Affect. Disord.

    (2009)
  • Z. Nahas

    Bilateral epidural prefrontal cortical stimulation for treatment-resistant depression

    Biol. Psychiatry

    (2010)
  • J.J. Pancrazio

    Neuromodulation: Comprehensive Textbook of Principles, Technologies, and Therapies

    (2018)
  • A. Pandurangi et al.

    Brain stimulation therapies for psychiatric disorders: the first decade of the new millennium—a review

    Asian J. Psychiatr.

    (2012)
  • E.L. Pavlova

    Transcranial direct current stimulation of 20- and 30-minutes combined with sertraline for the treatment of depression

    Prog. Neuro-Psychopharmacol. Biol. Psychiatry

    (2018)
  • W. Rief et al.

    A new approach to the assessment of the treatment effects of somatoform disorders

    Psychosomatics

    (2003)
  • L.M. Schrader et al.

    Trigeminal nerve stimulation in major depressive disorder: first proof of concept in an open pilot trial

    Epilepsy & behavior: E&B

    (2011)
  • P. Shiozawa et al.

    Trigeminal nerve stimulation (TNS) protocol for treating major depression: An open-label proof-of-concept trial

    Epilepsy & Behavior

    (2014)
  • A.P. Trevizol

    Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: An Open Label Proof-of-Concept Trial

    Brain Stimulation

    (2016)
  • S.J. Tsai

    Transcranial focused ultrasound as a possible treatment for major depression

    Med. Hypotheses

    (2015)
  • Y. Tufail

    Transcranial pulsed ultrasound stimulates intact brain circuits

    Neuron

    (2010)
  • Y. Wang

    Transcranial direct current stimulation for the treatment of major depressive disorder: a meta-analysis of randomized controlled trials

    Psychiatry Res.

    (2019)
  • J. Wang

    Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: a pilot study

    J. Affect. Disord.

    (2020)
  • Q. Zhou

    The effects of repeated transcranial direct current stimulation on sleep quality and depression symptoms in patients with major depression and insomnia

    Sleep Med.

    (2020)
  • H. Akhtar et al.

    Therapeutic efficacy of neurostimulation for depression: techniques, current modalities, and future challenges

    Neurosci. Bull.

    (2016)
  • M.L. Alexander

    Double-blind, randomized pilot clinical trial targeting alpha oscillations with transcranial alternating current stimulation (tACS) for the treatment of major depressive disorder (MDD)

    Transl. Psychiatry

    (2019)
  • M. Bares et al.

    Transcranial direct-current stimulation (tDCS) versus venlafaxine ER in the treatment of depression: a randomized, double-blind, single-center study with open-label, follow-up

    Neuropsychiatr. Dis. Treat.

    (2019)
  • D. Barrett et al.

    Transcranial infrared laser stimulation produces beneficial cognitive and emotional effects in humans

    Neuroscience

    (2012)
  • A.T. Beck et al.

    An inventory for measuring depression

    Arch. Gen. Psychiatry

    (1961)
  • A.T. Beck et al.

    An inventory for measuring clinical anxiety: psychometric properties

    J. Consult. Clin. Psychol.

    (1988)
  • I.O. Bergfeld

    Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression a randomized clinical trial

    Jama Psychiatry

    (2016)
  • D.M. Blumberger et al.

    A randomized double-blind sham-controlled study of transcranial direct current stimulation for treatment-resistant major depression

    Front Psychiatry

    (2012)
  • J.M. Bottomley et al.

    Vagus nerve stimulation (VNS) therapy in patients with treatment resistant depression: a systematic review and meta-analysis

    Compr. Psychiatry

    (2019)
  • A.R. Brunoni

    The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial

    JAMA Psychiatry

    (2013)
  • A. Brunoni

    Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes a systematic review with network meta-analysis supplemental content

    JAMA Psychiatry

    (2017)
  • P. Cassano

    Near-infrared transcranial radiation for major depressive disorder: proof of concept study

    Psychiatry J.

    (2015)
  • K.A. Caulfield et al.

    The future of brain stimulation treatments

    Psychiatr. Clin. N. Am.

    (2018)
  • E. Cretaz et al.

    Magnetic seizure therapy for unipolar and bipolar depression: a systematic review

    Neural Plast

    (2015)
  • G. Curcio

    Validity of the Italian version of the Pittsburgh Sleep Quality Index (PSQI)

    Neurol. Sci.

    (2013)
  • S. Disner et al.

    Transcranial laser stimulation as neuroenhancement for attention bias modification in adults with elevated depression symptoms

    Brain Stimulation

    (2016)
  • D.A. Dunstan et al.

    Screening for anxiety and depression: reassessing the utility of the Zung scales

    BMC Psychiatry

    (2017)
  • J. Endicott et al.

    Quality of life enjoyment and satisfaction questionnaire: a new measure

    Psychopharmacol. Bull.

    (1993)
  • J.I. Escobar et al.

    Somatic symptom index (SSI): a new and abridged somatization construct. Prevalence and epidemiological correlates in two large community samples

    J. Nerv. Ment. Dis.

    (1989)
  • Cited by (6)

    • Recent advances and challenges in major depressive disorder

      2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
    • Central effects of trigeminal electrical stimulation

      2023, Cranio - Journal of Craniomandibular and Sleep Practice
    View full text