. 2022 Aug 1;79(8):770-779.

doi: 10.1001/jamapsychiatry.2022.1513.

Assessment of Noninvasive Brain Stimulation Interventions for Negative Symptoms of Schizophrenia: A Systematic Review and Network Meta-analysis

Ping-Tao Tseng^{1

2

3

4}, Bing-Syuan Zeng⁵, Chao-Ming Hung^{6

7}, Chih-Sung Liang^{8

9}, Brendon Stubbs^{10

11}, Andre F Carvalho¹², Andre R Brunoni^{13

14}, Kuan-Pin Su^{10

15

16

17}, Yu-Kang Tu^{18

19}, Yi-Cheng Wu²⁰, Tien-Yu Chen^{21

22}, Dian-Jeng Li²³, Pao-Yen Lin^{24

25}, Chih-Wei Hsu²⁴, Yen-Wen Chen², Mein-Woei Suen^{1

26

27

28}, Kazumi Satogami²⁹, Shun Takahashi^{29

30

31

32

33}, Ching-Kuan Wu³⁴, Wei-Cheng Yang^{23

35}, Yow-Ling Shiue³, Tiao-Lai Huang^{24

36

37}, Cheng-Ta Li^{4

38

39}

Affiliations

¹ Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
² Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan.
³ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁴ Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
⁵ Department of Internal Medicine, E-DA Cancer Hospital, Kaohsiung, Taiwan.
⁶ Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, Kaohsiung, Taiwan.
⁷ School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
⁸ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
⁹ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
¹⁰ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
¹¹ Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, United Kingdom.
¹² Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia.
¹³ Service of Interdisciplinary Neuromodulation, National Institute of Biomarkers in Psychiatry, Laboratory of Neurosciences (LIM-27), Departamento e Instituto de Psiquiatria, Faculdade de Medicina da University of Sao Paulo, Sao Paulo, Brazil.
¹⁴ Departamento de Ciências Médicas, Faculdade de Medicina da University of Sao Paulo, Sao Paulo, Brazil.
¹⁵ Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan.
¹⁶ College of Medicine, China Medical University, Taichung, Taiwan.
¹⁷ An-Nan Hospital, China Medical University, Tainan, Taiwan.
¹⁸ Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹⁹ Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
²⁰ Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan.
²¹ Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
²² Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
²³ Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan.
²⁴ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
²⁵ Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
²⁶ Gender Equality Education and Research Center, Asia University, Taichung, Taiwan.
²⁷ Department of Medical Research, Asia University Hospital, Asia University, Taichung, Taiwan.
²⁸ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
²⁹ Department of Neuropsychiatry, Wakayama Medical University, Wakayama, Japan.
³⁰ Clinical Research and Education Center, Asakayama General Hospital, Sakai, Japan.
³¹ Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino, Japan.
³² Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
³³ Graduate School of Rehabilitation Science, Osaka Metropolitan University, Habikino, Japan.
³⁴ Department of Psychiatry, Kaohsiung Kingswood Psychiatric Clinic, Kaohsiung, Taiwan.
³⁵ Department of Adult Psychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung City, Taiwan.
³⁶ Department of Psychiatry, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
³⁷ Genomic and Proteomic Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
³⁸ Division of Psychiatry, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³⁹ Institute of Brain Science and Brain Research Center, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

PMID: 35731533
PMCID: PMC9218931
DOI: 10.1001/jamapsychiatry.2022.1513

Assessment of Noninvasive Brain Stimulation Interventions for Negative Symptoms of Schizophrenia: A Systematic Review and Network Meta-analysis

Ping-Tao Tseng et al. JAMA Psychiatry. 2022.

. 2022 Aug 1;79(8):770-779.

doi: 10.1001/jamapsychiatry.2022.1513.

Authors

Affiliations

¹ Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
² Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan.
³ Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁴ Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
⁵ Department of Internal Medicine, E-DA Cancer Hospital, Kaohsiung, Taiwan.
⁶ Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, Kaohsiung, Taiwan.
⁷ School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
⁸ Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
⁹ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
¹⁰ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
¹¹ Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, United Kingdom.
¹² Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia.
¹³ Service of Interdisciplinary Neuromodulation, National Institute of Biomarkers in Psychiatry, Laboratory of Neurosciences (LIM-27), Departamento e Instituto de Psiquiatria, Faculdade de Medicina da University of Sao Paulo, Sao Paulo, Brazil.
¹⁴ Departamento de Ciências Médicas, Faculdade de Medicina da University of Sao Paulo, Sao Paulo, Brazil.
¹⁵ Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan.
¹⁶ College of Medicine, China Medical University, Taichung, Taiwan.
¹⁷ An-Nan Hospital, China Medical University, Tainan, Taiwan.
¹⁸ Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹⁹ Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
²⁰ Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan.
²¹ Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan.
²² Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
²³ Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan.
²⁴ Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
²⁵ Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
²⁶ Gender Equality Education and Research Center, Asia University, Taichung, Taiwan.
²⁷ Department of Medical Research, Asia University Hospital, Asia University, Taichung, Taiwan.
²⁸ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
²⁹ Department of Neuropsychiatry, Wakayama Medical University, Wakayama, Japan.
³⁰ Clinical Research and Education Center, Asakayama General Hospital, Sakai, Japan.
³¹ Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino, Japan.
³² Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
³³ Graduate School of Rehabilitation Science, Osaka Metropolitan University, Habikino, Japan.
³⁴ Department of Psychiatry, Kaohsiung Kingswood Psychiatric Clinic, Kaohsiung, Taiwan.
³⁵ Department of Adult Psychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung City, Taiwan.
³⁶ Department of Psychiatry, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
³⁷ Genomic and Proteomic Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
³⁸ Division of Psychiatry, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³⁹ Institute of Brain Science and Brain Research Center, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

PMID: 35731533
PMCID: PMC9218931
DOI: 10.1001/jamapsychiatry.2022.1513

Abstract

Importance: Negative symptoms have a detrimental impact on functional outcomes and quality of life in people with schizophrenia, and few therapeutic options are considered effective for this symptomatic dimension. Studies have suggested that noninvasive brain stimulation (NIBS) interventions may be effective in treating negative symptoms. However, the comparative efficacy of different NIBS protocols for relieving negative symptoms remains unclear.

Objective: To compare the efficacy and acceptability of different NIBS interventions for treating negative symptoms.

Data sources: The ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, ClinicalTrials.gov, and Web of Science electronic databases were systematically searched from inception through December 7, 2021.

Study selection: A frequentist model network meta-analysis was conducted to assess the pooled findings of trials that evaluated the efficacy of repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation, transcranial random noise stimulation, transcutaneous vagus nerve stimulation, and transcranial direct current stimulation on negative symptoms in schizophrenia. Randomized clinical trials (RCTs) examining NIBS interventions for participants with schizophrenia were included.

Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were independently extracted by multiple observers. The pair-wise meta-analytic procedures were conducted using a random-effects model.

Main outcomes and measures: The coprimary outcomes were changes in the severity of negative symptoms and acceptability (ie, dropout rates owing to any reason). Secondary outcomes were changes in positive and depressive symptoms.

Results: Forty-eight RCTs involving 2211 participants (mean [range] age, 38.7 [24.0-57.0] years; mean [range] proportion of female patients, 30.6% [0%-70.0%]) were included. Compared with sham control interventions, excitatory NIBS strategies (standardized mean difference [SMD]: high-definition transcranial random noise stimulation, -2.19 [95% CI, -3.36 to -1.02]; intermittent theta-burst stimulation, -1.32 [95% CI, -1.88 to -0.76]; anodal transcranial direct current stimulation, -1.28 [95% CI, -2.55 to -0.02]; high-frequency rTMS, -0.43 [95% CI, -0.68 to -0.18]; extreme high-frequency rTMS, -0.45 [95% CI, -0.79 to -0.12]) over the left dorsolateral prefrontal cortex with or without other inhibitory stimulation protocols in the contralateral regions of the brain were associated with significantly larger reductions in negative symptoms. Acceptability did not significantly differ between the groups.

Conclusions and relevance: In this network meta-analysis, excitatory NIBS protocols over the left dorsolateral prefrontal cortex were associated with significantly large improvements in the severity of negative symptoms. Because relatively few studies were available for inclusion, additional well-designed, large-scale RCTs are warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Stubbs is supported by a clinical lectureship jointly funded by Health Education England and the National Institute for Health Research (NIHR); is part funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust; and is supported by the Maudsley Charity, King’s College London, and the NIHR South London Collaboration for Leadership in Applied Health Research and Care funding. Dr Brunoni reported grants from São Paulo Research Foundation, Brazilian National Council of Scientific Development, and University of Sao Paulo Medical School; support from the Newton Advanced Fellowship; and in-kind support from Flow Neuroscience and MagVenture during the conduct of the study. Dr Su is supported by grants from An Nan Hospital, China Medical University, Tainan, Taiwan and China Medical University, Taichung, Taiwan. Dr Tu was supported by a grant from the Ministry of Science and Technology in Taiwan. Dr Lin is supported by grants from the Ministry of Science and Technology in Taiwan and Kaohsiung Chang Gung Memorial Hospital in Taiwan. Dr Hsu is supported by grants from the Ministry of Science and Technology in Taiwan. Dr Takahashi reported speaker’s honoraria from Teijin Pharma Ltd during the conduct of the study and from Dainippon Sumitomo Pharma, Eisai, Meiji Seika, Mochida Pharmaceutical, Ono Pharmaceutical, Otsuka Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. No other disclosures were reported.

Figures

**Figure 1.. Network Meta-analysis Flowchart**

**Figure 2.. Forest Plot of Changes in Negative Symptom Severity**
When the effect size is less than 0, the specified intervention is associated with a greater improvement in negative symptom severity compared with sham controls. a Indicates anodal; c, cathodal; dTMS, deep repetitive transcranial magnetic stimulation; ehf, extreme high-definition; hd, high-definition; hf, high-frequency; iTBS, intermittent theta-burst stimulation; lf, low-frequency; OR, odds ratio; prTMS, priming repetitive transcranial magnetic stimulation; rTMS, repetitive transcranial magnetic stimulation; SMD, standardized mean difference; tACS, transcranial alternating current stimulation; tDCS; transcranial direct current stimulation; the, theta; tRNS, transcranial random noise stimulation; tVNS, transcutaneous vagus nerve stimulation.

**Figure 3.. Network Structure of Changes in Negative Symptom Severity**
Lines between nodes represent direct comparisons between trials, and circle size is proportional to the size of the population that received each treatment. Line thickness is proportional to the number of studies providing data to the comparison. a Indicates anodal; c, cathodal; dTMS, deep repetitive transcranial magnetic stimulation; ehf, extreme high-definition; hd, high-definition; hf, high-frequency; iTBS, intermittent theta-burst stimulation; lf, low-frequency; prTMS, priming repetitive transcranial magnetic stimulation; rTMS, repetitive transcranial magnetic stimulation; tACS, transcranial alternating current stimulation; tDCS; transcranial direct current stimulation; the, theta; tRNS, transcranial random noise stimulation; tVNS, transcutaneous vagus nerve stimulation.

See this image and copyright information in PMC

References

1. GBD 2019 Mental Disorders Collaborators . Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137-150. doi:10.1016/S2215-0366(21)00395-3 - DOI - PMC - PubMed
1. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia: an overview. JAMA Psychiatry. 2020;77(2):201-210. doi:10.1001/jamapsychiatry.2019.3360 - DOI - PubMed
1. Medalia A, Lim R. Treatment of cognitive dysfunction in psychiatric disorders. J Psychiatr Pract. 2004;10(1):17-25. doi:10.1097/00131746-200401000-00003 - DOI - PubMed
1. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. . Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939-951. doi:10.1016/S0140-6736(19)31135-3 - DOI - PMC - PubMed
1. Milev RV, Giacobbe P, Kennedy SH, et al. ; CANMAT Depression Work Group . Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4: neurostimulation treatments. Can J Psychiatry. 2016;61(9):561-575. doi:10.1177/0706743716660033 - DOI - PMC - PubMed

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Assessment of Noninvasive Brain Stimulation Interventions for Negative Symptoms of Schizophrenia: A Systematic Review and Network Meta-analysis

Affiliations

Assessment of Noninvasive Brain Stimulation Interventions for Negative Symptoms of Schizophrenia: A Systematic Review and Network Meta-analysis

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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Medical