Methods
Search strategy and methods
We searched for objective studies before 5 December 2018. The search terms were “generalized anxiety disorder”, “anxiety”, “transcranial magnetic stimulation”, “TMS” and “rTMS”. The Cochrane Library, PubMed, ISI Web of Knowledge, EMBASE and PsycInfo were retrieved. The Chinese search terms were ‘重复经颅磁刺激’, ‘磁刺激’, ‘经颅磁刺激’, ‘跨颅磁刺激’, ‘广泛性焦虑障碍’ and ‘焦虑症’. We searched the following Chinese data libraries: Wanfang Data, Chinese National Knowledge Infrastructure, VIP Information, Huayi-Taiwan data and SinoMed.
Studies were included in accordance with PICOS (Participants, Intervention, Comparison, Outcomes and Study design) inclusion criteria: (1) participants: have a diagnosis of GAD according to one of the following diagnostic criteria: the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),39 the 10th revision of the International Classification of Disease (ICD-10),40 the third edition of the Chinese Mental Illness Diagnostic Standard (CCMD-3)41 or the MINI-international Neuropsychiatric Interview (MINI);42 (2) intervention: used rTMS intervention; rTMS could be combined with drug therapy; (3) comparison: the control group used sham rTMS or received no intervention; (4) outcomes: the primary outcome was rTMS efficacy in decreasing the anxiety symptoms of patients with GAD; the secondary outcomes were acceptability and safety of rTMS; (5) study design: RCT. Studies such as case reports, case series, observational studies, meta-analyses and systematic reviews were not included in this study.
Literature search and data extraction
Two reviewers (HC and LJ) independently performed the literature search using the same search strategy. All retrieved literature was managed using the EndNote X7 software. Literature screening and data extraction were performed as follows: (1) duplicates of retrieved studies were excluded. (2) The studies were screened by checking the titles together with their abstracts and studies found to be inappropriate were excluded. (3) As for the remaining literature, full text was checked to confirm their eligibility for inclusion. If the two search results were different, the two researchers reviewed the literature together and analysed the reasons for differences. If the opinions were still inconsistent, a third researcher (HL) would examine the literature and make a final decision. The literature screening process of this study is shown in figure 1.
Figure 1Flowchart of the literature screening.
The extraction form for included information was developed by HC. Two researchers (LJ and JZ) extracted the relevant data independently. The extracted data included the following items: study author, year of publication, diagnostic criteria, blind method, sample characteristics, stimulation site, stimulation frequency, stimulation intensity based on resting motor threshold, treatment regimen and sham rTMS methods. HRC checked the extraction results.
Quality evaluation of literature
In accordance with the criteria of bias risk given by the Cochrane handbook, two researchers (HL and WL) independently evaluated the risk of bias. When there was discrepancy between the evaluations of the two researchers, the conclusion would be determined by a third researcher (JP). The specific contents included the following: (1) random sequence generation (selection bias); (2) allocation concealment (selection bias); (3) blinding of subjects and researchers (performance bias); (4) blinding of outcome data (detection bias); (5) incomplete outcome data (attribution bias); (6) selective reporting (reporting bias); (7) other bias. When the assessment information was lacking, we contacted the corresponding author via email.
Outcome measures
The primary outcome of this study was rTMS efficacy in decreasing the anxiety symptoms of patients with GAD, which was measured using the reductions of anxiety symptoms assessed by the Hamilton Anxiety Scale (HAMA).43
The secondary outcomes: (1) acceptability, which was measured using the dropout rates during the treatment courses. (2) Safety, which was assessed using the number of adverse events like nausea, headache, syncope, insomnia, epilepsy or burned by electrode.
We used Review Manager (RevMan) V.5.3 to compute the combined effects of relative risk (RR), standardised mean deviation (SMD) and CIs. I2 test was used to estimate heterogeneity level (I2=25% meant low-level heterogeneity, 50% medium and 75% high).44 A fixed-effects model was used when there was no significant heterogeneity (I2<50%, p≥0.1), while a random-effects model was selected when heterogeneity was significant (I2≥50%, p<0.1).
Subgroup analysis and meta-regression analysis
Subgroup analyses were conducted in the left hemisphere versus right hemisphere studies, high frequency (>1 Hz) versus low frequency (≤1 Hz) studies, and high treatment times (>20 times) versus low treatment times (≤20 times) studies.
The sources of heterogeneity were explored using meta-regression analysis. Meta-regression analysis was performed using Stata V.15.0 statistical software.45
Assessment of reporting biases and sensitivity analysis
The Cochrane funnel plot was used to detect potential publication bias. The planned sensitivity analyses: (1) open-label RCTs will be excluded. (2) The international studies will be excluded.
GRADE assessment
Quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method.46 The quality of evidence grades were as follows: (1) high quality, further study was difficult to affect the reliability of the efficacy evaluation results; (2) medium quality, further study was easy to affect the reliability of the efficacy evaluation results and was very likely to change the outcome of the evaluation; (3) low quality, further research was very easy to affect the reliability of the efficacy evaluation results and the evaluation outcome was very likely to change; (4) extremely low quality, the results of any efficacy evaluation were uncertain. Two authors (YW and WL) independently used the GRADE method to rate the overall evidence quality.