Next Article in Journal
Individualizing Fluid Management in Patients with Acute Respiratory Distress Syndrome and with Reduced Lung Tissue Due to Surgery—A Narrative Review
Previous Article in Journal
Factors Deciding Conservative or Intervention Treatment for Prostate Abscess: A Retrospective Case-Control Study
Previous Article in Special Issue
Comparison of Efficacy and Safety of Magnetic Seizure Therapy and Electroconvulsive Therapy for Depression: A Systematic Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 13
Issue 3
10.3390/jpm13030485
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Brief Report

A Systematic Review of Intermittent Theta Burst Stimulation for Neurocognitive Dysfunction in Older Adults with Schizophrenia

by
Xinyang Zhang
1,2,†,
Xinhu Yang
1,†,
Zhanming Shi
3,
Rui Xu
1,
Jianqiang Tan
1,
Jianwen Yang
1,
Xiong Huang
1,
Xingbing Huang
1 and
Wei Zheng
1,*
1
The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510260, China
2
Laboratory of Laser Sports Medicine, School of Sports Science, South China Normal University, Guangzhou 510260, China
3
Chongqing Jiangbei Mental Health Center, Chongqing 400000, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Pers. Med. 2023, 13(3), 485; https://doi.org/10.3390/jpm13030485
Submission received: 3 February 2023 / Revised: 1 March 2023 / Accepted: 6 March 2023 / Published: 8 March 2023
(This article belongs to the Special Issue Neuromodulation in the Clinical Treatment of Psychiatric Disorders)
Browse Figures
Review Reports Versions Notes

Abstract

:
Objective: Neurocognitive dysfunction is thought to be one of the core clinical features of schizophrenia, and older adults with schizophrenia exhibited greater overall cognitive deficits than younger adults. The aim of this systematic review was to examine the neurocognitive effects of intermittent theta burst stimulation (iTBS) as an adjunctive treatment for older adults suffering from schizophrenia. Methods: Randomized double-blinded controlled trials (RCTs) investigating the neurocognitive effects of adjunctive active iTBS versus sham iTBS in older adults with schizophrenia were systematically identified by independent investigators searching Chinese and English databases. Results: Two double-blinded RCTs (n = 132) compared the neurocognitive effects of adjunctive active iTBS (n = 66) versus sham iTBS (n = 66) in patients that fulfilled the inclusion criteria of this systematic review and were analyzed. One RCT found significant superiority of active iTBS over sham iTBS in improving neurocognitive performance in older adults with schizophrenia. In the other RCT, the findings on the neurocognitive effects of iTBS as measured by three different measurement tools were inconsistent. The dropout rate was reported in the two RCTs, ranging from 3.8% (3/80) to 7.7% (4/52). Conclusion: There is preliminary evidence that adjunctive iTBS may have some beneficial effects in the treatment of neurocognitive function in older patients with schizophrenia. Future RCTs with larger sample sizes focusing on the neurocognitive effects of adjunctive iTBS in older adults with schizophrenia are warranted to verify these findings.

1. Introduction

Neurocognitive dysfunction is thought to be one of the core clinical features of schizophrenia and has been found to be strongly associated with impairments in function. A previous study reported that up to 73% of patients with schizophrenia showed neurocognitive decline [1]. Compared with individuals suffering from mood disorders, neurocognitive impairment in schizophrenia is more severe and tends to be more independent of clinical symptoms [2]. A recent review reported that older adults with schizophrenia exhibited greater overall cognitive deficits than their healthy counterparts and had greater deficits in nearly all cognitive domains than younger adults [3]. Despite advances in psychopharmacologic therapy, the findings for enhancing cognition are mixed and unsatisfactory [4]. Consequently, augmentation strategies of antipsychotic drugs with nonpharmacological interventions, including aerobic exercise [5], cognitive remediation [6] and receptive transcranial magnetic stimulation (rTMS) [7], have been preliminarily used for older adults suffering from schizophrenia in clinical practice.
As a non-invasive physical therapy, rTMS can modulate brain network functioning by producing a local magnetic field that acts on the local cerebral cortex [8]. rTMS has been approved by the Food and Drug Administration of the United States to treat adult patients with major depressive disorder who fail to respond to antidepressants [9]. Numerous randomized controlled trials (RCTs) [10,11] and meta-analyses [12,13] also found the positive treatment effects of rTMS in adult patients suffering from schizophrenia. For example, a recent meta-analysis [12] found that high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) leads to significantly large improvements in treating negative symptoms of schizophrenia. Importantly, accumulating evidence also supports the safety and effectiveness of rTMS in children and adolescents with schizophrenia [14].
As a patterned form of rTMS, theta burst stimulation (TBS), either intermittent (iTBS) or continuous (cTBS) fashion, delivers a shorter stimulation duration and lower stimulation intensity in comparison to conventional rTMS protocols. TBS stimulation can induce more rapid and longer-lasting effects on synaptic plasticity and further regulate functional connectivity in the right posterior parietal cortex [15], which are closely associated with neurocognitive deficits in schizophrenia [16]. As an adjunctive treatment, the beneficial effects associated with TBS were observed in some neurocognitive task domains [17]. A recent review reported the beneficial effects of adjunctive TBS in improving neurocognitive function and auditory hallucinations in subjects with schizophrenia, even in elderly individuals with schizophrenia [18]. Compared with standard rTMS (total duration of 37.5 min), iTBS (total duration of 3 min 9 s) can markedly shorten the treatment duration and achieve rapid-acting antidepressant effects [19]. An animal study found that iTBS rather than cTBS was associated with improvements in learning and strongly reduced cortical protein expression, such as parvalbumin [20]. Furthermore, compared to cTBS, iTBS appeared to have a more favorable effect on the safety of treatments [21,22], which is vital for elderly people. Nevertheless, the research applied to evaluate the potential of adjunctive iTBS for improving neurocognitive function in older adults with schizophrenia has been inconsistent [23,24]. For example, Zhao et al. [23] found that iTBS can improve cognitive function as well as negative symptoms in older adults with schizophrenia. However, another study reported mixed findings on adjunctive iTBS for neurocognitive dysfunction in older adults suffering from schizophrenia [24].
To date, no systematic review on adjunctive iTBS for neurocognitive dysfunction in older adults with schizophrenia has been published. Thus, the aim of the current study was to focus on investigating the neurocognitive effects of adjunctive iTBS in older adults with schizophrenia. Based on the findings of a recent study [25], we hypothesized that adjunctive active iTBS has significant superiority in improving neurocognitive dysfunction for older adults with schizophrenia when compared to sham iTBS.

2. Methods

2.1. Search Strategy

English (PsycINFO, Cochrane Library, EMBASE, and PubMed) and Chinese (Chinese Journal Net and WanFang) databases were independently searched by two investigators (XYZ and XHY) on 25 January 2022. The search strategy was as follows: (intermittent theta burst stimulation OR iTBS OR intermittent theta burst transcranial magnetic stimulation OR transcranial magnetic intermittent theta-burst stimulation) AND (“schizophrenia”[MeSH] OR schizophrenic disorder OR disorder, schizophrenic OR schizophrenic disorders OR schizophrenias OR dementia praecox) AND (“aged”[MeSH] OR older OR elderly OR senior OR old-age OR aging). Additionally, we manually searched the reference lists from the included RCTs and relevant reviews.

2.2. Selection Criteria

In accordance with PRISMA guidelines [26], only studies meeting the following PICOS criteria were selected. Participants: Older adults (≥50 years old) suffering from schizophrenia. As recommended, an age ≥50 years has often been used as the cutoff value for “older adults” of the general population [27]. Intervention versus Comparison: Active iTBS plus antipsychotics versus antipsychotic monotherapy or sham iTBS plus antipsychotics. Outcomes: The primary outcome was the improvement in neurocognitive function as measured by the standardized rating scales such as the Mattis Dementia Rating Scale-2 (MDRS-2). The secondary outcomes recorded in this systematic review were total psychopathology as measured by the Brief Psychiatric Rating Scale (BPRS) [28] and the Positive and Negative Syndrome Scale (PANSS) [29], the dropout rate and adverse events. Study: Only published double-blinded RCTs investigating the neurocognitive effects of adjunctive iTBS in older adults suffering from schizophrenia were permitted for inclusion. Observational studies, review articles and case reports/series were excluded.

2.3. Data Extraction and Quality Assessment of Each Study

Data from each included RCT were extracted by two investigators (XYZ and XHY). If there were any differences, there was a discussion between the same investigators. A senior author (WZ) was consulted if needed. To acquire missing data from the included RCTs, we contacted the first and/or corresponding authors.
Two investigators (XYZ and XHY) independently assessed the study quality using the Jadad scale [30] and Cochrane risk of bias [31].

3. Results

3.1. Results of the Search

The PRISMA flow diagram of this systematic review is shown in Figure 1. A total of 100 hits in the English (n = 30) and Chinese databases (n = 70) were identified. Finally, two double-blinded RCTs [23,24] were included in this systematic review.

3.2. Sample Characteristics

Table 1 summarizes the characteristics of the two double-blinded RCTs (n = 132) that were included and compares the neurocognitive effects of adjunctive active iTBS (n = 66) versus sham iTBS (n = 66) in older adults with schizophrenia. The two RCTs were conducted in China. The total number of participants included in the analysis was 125 (Table 1). In the included RCTs, the mean age and illness duration were 63.4 years and 17.4 years, respectively. All patients were elderly people (100%) and inpatients (100%). Sessions were conducted five times per week with iTBS for four weeks in the two included RCTs. Male patients accounted for 53.6% of the sample. The use of antipsychotics is mentioned in detail in only one RCT (50%, 1/2) [24], involving a variety of antipsychotics (Table 1), and the doses of antipsychotics used in the two RCTs were 511 mg [23] and 535 mg [24] per day after the conversion to chlorpromazine equivalents, respectively.

3.3. Assessment of Study Quality

As shown in Figure 2, two RCTs were assessed as low risk regarding attrition bias and reporting bias according to the Cochrane risk of bias. Only one RCT was rated as low risk with regard to random sequence generation. The Jadad scores ranged from 4 to 5 across the two RCTs, indicating high-quality studies.

3.4. Neurocognitive Function

The neurocognitive effects of active iTBS compared with sham iTBS in older adults with schizophrenia are summarized in Table 2. Zhao et al. [23] found significant superiority of active iTBS over sham iTBS in improving neurocognitive function measured by MDRS-2 and its subscales (p < 0.05). In the other RCT [24], the findings on the neurocognitive effects of active iTBS compared with sham iTBS in older adults with schizophrenia were inconsistent (Table 2).

3.5. Total Psychopathology

As shown in Table 3, only one RCT reported the efficacy of active iTBS versus sham iTBS in treating total psychopathology in schizophrenia [23]. When compared to sham iTBS, active iTBS was significantly associated with improvement in total psychopathology as measured by the PANSS (p < 0.05) but not the BPRS (p > 0.05).

3.6. Dropout Rate and Adverse Events

The dropout rate and adverse events are summarized in Table 4. The dropout rate was reported in the two RCTs, ranging from 3.8% (3/80) to 7.7% (4/52). Only one study reported adverse events, finding no significant group difference.

4. Discussion

This study is the first systematic review to examine the neurocognitive effects of adjunctive iTBS in older adults suffering from schizophrenia. Only two RCTs [23,24] were included, involving 132 older adults with schizophrenia. The main findings of this systematic review are the following: first, two RCTs investigated the effects of adjunctive iTBS in treating neurocognitive function in older adults with schizophrenia, suggesting that iTBS may have some beneficial effects; second, only one RCT reported the efficacy of active iTBS versus sham iTBS in treating total psychopathology as measured by the PANSS and BPRS in schizophrenia, with mixed findings; and third, iTBS appeared to be safe and tolerable as an adjunct treatment in older adults with schizophrenia.
The main purpose of investigating iTBS is to monitor its neurocognitive effects, which has been achieved via multiple neurotherapeutic strategies including magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS) and nonconvulsive electrotherapy (NET) [32]. Several studies have found that NET appears to be effective as an adjunct treatment in schizophrenia [32] and treatment-refractory unipolar and bipolar depression [33,34,35] without serious associated neurocognitive impairments. However, the findings of the two RCTs [23,24] included in this systematic review on the neurocognitive effects of adjunctive iTBS for older adults with schizophrenia were inconsistent. Specifically, Zhao et al. [23] found iTBS affected all neurocognitive modalities, including five subscales (attention, initiation/perseveration, conceptualization, construction and memory), which reflected an overall improvement in attentional function, executive function, visuospatial skills and memory function [36]. However, Zhen et al. [24] found different effects of iTBS on neurocognitive patterns. Similarly, a recent systematic review reported inconsistent findings on the neurocognitive effects of MST in schizophrenia [37]. For example, Jiang et al. found that MST showed significantly less cognitive impairment with regard to immediate memory, language function, delayed memory and global cognitive function when compared to ECT [38]. Another study reported that MST led to a specific deficit in the Autobiographical Memory Inventory-Short Form (AMI-SF) without affecting other cognitive domains [39]. Taken together, the neurocognitive effects of neurotherapeutic strategies including iTBS and MST in patients with schizophrenia should be further investigated.
The mechanism of iTBS in improving the neurocognitive function of schizophrenia is unclear. A possible explanation for the mechanism is that iTBS could alter neuronal excitability levels in the primary motor cortex, which may affect neurocognitive function [40]. Although a meta-analysis of cognitive function may not be possible due to differences in measurements, we still found preliminary evidence that iTBS may have a modest enhancing effect on cognitive function in older adults with schizophrenia. Future studies focusing on the neurocognitive effects of adjunctive iTBS in older adults with schizophrenia need to be performed with specific cognitive batteries, such as the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) [41].
In this systematic review, only one RCT examined the effects of iTBS on total psychopathology as measured by the PANSS and BPRS in older adults with schizophrenia, and there were mixed findings [23]. Accumulating evidence has demonstrated the positive effects of iTBS on total psychopathology in younger adults with schizophrenia [25,42,43]. For example, a recent RCT found that iTBS had a particularly prominent effect as an adjunct treatment in improving the total symptoms in younger adults with schizophrenia [43]. In general, older adults suffering from schizophrenia have been associated with higher levels of depressive and anxiety symptoms than younger adults [44,45], which predicted poorer treatment outcomes. However, a recent study did not support the age-related differences in the antidepressant effects of citalopram in schizophrenia patients with subsyndromal depression [46]. The comparison of efficacy and safety of adjunctive iTBS in older versus younger adults with schizophrenia has not been investigated.
In this systematic review, the observed rates of discontinuation for any reason and adverse events were low in the iTBS groups, suggesting the good acceptability and the feasibility of adjunctive iTBS for older patients suffering from schizophrenia in clinical practice. Similarly, one systematic review focusing on the safety of adjunctive TBS for the general population found that 5% of subjects reported mild adverse events [47]. Another systematic review including studies focusing on children and adolescent patients found that TBS interventions were associated with mild adverse events [48]. Similarly, other neurotherapeutic strategies such as tDCS and tACS (transcranial alternating current stimulation) were safe and effective in treating patients with schizophrenia. For example, tDCS was effective and safe in ameliorating negative symptoms in patients with schizophrenia [49]. A recent review revealed that tACS was also a safe and effective strategy in improving neurocognitive function of patients with schizophrenia [50]. However, there have been no head-to-head studies comparing the safety of iTBS either with tDCS or tACS for older patients with schizophrenia.
The following limitations of this systematic review should be considered. First, given the heterogeneity in significance between the included RCTs, and the different methods they employed (for example, neurocognitive function was measured by four different assessment tools in the two RCTs), a meta-analysis could not be performed. Second, the small sample sizes (n = 132), ranging from 52 to 80, potentially reduced the studies’ power and increased the possibility of type II error. Third, only one RCT reported adverse events when evaluating the clinical efficacy of iTBS in older adults with schizophrenia. Finally, this systematic review on adjunctive iTBS for older adults suffering from schizophrenia has not been registered.

5. Conclusions

There is preliminary evidence for the beneficial effects of adjunctive iTBS in treating neurocognitive function in older adults with schizophrenia. Future RCTs with larger sample sizes focusing on the neurocognitive effects of adjunctive iTBS in older adults with schizophrenia are warranted to verify these findings.

Author Contributions

Study design: W.Z.; data extraction: X.Z. and X.Y.; data analysis: R.X., J.T., J.Y. and Z.S.; drafting the manuscript: X.Z. and X.Y.; critical revision of the manuscript: W.Z., X.H. (Xiong Huang) and X.H. (Xingbing Huang) All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by the Science and Technology Planning Project of Liwan District of Guangzhou (202004034), National Natural Science Foundation of China (82101609), Scientific Research Project of Guangzhou Bureau of Education (202032762), Guangzhou Health Science and Technology Project (20211A011045), Guangzhou Science and Technology Project of Traditional Chinese Medicine and Integrated Traditional Chinese and Western Medicine (20212A011018), China International Medical Exchange Foundation (Z-2018-35-2002), Guangzhou Clinical Characteristic Technology Project (2019TS67) and Science and Technology Program Project of Guangzhou (202102020658). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors declare no conflict of interest in conducting this study or preparing the manuscript.

References

  1. Palmer, B.W.; Heaton, R.K.; Paulsen, J.S.; Kuck, J.; Braff, D.; Harris, M.J.; Zisook, S.; Jeste, D.V. Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology 1997, 11, 437–446. [Google Scholar] [CrossRef] [PubMed]
  2. Keefe, R.S.; Fenton, W.S. How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophr. Bull. 2007, 33, 912–920. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Murante, T.; Cohen, C.I. Cognitive functioning in older adults with schizophrenia. Focus 2017, 15, 26–34. [Google Scholar] [CrossRef] [PubMed]
  4. McCleery, A.; Nuechterlein, K.H. Cognitive impairment in psychotic illness: Prevalence, profile of impairment, developmental course, and treatment considerations. Dialogues Clin. Neurosci. 2019, 21, 239–248. [Google Scholar] [CrossRef] [PubMed]
  5. Firth, J.; Stubbs, B.; Rosenbaum, S.; Vancampfort, D.; Malchow, B.; Schuch, F.; Elliott, R.; Nuechterlein, K.H.; Yung, A.R. Aerobic exercise improves cognitive functioning in people with schizophrenia: A systematic review and meta-analysis. Schizophr. Bull. 2017, 43, 546–556. [Google Scholar] [CrossRef] [Green Version]
  6. Golas, A.C.; Kalache, S.M.; Tsoutsoulas, C.; Mulsant, B.H.; Bowie, C.R.; Rajji, T.K. Cognitive remediation for older community-dwelling individuals with schizophrenia: A pilot and feasibility study. Int. J. Geriatr. Psychiatry 2015, 30, 1129–1134. [Google Scholar] [CrossRef]
  7. Mogg, A.; Purvis, R.; Eranti, S.; Contell, F.; Taylor, J.P.; Nicholson, T.; Brown, R.G.; McLoughlin, D.M. Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: A randomized controlled pilot study. Schizophr. Res. 2007, 93, 221–228. [Google Scholar] [CrossRef]
  8. Brunoni, A.R.; Sampaio-Junior, B.; Moffa, A.H.; Aparício, L.V.; Gordon, P.; Klein, I.; Rios, R.M.; Razza, L.B.; Loo, C.; Padberg, F.; et al. Noninvasive brain stimulation in psychiatric disorders: A primer. Braz. J. Psychiatry 2019, 41, 70–81. [Google Scholar] [CrossRef] [Green Version]
  9. Perera, T.; George, M.S.; Grammer, G.; Janicak, P.G.; Pascual-Leone, A.; Wirecki, T.S. The clinical TMS society consensus review and treatment recommendations for TMS therapy for major depressive disorder. Brain Stimul. 2016, 9, 336–346. [Google Scholar] [CrossRef] [Green Version]
  10. Goyal, N.; Nizamie, S.H.; Desarkar, P. Efficacy of adjuvant high frequency repetitive transcranial magnetic stimulation on negative and positive symptoms of schizophrenia: Preliminary results of a double-blind sham-controlled study. J. Neuropsychiatry Clin. Neurosci 2007, 19, 464–467. [Google Scholar] [CrossRef]
  11. Lee, S.-H.; Kim, W.; Chung, Y.-C.; Jung, K.-H.; Bahk, W.-M.; Jun, T.-Y.; Kim, K.-S.; George, M.S.; Chae, J.-H. A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations. Neurosci. Lett. 2005, 376, 177–181. [Google Scholar] [CrossRef] [PubMed]
  12. Tseng, P.-T.; Zeng, B.-S.; Hung, C.-M.; Liang, C.-S.; Stubbs, B.; Carvalho, A.F.; Brunoni, A.R.; Su, K.-P.; Tu, Y.-K.; Wu, Y.-C.; et al. Assessment of noninvasive brain stimulation interventions for negative symptoms of schizophrenia: A systematic review and network meta-analysis. JAMA Psychiatry 2022, 79, 770–779. [Google Scholar] [CrossRef] [PubMed]
  13. Hovington, C.L.; McGirr, A.; Lepage, M.; Berlim, M.T. Repetitive transcranial magnetic stimulation (rTMS) for treating major depression and schizophrenia: A systematic review of recent meta-analyses. Ann. Med. 2013, 45, 308–321. [Google Scholar] [CrossRef] [PubMed]
  14. Zheng, W.; Lan, X.-J.; Qin, Z.-J.; Yang, X.-H.; Shi, Z.-M. Low-frequency repetitive transcranial magnetic stimulation for children and adolescents with first-episode and drug-naïve major depressive disorder: A systematic review. Front. Psychiatry 2023, 14, 123. [Google Scholar]
  15. Whybird, M.; Coats, R.; Vuister, T.; Harrison, S.; Booth, S.; Burke, M. The role of the posterior parietal cortex on cognition: An exploratory study. Brain Res. 2021, 1764, 147452. [Google Scholar] [CrossRef]
  16. Hahn, B.; Robinson, B.M.; Leonard, C.J.; Luck, S.J.; Gold, J.M. Posterior parietal cortex dysfunction Is central to working memory storage and broad cognitive deficits in schizophrenia. J. Neurosci. 2018, 38, 8378–8387. [Google Scholar] [CrossRef] [Green Version]
  17. Zheng, L.N.; Guo, Q.; Li, H.; Li, C.B.; Wang, J.J. Effects of repetitive transcranial magnetic stimulation with different paradigms on the cognitive function and psychotic symptoms of schizophrenia patients. J. Peking Univ. Health Sci. 2012, 44, 732–736. [Google Scholar]
  18. Rachid, F. Safety and efficacy of theta-burst stimulation in the treatment of psychiatric disorders: A review of the literature. J. Nerv. Ment. Dis. 2017, 205, 823–839. [Google Scholar] [CrossRef]
  19. Blumberger, D.M.; Vila-Rodriguez, F.; Thorpe, K.E.; Feffer, K.; Noda, Y.; Giacobbe, P.; Knyahnytska, Y.; Kennedy, S.H.; Lam, R.W.; Daskalakis, Z.J.; et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): A randomised non-inferiority trial. Lancet 2018, 391, 1683–1692. [Google Scholar] [CrossRef]
  20. Mix, A.; Benali, A.; Eysel, U.T.; Funke, K. Continuous and intermittent transcranial magnetic theta burst stimulation modify tactile learning performance and cortical protein expression in the rat differently. Eur. J. Neurosci. 2010, 32, 1575–1586. [Google Scholar] [CrossRef]
  21. Grossheinrich, N.; Rau, A.; Pogarell, O.; Hennig-Fast, K.; Reinl, M.; Karch, S.; Dieler, A.; Leicht, G.; Mulert, C.; Sterr, A.; et al. Theta burst stimulation of the prefrontal cortex: Safety and impact on cognition, mood, and resting electroencephalogram. Biol. Psychiatry 2009, 65, 778–784. [Google Scholar] [CrossRef] [PubMed]
  22. Walther, S.; Kunz, M.; Müller, M.; Zürcher, C.; Vladimirova, I.; Bachofner, H.; Scherer, K.A.; Nadesalingam, N.; Stegmayer, K.; Bohlhalter, S.; et al. Single session transcranial magnetic stimulation ameliorates hand gesture deficits in schizophrenia. Schizophr. Bull. 2020, 46, 286–293. [Google Scholar] [CrossRef] [PubMed]
  23. Zhao, J.; Guo, Y.M.; Li, M.N.; Gao, J.; Fang, X.Y.; Zhou, C.; Chen, J.; Zhang, F.Q.; Zhang, X.R. Effects of theta burst stimulation mode repetitive transcranial magnetic stimulation on negative symptoms and cognitive function in elderly patients with chronic schizophrenia (in Chinese). Chin. J. Behav. Med. Brain Sci. 2021, 30, 577–583. [Google Scholar]
  24. Zhen, L.L.; Zou, X.J.; Peng, G.H.; Zou, K. Effects of theta burst stimulation mode repetitive transcranial magnetic stimulation on executive function in elderly patients with chronic schizophrenia (in Chinese). Chin. J. Gerontol. 2018, 38, 2947–2950. [Google Scholar]
  25. Wu, Y.; Wang, L.; Yu, F.; Ji, G.J.; Xiao, G.; Feifei, X.; Chunyan, Z.; Xingui, C.; Wang, K. Intermittent theta burst stimulation (iTBS) as an optimal treatment for schizophrenia risk decision: An ERSP study. Front. Psychiatry 2021, 12, 594102. [Google Scholar] [CrossRef] [PubMed]
  26. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [Google Scholar] [CrossRef] [Green Version]
  27. Zheng, W.; Luo, X.N.; Li, H.Y.; Ke, X.Y.; Dai, Q.; Zhang, C.J.; Ng, C.H.; Ungvari, G.S.; Xiang, Y.T.; Ning, Y.P. Prevalence of insomnia symptoms and their associated factors in patients treated in outpatient clinics of four general hospitals in Guangzhou, China. BMC Psychiatry 2018, 18, 232. [Google Scholar] [CrossRef] [Green Version]
  28. Overall, J.E.; Beller, S.A. The Brief Psychiatric Rating Scale (BPRS) in geropsychiatric research: I. Factor structure on an inpatient unit. J. Gerontol. 1984, 39, 187–193. [Google Scholar] [CrossRef]
  29. Kay, S.R.; Fiszbein, A.; Opler, L.A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 1987, 13, 261–276. [Google Scholar] [CrossRef]
  30. Jadad, A.R.; Moore, R.A.; Carroll, D.; Jenkinson, C.; Reynolds, D.J.; Gavaghan, D.J.; McQuay, H.J. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control. Clin. Trials 1996, 17, 1–12. [Google Scholar] [CrossRef]
  31. Higgins, J.P.; Altman, D.G.; Gotzsche, P.C.; Juni, P.; Moher, D.; Oxman, A.D.; Savovic, J.; Schulz, K.F.; Weeks, L.; Sterne, J.A.; et al. The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011, 343, d5928. [Google Scholar] [CrossRef] [Green Version]
  32. Li, M.Z.; Chen, L.C.; Rong, H.; Xu, S.X.; Li, Y.; Yang, Q.F.; Deng, W.F.; Yang, H.Z.; Kong, X.M.; Xiao, L.; et al. Low-charge electrotherapy for patients with schizophrenia: A double-blind, randomised controlled pilot clinical trial. Psychiatry Res. 2019, 272, 676–681. [Google Scholar] [CrossRef] [PubMed]
  33. Zheng, W.; Jiang, M.L.; He, H.B.; Li, R.P.; Li, Q.L.; Zhang, C.P.; Zhou, S.M.; Yan, S.; Ning, Y.P.; Huang, X. A preliminary study of adjunctive nonconvulsive electrotherapy for treatment-refractory depression. Psychiatr. Q. 2021, 92, 311–320. [Google Scholar] [CrossRef] [PubMed]
  34. Cai, D.B.; Zhou, H.R.; Liang, W.N.; Gu, L.M.; He, M.; Huang, X.; Shi, Z.M.; Hou, H.C.; Zheng, W. Adjunctive nonconvulsive electrotherapy for patients with depression: A systematic review. Psychiatr. Q. 2021, 92, 1645–1656. [Google Scholar] [CrossRef] [PubMed]
  35. Regenold, W.T.; Noorani, R.J.; Piez, D.; Patel, P. Nonconvulsive electrotherapy for treatment resistant unipolar and bipolar major depressive disorder: A proof-of-concept trial. Brain Stimul. 2015, 8, 855–861. [Google Scholar] [CrossRef]
  36. Matteau, E.; Dupré, N.; Langlois, M.; Jean, L.; Thivierge, S.; Provencher, P.; Simard, M. Mattis Dementia Rating Scale 2: Screening for MCI and dementia. Am. J. Alzheimers Dis. Other Demen 2011, 26, 389–398. [Google Scholar] [CrossRef] [PubMed]
  37. Zhang, X.Y.; Chen, H.D.; Liang, W.N.; Yang, X.H.; Cai, D.B.; Huang, X.; Huang, X.B.; Liu, C.Y.; Zheng, W. Adjunctive magnetic seizure therapy for schizophrenia: A systematic review. Front. Psychiatry 2021, 12, 813590. [Google Scholar] [CrossRef]
  38. Jiang, J.; Li, J.; Xu, Y.; Zhang, B.; Sheng, J.; Liu, D.; Wang, W.; Yang, F.; Guo, X.; Li, Q.; et al. Magnetic seizure therapy compared to electroconvulsive therapy for schizophrenia: A randomized controlled Trial. Front. Psychiatry 2021, 12, 770647. [Google Scholar] [CrossRef]
  39. Tang, V.M.; Blumberger, D.M.; McClintock, S.M.; Kaster, T.S.; Rajji, T.K.; Downar, J.; Fitzgerald, P.B.; Daskalakis, Z.J. Magnetic seizure therapy in treatment-resistant schizophrenia: A pilot study. Front. Psychiatry 2017, 8, 310. [Google Scholar] [CrossRef] [Green Version]
  40. Wischnewski, M.; Schutter, D.J.L.G. Efficacy and time course of theta burst stimulation in healthy humans. Brain Stimul. 2015, 8, 685–692. [Google Scholar] [CrossRef]
  41. Marder, S.R.; Fenton, W. Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr. Res. 2004, 72, 5–9. [Google Scholar] [CrossRef] [PubMed]
  42. Chen, X.; Ji, G.J.; Zhu, C.; Bai, X.; Wang, L.; He, K.; Gao, Y.; Tao, L.; Yu, F.; Tian, Y.; et al. Neural correlates of auditory verbal hallucinations in schizophrenia and the therapeutic response to theta-burst transcranial magnetic stimulation. Schizophr. Bull. 2019, 45, 474–483. [Google Scholar] [CrossRef] [PubMed]
  43. Wang, L.; Chen, X.; Wu, Y.; He, K.; Xu, F.; Xiao, G.; Hu, P.; Qiu, B.; Ji, G.J.; Wang, K. Intermittent theta burst stimulation (iTBS) adjustment effects of schizophrenia: Results from an exploratory outcome of a randomized double-blind controlled study. Schizophr. Res. 2020, 216, 550–553. [Google Scholar] [CrossRef]
  44. Jin, H.; Zisook, S.; Palmer, B.W.; Patterson, T.L.; Heaton, R.K.; Jeste, D.V. Association of depressive symptoms with worse functioning in schizophrenia: A study in older outpatients. J. Clin. Psychiatry 2001, 62, 797–803. [Google Scholar] [CrossRef] [PubMed]
  45. Rado, J.; Janicak, P.G. Pharmacological and clinical profile of recently approved second-generation antipsychotics: Implications for treatment of schizophrenia in older patients. Drugs Aging 2012, 29, 783–791. [Google Scholar] [CrossRef] [PubMed]
  46. Kasckow, J.; Fellows, I.; Golshan, S.; Solorzano, E.; Meeks, T.; Zisook, S. Treatment of subsyndromal depressive symptoms in middle-age and older patients with schizophrenia: Effect of age on response. Am. J. Geriatr. Psychiatry 2010, 18, 853–857. [Google Scholar] [CrossRef] [Green Version]
  47. Oberman, L.; Edwards, D.; Eldaief, M.; Pascual-Leone, A. Safety of theta burst transcranial magnetic stimulation: A systematic review of the literature. J. Clin. Neurophysiol. 2011, 28, 67–74. [Google Scholar] [CrossRef] [Green Version]
  48. Elmaghraby, R.; Sun, Q.; Ozger, C.; Shekunov, J.; Romanowicz, M.; Croarkin, P.E. A systematic review of the safety and tolerability of theta burst stimulation in children and adolescents. Neuromodulation 2022, 25, 494–503. [Google Scholar] [CrossRef]
  49. Valiengo, L.d.C.L.; Goerigk, S.; Gordon, P.C.; Padberg, F.; Serpa, M.H.; Koebe, S.; Santos, L.A.D.; Lovera, R.A.M.; Carvalho, J.B.d.; van de Bilt, M.; et al. Efficacy and safety of transcranial direct current stimulation for treating negative symptoms in schizophrenia: A randomized clinical trial. JAMA Psychiatry 2020, 77, 121–129. [Google Scholar] [CrossRef]
  50. Farcas, A.; Iftene, F. Findings, limitations and new directions in tACS studies in schizophrenia research: A scoping review. J. Psychiatr. Res. 2022, 151, 291–298. [Google Scholar] [CrossRef]
Jpm 13 00485 g001 550
Figure 1. PRISMA flow diagram.
Figure 1. PRISMA flow diagram.
Jpm 13 00485 g001
Jpm 13 00485 g002 550
Figure 2. Risk of bias [23,24]. Abbreviations: + or green: low risk of bias; ? or yellow: unclear risk of bias.
Figure 2. Risk of bias [23,24]. Abbreviations: + or green: low risk of bias; ? or yellow: unclear risk of bias.
Jpm 13 00485 g002
Table
Table 1. Summary of the characteristics of the included studies.
Table 1. Summary of the characteristics of the included studies.
Study
(Country)		N aSex b: Male (%)Diagnosis (%)Diagnostic CriteriaAge b: yrs (Range)Duration b of Illness (yrs)-Design
-Analysis
-Setting		AP: Dose (mg/d)Intervention:
-Device
-Brain region
-Stimulation Intensity		Treatment Duration (n/wks)Jadad Scores
Zhao et al., 2021
(China)		total: 52
iTBS: 26
sham: 26		66.7SCZ
(100%)		ICD-1063.3
(59–71)		33.2-DB
-OC
-inpatients		iTBS: CPZ-equ = 495
sham: CPZ-equ = 527		-NR
-L-DLPFC
-iTBS (100% MT) versus sham (100% MT, tilt the coil 90 degrees from the original stimulation position relative to the scalp)		4 (5/wks)5
Zhen et al., 2018 (China)total: 80
iTBS: 40
sham: 40		45.5SCZ
(100%)		DSM-IV63.4
(NR)		7.5-DB
-OC
-inpatients		iTBS: CPZ-equ = 554 c
sham: CPZ-equ = 516 c		-Magpro R100 (Tonica Elektronik A/S)
-L-DLPFC
-iTBS (80% MT) versus sham (80% MT, tilt the coil 180 degrees from the original stimulation position relative to the scalp)		4 (5/wks)4
a Data were extracted based on random assignment and the total number of participants included in the analysis was 125, of which 48 were from Zhao et al. (2021) and 77 were from Zhen et al. (2018). b Available data were extracted based on the mean baseline value of each included trial. c Including risperidone (n = 24), olanzapine (n = 22), aripiprazole (n = 9), quetiapine (n = 17), chlorpromazine (n = 4), ziprasidone (n = 4). Abbreviations: AP = antipsychotics; CPZ-equ = chlorpromazine equivalents; DB = double blind; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th version; ICD-10 = International Classification of Diseases, 10th version; iTBS = intermittent theta burst stimulation; L-DLPFC = left dorsolateral prefrontal cortex; MT = motor threshold; n = number of times; N = number of patients; NR = not reported; OC = observed case; SCZ = schizophrenia; sham = sham stimulation; wks = weeks; yrs = years.
Table
Table 2. Improvement in cognitive function after iTBS.
Table 2. Improvement in cognitive function after iTBS.
StudyCognitive FunctionPre-iTBS (Mean ± SD)Post-iTBS (Mean ± SD)Pre-Sham (Mean ± SD)Post-Sham (Mean ± SD)Findings a
Zhao et al., 2021MDRS-2:
Total scores109.7 ± 6.8116.5 ± 6.7107.9 ± 7.5108.7 ± 7.3p < 0.05
Attention30.3 ± 2.032.1 ± 2.030.3 ± 2.230.4 ± 2.2p < 0.05
Initiation/perseveration31.1 ± 1.833.3 ± 1.830.3 ± 2.230.5 ± 2.2p < 0.05
Conceptualization30.0 ± 1.531.4 ± 2.030.0 ± 1.930.3 ± 1.8p < 0.05
Construction4.9 ± 0.75.3 ± 0.54.6 ± 0.64.7 ± 0.6p < 0.05
Memory13.3 ± 2.114.4 ± 2.512.7 ± 1.612.9 ± 1.6p < 0.05
Zhen et al., 2018Digit span test:
Total scores15.6 ± 4.116.1 ± 4.216.2 ± 4.415.8 ± 3.9NS
Digit span forward10.6 ± 2.511.3 ± 1.910.8 ± 2.110.6 ± 2.5p < 0.05
Digit span backward5.2 ± 2.55.4 ± 2.15.1 ± 1.94.9 ± 1.6NS
Spatial span test:
Total scores12.0 ± 4.416.3 ± 4.211.9 ± 4.110.2 ± 3.9p < 0.05
Spatial span forward5.8 ± 2.17.5 ± 2.25.6 ± 1.96.2 ± 2.1p < 0.05
Spatial span backward6.2 ± 2.46.9 ± 3.16.5 ± 1.75.9 ± 2.4NS
WCST:
Response administered118.0 ± 14.0120.0 ± 17.0121.0 ± 15.0120.0 ± 11.0NS
Categories completed4.7 ± 1.35.2 ± 1.14.7 ± 1.14.6 ± 1.3NS
Total correct responses50.0 ± 10.054.0 ± 9.051.0 ± 9.049.0 ± 10.0NS
Total errors70.0 ± 18.063.0 ± 22.069.0 ± 21.072.0 ± 19.0NS
Percent errors59.8 ± 14.751.5 ± 12.256.4 ± 14.158.2 ± 12.1p < 0.05
Trials to complete first category25.2 ± 13.521.7 ± 14.123.5 ± 9.725.0 ± 11.4NS
Perseverative responses37.0 ± 11.541.1 ± 12.335.9 ± 13.239.8 ± 14.3NS
Perseverative errors55.3 ± 18.044.2 ± 17.651.5 ± 20.156.8 ± 22.3p < 0.05
Percent perseverative errors71.3 ± 12.662.7 ± 11.466.1 ± 11.770.5 ± 14.5p < 0.05
Nonperseverative errors17.4 ± 5.117.1 ± 7.518.6 ± 6.720.9 ± 5.8NS
Percent nonperseverative errors28.7 ± 12.230.3 ± 13.129.7 ± 11.432.1 ± 13.6NS
Failure to maintain set14.9 ± 6.813.3 ± 7.611.5 ± 6.713.5 ± 5.4NS
Percent conceptual level responses53.3 ± 17.063.5 ± 15.951.8 ± 18.856.9 ± 17.6p < 0.05
Abbreviations: iTBS = intermittent theta burst stimulation; MDRS-2 = Mattis Dementia Rating Scale-2; NS = not significant; WCST = Wisconsin Card Sorting Test. a Reflect the differences between groups in change between pre- and post-intervention values.
Table
Table 3. Improvement in clinical symptoms after iTBS.
Table 3. Improvement in clinical symptoms after iTBS.
StudyClinical EffectsPre-iTBS (Mean ± SD)Post-iTBS (Mean ± SD)Pre-Sham (Mean ± SD)Post-Sham (Mean ± SD)Findings a
Zhao et al., 2021BPRS32.1 ± 1.931.3 ±1.932.3 ± 2.432.2 ± 2.3NS
PANSS60.2 ± 3.756.7 ± 3.161.0 ± 2.860.7 ± 2.7p < 0.05
Zhen et al., 2018NR
Abbreviations: BPRS = Brief Psychiatric Rating Scale; iTBS = intermittent theta burst stimulation; NR = not reported; NS = not significant; PANSS = Positive and Negative Syndrome Scale. a Differences between groups in change between pre- and post-intervention values. a Differences between groups in change between pre- and post-intervention values.
Table
Table 4. Rates of dropout and adverse events.
Table 4. Rates of dropout and adverse events.
StudyAdverse EventsDropout Rate
EventsTotal (%)iTBS Group (%)Sham Group (%)Total (%)iTBS Group (%)Sham Group (%)
Zhao et al., 2021Intolerance1 (1.9)1 (3.8)04 (7.7)2 (7.7)2 (7.7)
Zhen et al., 2018NR3 (3.8)2 (5.0)1 (2.5)
Abbreviations: AEs = adverse events; iTBS = intermittent theta burst stimulation; NR = not reported.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Zhang, X.; Yang, X.; Shi, Z.; Xu, R.; Tan, J.; Yang, J.; Huang, X.; Huang, X.; Zheng, W. A Systematic Review of Intermittent Theta Burst Stimulation for Neurocognitive Dysfunction in Older Adults with Schizophrenia. J. Pers. Med. 2023, 13, 485. https://doi.org/10.3390/jpm13030485

AMA Style

Zhang X, Yang X, Shi Z, Xu R, Tan J, Yang J, Huang X, Huang X, Zheng W. A Systematic Review of Intermittent Theta Burst Stimulation for Neurocognitive Dysfunction in Older Adults with Schizophrenia. Journal of Personalized Medicine. 2023; 13(3):485. https://doi.org/10.3390/jpm13030485

Chicago/Turabian Style

Zhang, Xinyang, Xinhu Yang, Zhanming Shi, Rui Xu, Jianqiang Tan, Jianwen Yang, Xiong Huang, Xingbing Huang, and Wei Zheng. 2023. "A Systematic Review of Intermittent Theta Burst Stimulation for Neurocognitive Dysfunction in Older Adults with Schizophrenia" Journal of Personalized Medicine 13, no. 3: 485. https://doi.org/10.3390/jpm13030485

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop