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. 2024 Oct 1;7(10):e2441159.
doi: 10.1001/jamanetworkopen.2024.41159.

Theta Burst Stimulation Protocols for Schizophrenia: A Systematic Review and Network Meta-Analysis

Taro Kishi  1 , Toshikazu Ikuta  2 , Kenji Sakuma  1 , Shun Hamanaka  1 , Yasufumi Nishii  1 , Masakazu Hatano  3 , Shinsuke Kito  4 , Nakao Iwata  1
Affiliations

Theta Burst Stimulation Protocols for Schizophrenia: A Systematic Review and Network Meta-Analysis

Taro Kishi et al. JAMA Netw Open. .

Abstract

Importance: To date, several theta burst stimulation (TBS) protocols, such as intermittent TBS (iTBS), have been proposed; however, previous systematic reviews have revealed inconsistent efficacy findings in individual TBS studies for schizophrenia.

Objective: To examine which TBS protocols are associated with the most favorable and acceptable outcomes in adults with schizophrenia.

Data sources: The Cochrane Library, PubMed, and Embase databases were searched for studies published before May 22, 2024.

Study selection: The inclusion criteria were as follows: (1) published and unpublished randomized clinical trials (RCTs) of any TBS treatment and (2) RCTs including individuals with schizophrenia spectrum disorders, other psychotic disorders, or both.

Data extraction and synthesis: This study followed the Cochrane standards for data extraction and data quality assessment and used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline for reporting. The risk of bias of individual studies was assessed using the second version of the Cochrane risk of bias tool, and the Confidence in Network Meta-Analysis application was used to rate the certainty of evidence for meta-analysis results. At least 2 authors double-checked the literature search, data transfer accuracy, and calculations.

Main outcomes and measures: The primary outcome of this study was improvement in scores related to negative symptoms. Our frequentist network meta-analysis used a random-effects model. The standardized mean difference (SMD) or odds ratio for continuous or dichotomous variables, respectively, was calculated with 95% CIs.

Results: A total of 30 RCTs of 9 TBS protocols, with 1424 participants, were included. Only iTBS over the left dorsolateral prefrontal cortex (L-DLPFC) was associated with reduced negative symptom scores (SMD, -0.89; 95% CI, -1.24 to -0.55), overall symptom scores (SMD, -0.81; 95% CI, -1.15 to -0.48), Positive and Negative Syndrome Scale general subscale scores (SMD, -0.57; 95% CI, -0.89 to -0.25), depressive symptom scores (SMD, -0.70; 95% CI, -1.04 to -0.37), and anxiety symptom scores (SMD, -0.58; 95% CI, -0.92 to -0.24) and improved overall cognitive impairment scores (SMD, -0.52; 95% CI, -0.89 to -0.15) compared with a sham. However, positive symptom score changes, all-cause discontinuation rate, discontinuation rate due to adverse events, headache incidence, and dizziness incidence did not significantly differ between any TBS protocols and sham.

Conclusions and relevance: In this network meta-analysis, iTBS over the L-DLPFC was associated with improved scores for negative, depressive, anxiety, and cognitive symptoms in individuals with schizophrenia and was well tolerated by the participants. Other forms of TBS were not associated with benefit. Further research is needed to assess the potential role of TBS in the treatment of schizophrenia.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kishi reported receiving speaker honoraria from Eisai, Janssen, Meiji, Otsuka, Sumitomo, Takeda, Mitsubishi-Tanabe, Kyowa, Yoshitomi, and Viatris and research grants from Eisai, JSPS KAKENHI, Japan Agency for Medical Research and Development, and the Japanese Ministry of Health, Labour and Welfare. Dr Sakuma reported receiving speaker honoraria from Daiichi Sankyo, Eisai, Janssen, Kyowa, Meiji, Otsuka, Sumitomo, and Takeda and receiving a Fujita Health University School of Medicine Research Grant for Early-Career Scientists, Grant-in-Aid for Young Scientists, Grant-in-Aid for Scientific Research, and Japan Agency for Medical Research and Development. Dr Hamanaka reported receiving speaker honoraria from Meiji, Otsuka, and Sumitomo. Dr Nishii reported receiving speaker honoraria from Meiji, Otsuka, and Sumitomo. Dr Hatano reported receiving speaker honoraria from Meiji and Sumitomo and receiving Grant-in-Aid for Early-Career Scientists. Dr Kito reported receiving speaker honoraria from Inter Reha, Lundbeck, Sumitomo, Otsuka, Takeda, Teijin, and Viatris; receiving consulting fees from Teijin; and receiving grants from Teijin, Daiichi Sankyo, Eisai, Meiji, Otsuka, Sumitomo, Takeda, Tanabe-Mitsubishi, Grant-in-Aid for Scientific Research, and Japan Agency for Medical Research and Development outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Forest Plots for Negative, Positive, and Overall Symptoms and Positive and Negative Syndrome Scale (PANSS) General Subscale
Active treatments were compared with sham treatments. cTBS indicates continuous theta burst stimulation; CV, cerebellar vermis; iTBS, intermittent theta burst stimulation; L-DLPFC, left dorsolateral prefrontal cortex; L-M1, left primary motor cortex; L-SMA, left supplementary motor area, L-TPC, left temporoparietal cortex; R-DLPFC, right dorsolateral prefrontal cortex; R-IPL, right inferior parietal lobule; R-TPC, right tempoparietal cortex; and SMD, standardized mean difference.
Figure 2.
Figure 2.. Forest Plots for Depressive, Overall Cognitive, and Anxiety Symptoms and All-Cause Discontinuation
B, The algebraic sign of the numerical scores for overall cognitive symptoms was reversed because lower scores indicate a higher impairment. Active treatments were compared with the sham. cTBS indicates continuous theta burst stimulation; CV, cerebellar vermis; iTBS, intermittent theta burst stimulation; L-DLPFC, left dorsolateral prefrontal cortex; L-M1, left primary motor cortex; L-SMA, left supplementary motor area; L-TPC, left temporoparietal cortex; OR, odds ratio; R-DLPFC, right dorsolateral prefrontal cortex; R-IPL, right inferior parietal lobule; R-TPC, right tempoparietal cortex; and SMD, standardized mean difference.
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