Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

doi:10.1136/bmj.l1079

Meta-Analysis

. 2019 Mar 27:364:l1079.

doi: 10.1136/bmj.l1079.

Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

Julian Mutz¹, Vijeinika Vipulananthan², Ben Carter³, René Hurlemann⁴, Cynthia H Y Fu^{5

6}, Allan H Young^{2

6}

Affiliations

¹ Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK julian.mutz@gmail.com.
² South London and Maudsley Foundation NHS Trust, London, UK.
³ Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁴ Department of Psychiatry and Division of Medical Psychology, University of Bonn Medical Centre, Bonn, Germany.
⁵ School of Psychology, College of Applied Health and Communities, University of East London, London, UK.
⁶ Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

PMID: 30917990
PMCID: PMC6435996
DOI: 10.1136/bmj.l1079

Meta-Analysis

Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

Julian Mutz et al. BMJ. 2019.

. 2019 Mar 27:364:l1079.

doi: 10.1136/bmj.l1079.

Authors

Julian Mutz¹, Vijeinika Vipulananthan², Ben Carter³, René Hurlemann⁴, Cynthia H Y Fu^{5

6}, Allan H Young^{2

6}

Affiliations

¹ Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK julian.mutz@gmail.com.
² South London and Maudsley Foundation NHS Trust, London, UK.
³ Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁴ Department of Psychiatry and Division of Medical Psychology, University of Bonn Medical Centre, Bonn, Germany.
⁵ School of Psychology, College of Applied Health and Communities, University of East London, London, UK.
⁶ Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

PMID: 30917990
PMCID: PMC6435996
DOI: 10.1136/bmj.l1079

Abstract

Objective: To estimate the comparative clinical efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults.

Design: Systematic review with pairwise and network meta-analysis.

Data sources: Electronic search of Embase, PubMed/Medline, and PsycINFO up to 8 May 2018, supplemented by manual searches of bibliographies of several reviews (published between 2009 and 2018) and included trials.

Eligibility criteria for selecting studies: Clinical trials with random allocation to electroconvulsive therapy (ECT), transcranial magnetic stimulation (repetitive (rTMS), accelerated, priming, deep, and synchronised), theta burst stimulation, magnetic seizure therapy, transcranial direct current stimulation (tDCS), or sham therapy.

Main outcome measures: Primary outcomes were response (efficacy) and all cause discontinuation (discontinuation of treatment for any reason) (acceptability), presented as odds ratios with 95% confidence intervals. Remission and continuous depression severity scores after treatment were also examined.

Results: 113 trials (262 treatment arms) that randomised 6750 patients (mean age 47.9 years; 59% women) with major depressive disorder or bipolar depression met the inclusion criteria. The most studied treatment comparisons were high frequency left rTMS and tDCS versus sham therapy, whereas recent treatments remain understudied. The quality of the evidence was typically of low or unclear risk of bias (94 out of 113 trials, 83%) and the precision of summary estimates for treatment effect varied considerably. In network meta-analysis, 10 out of 18 treatment strategies were associated with higher response compared with sham therapy: bitemporal ECT (summary odds ratio 8.91, 95% confidence interval 2.57 to 30.91), high dose right unilateral ECT (7.27, 1.90 to 27.78), priming transcranial magnetic stimulation (6.02, 2.21 to 16.38), magnetic seizure therapy (5.55, 1.06 to 28.99), bilateral rTMS (4.92, 2.93 to 8.25), bilateral theta burst stimulation (4.44, 1.47 to 13.41), low frequency right rTMS (3.65, 2.13 to 6.24), intermittent theta burst stimulation (3.20, 1.45 to 7.08), high frequency left rTMS (3.17, 2.29 to 4.37), and tDCS (2.65, 1.55 to 4.55). Network meta-analytic estimates of active interventions contrasted with another active treatment indicated that bitemporal ECT and high dose right unilateral ECT were associated with increased response. All treatment strategies were at least as acceptable as sham therapy.

Conclusions: These findings provide evidence for the consideration of non-surgical brain stimulation techniques as alternative or add-on treatments for adults with major depressive episodes. These findings also highlight important research priorities in the specialty of brain stimulation, such as the need for further well designed randomised controlled trials comparing novel treatments, and sham controlled trials investigating magnetic seizure therapy.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: JM received funding as a student from the German National Academic Foundation (Studienstifung des Deutschen Volkes) and a board grant from the International Master in Affective Neuroscience programme of Maastricht University and the University of Florence in support of this work. He declares current studentship funding from the Biotechnology and Biological Sciences Research Council and Eli Lilly outside of this work. AHY is employed by King’s College London and is an honorary consultant at SLaM (NHS UK). He discloses being paid for lectures and advisory boards for the following companies with drugs used in affective and related disorders: AstraZenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, and Janssen. He is a consultant to Johnson and Johnson. He declares no shareholdings in pharmaceutical companies. He declares lead investigator status for Embolden Study (AstraZeneca), BCI Neuroplasticity study, and Aripiprazole Mania Study, and investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck, Wyeth, and Janssen. He acknowledges grant funding (past and present) from National Institute of Mental Health (USA), Canadian Institutes of Health Research (Canada), National Alliance for the Research of Schizophrenia and Depression (USA), Stanley Medical Research Institute (USA), Medical Research Council (UK), Wellcome Trust (UK), Royal College of Physicians (Edinburgh), British Medical Association (UK), UBC-VGH Foundation (Canada), WEDC Foundation (Canada), CCS Depression Research Fund (Canada), Michael Smith Foundation for Health Research (Canada), NIHR (UK), and Janssen (UK) all outside of the submitted work.

Figures

**Fig 2**
Network meta-analysis of response and all cause discontinuation rates. Effect sizes represent summary odds ratios and 95% confidence intervals. For the lower triangle (response rates) and upper triangle (all cause discontinuation rates), values less than 1 favour the treatment in the corresponding row, whereas values greater than 1 favour the treatment in the corresponding column. aTMS=accelerated transcranial magnetic stimulation; BF ECT=bifrontal electroconvulsive therapy (ECT); BL rTMS=bilateral repetitive transcranial magnetic stimulation; blTBS=bilateral theta burst stimulation; BT ECT=bitemporal ECT; cTBS=continuous theta burst stimulation; dTMS=deep transcranial magnetic stimulation; HFL rTMS=high frequency left repetitive transcranial magnetic stimulation; HFR rTMS=high frequency right repetitive transcranial magnetic stimulation; HRUL ECT=high dose right unilateral ECT; iTBS=intermittent theta burst stimulation; LFL rTMS=low frequency left repetitive transcranial magnetic stimulation; LFR rTMS=low frequency right repetitive transcranial magnetic stimulation; LMRUL ECT=low to moderate dose right unilateral ECT; MST=magnetic seizure therapy; pTMS=priming transcranial magnetic stimulation; SHM=sham therapy; sTMS=synchronised transcranial magnetic stimulation; tDCS=transcranial direct current stimulation

**Fig 3**
Network plot of available treatment comparisons for response rates. Size of node is proportional to number of patients randomised to each treatment. Line width is proportional to number of randomised controlled trials comparing each pair of treatments. aTMS=accelerated transcranial magnetic stimulation; BF ECT=bifrontal electroconvulsive therapy (ECT); BL rTMS=bilateral repetitive transcranial magnetic stimulation; blTBS=bilateral theta burst stimulation; BT ECT=bitemporal ECT; cTBS=continuous theta burst stimulation; dTMS=deep transcranial magnetic stimulation; HFL rTMS=high frequency left repetitive transcranial magnetic stimulation; HFR rTMS=high frequency right repetitive transcranial magnetic stimulation; HRUL ECT=high dose right unilateral ECT; iTBS=intermittent theta burst stimulation; LFL rTMS=low frequency left repetitive transcranial magnetic stimulation; LFR rTMS=low frequency right repetitive transcranial magnetic stimulation; LMRUL ECT=low to moderate dose right unilateral ECT; MST=magnetic seizure therapy; pTMS=priming transcranial magnetic stimulation; SHM=sham therapy; sTMS=synchronised transcranial magnetic stimulation; tDCS=transcranial direct current stimulation

**Fig 4**
Forest plot of active versus sham treatment comparisons for response rates. Effect sizes represent summary odds ratios with 95% confidence intervals and 95% prediction intervals estimates from network meta-analysis. aTMS=accelerated transcranial magnetic stimulation; BF ECT=bifrontal electroconvulsive therapy (ECT); BL rTMS=bilateral repetitive transcranial magnetic stimulation; blTBS=bilateral theta burst stimulation; BT ECT=bitemporal ECT; cTBS=continuous theta burst stimulation; dTMS=deep transcranial magnetic stimulation; HFL rTMS=high frequency left repetitive transcranial magnetic stimulation; HFR rTMS=high frequency right repetitive transcranial magnetic stimulation; HRUL ECT=high dose right unilateral ECT; iTBS=intermittent theta burst stimulation; LFL rTMS=low frequency left repetitive transcranial magnetic stimulation; LFR rTMS=low frequency right repetitive transcranial magnetic stimulation; LMRUL ECT=low to moderate dose right unilateral ECT; MST=magnetic seizure therapy; pTMS=priming transcranial magnetic stimulation; sTMS=synchronised transcranial magnetic stimulation; tDCS=transcranial direct current stimulation

**Fig 5**
Network plot of available treatment comparisons for all cause discontinuation rates. Size of node is proportional to number of patients randomised to each treatment. Line width is proportional to number of randomised controlled trials comparing each pair of treatments. aTMS=accelerated transcranial magnetic stimulation; BF ECT=bifrontal electroconvulsive therapy (ECT); BL rTMS=bilateral repetitive transcranial magnetic stimulation; blTBS=bilateral theta burst stimulation; BT ECT=bitemporal ECT; cTBS=continuous theta burst stimulation; dTMS=deep transcranial magnetic stimulation; HFL rTMS=high frequency left repetitive transcranial magnetic stimulation; HFR rTMS=high frequency right repetitive transcranial magnetic stimulation; HRUL ECT=high dose right unilateral ECT; iTBS=intermittent theta burst stimulation; LFL rTMS=low frequency left repetitive transcranial magnetic stimulation; LFR rTMS=low frequency right repetitive transcranial magnetic stimulation; LMRUL ECT=low to moderate dose right unilateral ECT; MST=magnetic seizure therapy; pTMS=priming transcranial magnetic stimulation; SHM=sham therapy; sTMS=synchronised transcranial magnetic stimulation; tDCS=transcranial direct current stimulation

**Fig 6**
Forest plot of active versus sham treatment comparisons for all cause discontinuation rates. Effect sizes represent summary odds ratios with 95% confidence intervals and 95% prediction intervals estimates from network meta-analysis. aTMS=accelerated transcranial magnetic stimulation; BF ECT=bifrontal electroconvulsive therapy (ECT); BL rTMS=bilateral repetitive transcranial magnetic stimulation; blTBS=bilateral theta burst stimulation; BT ECT=bitemporal ECT; cTBS=continuous theta burst stimulation; dTMS=deep transcranial magnetic stimulation; HFL rTMS=high frequency left repetitive transcranial magnetic stimulation; HFR rTMS=high frequency right repetitive transcranial magnetic stimulation; HRUL ECT=high dose right unilateral ECT; iTBS=intermittent theta burst stimulation; LFL rTMS=low frequency left repetitive transcranial magnetic stimulation; LFR rTMS=low frequency right repetitive transcranial magnetic stimulation; LMRUL ECT=low to moderate dose right unilateral ECT; MST=magnetic seizure therapy; pTMS=priming transcranial magnetic stimulation; sTMS=synchronised transcranial magnetic stimulation; tDCS=transcranial direct current stimulation

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References

1. Kessler RC, Berglund P, Demler O, et al. National Comorbidity Survey Replication The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095-105. 10.1001/jama.289.23.3095 - DOI - PubMed
1. Murray CJ, Barber RM, Foreman KJ, et al. GBD 2013 DALYs and HALE Collaborators Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet 2015;386:2145-91. 10.1016/S0140-6736(15)61340-X - DOI - PMC - PubMed
1. Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, Cleare AJ. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord 2009;116:4-11. 10.1016/j.jad.2008.10.014 - DOI - PubMed
1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905-17. 10.1176/ajp.2006.163.11.1905 - DOI - PubMed
1. Kikuchi T, Suzuki T, Uchida H, Watanabe K, Mimura M. Association between antidepressant side effects and functional impairment in patients with major depressive disorders. Psychiatry Res 2013;210:127-33. 10.1016/j.psychres.2013.05.007 - DOI - PubMed

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[1] Kessler RC, Berglund P, Demler O, et al. National Comorbidity Survey Replication The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095-105. 10.1001/jama.289.23.3095 - DOI - PubMed

[2] Kessler RC, Berglund P, Demler O, et al. National Comorbidity Survey Replication The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095-105. 10.1001/jama.289.23.3095 - DOI - PubMed

[3] Murray CJ, Barber RM, Foreman KJ, et al. GBD 2013 DALYs and HALE Collaborators Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet 2015;386:2145-91. 10.1016/S0140-6736(15)61340-X - DOI - PMC - PubMed

[4] Murray CJ, Barber RM, Foreman KJ, et al. GBD 2013 DALYs and HALE Collaborators Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet 2015;386:2145-91. 10.1016/S0140-6736(15)61340-X - DOI - PMC - PubMed

[5] Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, Cleare AJ. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord 2009;116:4-11. 10.1016/j.jad.2008.10.014 - DOI - PubMed

[6] Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, Cleare AJ. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord 2009;116:4-11. 10.1016/j.jad.2008.10.014 - DOI - PubMed

[7] Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905-17. 10.1176/ajp.2006.163.11.1905 - DOI - PubMed

[8] Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905-17. 10.1176/ajp.2006.163.11.1905 - DOI - PubMed

[9] Kikuchi T, Suzuki T, Uchida H, Watanabe K, Mimura M. Association between antidepressant side effects and functional impairment in patients with major depressive disorders. Psychiatry Res 2013;210:127-33. 10.1016/j.psychres.2013.05.007 - DOI - PubMed

[10] Kikuchi T, Suzuki T, Uchida H, Watanabe K, Mimura M. Association between antidepressant side effects and functional impairment in patients with major depressive disorders. Psychiatry Res 2013;210:127-33. 10.1016/j.psychres.2013.05.007 - DOI - PubMed

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Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

Affiliations

Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

Authors

Affiliations

Abstract

Conflict of interest statement

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