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Completeness of Descriptions of Repetitive Transcranial Magnetic Stimulation Intervention

A Systematic Review of Randomized Controlled Trials of rTMS in Depression

Chantebel, Romain, MD*; Chesneau, Adélise, MD*; Tavernier, Elsa, PhD†‡; El-Hage, Wissam, MD, PhD*†§; Caille, Agnès, MD, PhD†‡

doi: 10.1097/YCT.0000000000000546
Review
Open
SDC

Objectives Repetitive transcranial magnetic stimulation (rTMS) is an innovative therapeutic option in major depressive disorder (MDD). A complete description of the procedure in reports of randomized controlled trials (RCTs) is a prerequisite for implementation of rTMS in clinical practice. The aim of this study was to evaluate the completeness of descriptions of the intervention in RCTs assessing rTMS in MDD.

Methods We performed a systematic review of RCTs evaluating rTMS in MDD and published until August 2016. We searched PubMed, the Cochrane library, and PsycINFO to identify eligible trials. The completeness of the intervention description was evaluated by the use of an adapted-to-rTMS version of the Template for Intervention Description and Replication (TIDieR) checklist. We defined core items that are the most essential to be reported. Missing information was then sought from additional sources and by e-mailing authors.

Results We identified 98 trials reporting 134 interventions. None of the interventions were completely described in the full text of the articles, even after searching additional sources. After contacting the authors, 14 (10.4%) of 134 interventions were completely described. The core items were completely described in 74 (55.2%) of 134 interventions after contacting the authors.

Conclusions We found that rTMS interventions delivered in RCTs are incompletely reported, which prevents their adequate implementation in clinical practice and accurate interpretation of their efficacy. We encourage authors, editors, and reviewers to use the existing reporting guidelines and specifically the TIDieR checklist when describing the intervention. We provide an adapted-to-rTMS TIDieR checklist that could help in the reporting of future trials.

From the *Clinique Psychiatrique Universitaire,

INSERM, CHRU de Tours;

Université de Tours, Université de Nantes, INSERM; and

§Université de Tours, INSERM, iBrain, Tours, France.

Received for publication May 16, 2018; accepted August 10, 2018.

Reprints: Agnès Caille, MD, PhD, CHU de Tours, CIC 1415, 2 Blvd, Tonnellé, 37000 Tours, France (e-mail: agnes.caille@univ-tours.fr).

W.E.H. reports personal fees from EISAI, personal fees from Janssen, personal fees from Lundbeck, personal fees from Otsuka, personal fees from UCB, grants from the Fondation de France, and grants from the French Ministry of Health, French National Hospital Program for Clinical Research (PHRC), outside the submitted work. The remaining authors have no conflicts of interest or financial disclosures to report.

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Major depressive disorder (MDD) has been considered a clinical manifestation of altered activities of the brain neuronal networks and their synchronization.1–3 One of the current fields of interest in psychiatry is the modulation of brain network activities in which loops in the cortex network are targeted with different techniques. Recent years have been marked by growing interest in 2 neuromodulation techniques, namely, transcranial direct current stimulation and repetitive transcranial magnetic stimulation (rTMS).

Several studies have assessed rTMS to treat MDD with different rTMS regimens, but few systematic reviews have evaluated the effectiveness of rTMS in MDD.4,5 Results of meta-analysis are inconsistent and vary from supporting the short-term efficacy of rTMS in MDD treatment6 and in treatment-resistant MDD7 to not supporting novel (accelerated, synchronized, and deep) rTMS intervention efficacy in unipolar or bipolar depression.5 Research concerning rTMS is still ongoing8 and contradictory results in the assessment of the efficacy of rTMS call for well-designed and well-performed studies to correctly assess the best settings and indications.

From a methodological point of view, rTMS is a typical example of a nonpharmacological complex intervention used in psychiatry. Repetitive transcranial magnetic stimulation comprises several components that can influence treatment response.9 The effects of rTMS can depend on stimulation parameters that affect the electromagnetic field generated in the body such as coil configuration, waveform parameters, pulses and session programming, but also environmental factors that could affect the clinical response such as cognitive activity during rTMS sessions.10 Repetitive transcranial magnetic stimulation requires a precise description of the spatial and temporal characteristics of the magnetic signal defining the dosage of the intervention. However, such a description may not be exhaustive enough, which results in an apparently unexplained variation in therapeutic effect. Thus, a detailed description of such nonpharmacological complex interventions is crucial11 to facilitate the inclusion of trials in systematic reviews and to allow intervention transfer to clinical practice.

The Consolidated Standards of Reporting Trials (CONSORT) 2010 statement has been developed to improve the overall quality of reporting of randomized controlled trials (RCTs).12 More recently, the issue of intervention description was more specifically addressed in the Template for Intervention Description and Replication (TIDieR) developed to increase the completeness of intervention reporting and the replicability of interventions. The TIDieR is a 12-item checklist developed by an international group of experts and stakeholders in collaboration with the CONSORT steering group12 that aims to provide the minimum information that needs to be described when reporting an intervention. The TIDieR checklist has also been used to assess the quality of reporting of complex interventions such as nonpharmacological stroke intervention or cardiac rehabilitation.13,14 Although the importance of adequate reporting of rTMS protocols has been underlined,10 to our knowledge, no study has systematically assessed the completeness of descriptions of rTMS in published RCTs. Incomplete reporting can limit rTMS implementation in clinical practice and hamper accurate interpretation and comparison of study results.

The aim of this study was to assess the completeness of reporting of rTMS procedures in published RCTs of MDD by using the TIDieR checklist and to assess whether missing information on intervention can be found in additional sources or by e-mailing trial authors.

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MATERIALS AND METHODS

Eligibility Criteria for RCTs

To be eligible for inclusion in this methodological systematic review, studies had to be RCTs comparing one or more rTMS interventions targeting any region of the cortex to any sham method as a control. Trials assessing theta burst stimulation were excluded. Participants of the trials had to have a diagnosis of MDD as defined in the Diagnostic and Statistical Manual of Mental Disorders III, IV, or V. Trials must have reported at least one depression scale rating as an outcome. Reports of secondary publications of RCTs, phase I/II trials, pilot studies, nonrandomized and pseudo-randomized studies, observational studies, protocols of RCTs, meeting abstracts, letters, comments, books, and reports of studies pooling data from more than one RCT were excluded. Participants may have had ongoing pharmacological or psychotherapeutic treatment together with the rTMS protocol; however, our assessment focused on the quality of rTMS reporting. If multiple arms with rTMS co-existed in the same trial, we considered each rTMS arm as a separate intervention. Reports had to be published in English.

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Search Strategy

The sample of RCTs was identified via a systematic search of the following electronic databases: Cochrane Central Register of Controlled Trials, NCBI PubMed, and PsycINFO. We included all eligible publications up to August 31, 2016. Search equations varied according to the database and are provided in Appendix 1 (Supplemental Digital Content 1, http://links.lww.com/JECT/A76). Reference lists of all included RCTs and meta-analyses of the use of rTMS in MDD were also searched to identify eligible trials. All retrieved references were downloaded in Zotero and duplicates were deleted. Two reviewers (R.C., E.T.) independently screened titles and abstracts in a random order to identify the relevant studies according to eligibility criteria. The same two researchers also examined the full texts and assessed their eligibility. Any concerns about study eligibility were discussed by the authors and resolved by discussion and consensus.

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Data Extraction

A standardized Microsoft Excel extraction form was used and the data extraction sheet was explained to all reviewers before the beginning of extraction. The first 10 articles of RCTs were assessed independently in a random order by two of four reviewers: two psychiatrists (A.Ch. and R.C.) and two methodologists (E.T. and A.Ca.). Disagreements in ratings were discussed after assessment of the 10 RCT articles to standardize the extraction process. These 10 RCT articles were included in the final analysis. The remaining RCTs were screened by two reviewers among two psychiatrists (A.Ch., R.C.) and one methodologist (E.T.), who independently assessed the completeness of rTMS reporting. Each RCT article was assessed by two reviewers. Disagreements were resolved by discussion and consensus between reviewers, with the third reviewer arbitrating if needed. Reviewers were not blinded to the journal titles or to the study authors or institutions.

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General Characteristics of Individual Trials

For each trial, we recorded the general characteristics, such as journal, year of publication, and number of patients randomly allocated.

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Assessment of Intervention Description

Completeness of the intervention description was assessed by using the TIDieR checklist that we adapted to fit rTMS settings. From the 12 items of the original TIDieR, we excluded number 6, the “How” item that recommends the description of the mode of delivery because it was not relevant in the assessment of rTMS protocols. Repetitive transcranial magnetic stimulation is an intervention with only one possible mode of delivery: individually and face to face. For 5 items, we added subitems to specify relevant-to-rTMS elements that need to be described. An item was considered adequately reported if all the subitems were reported. Our modified TIDieR form (Table 1, column A) was reviewed by a psychiatrist trained in the use of rTMS (W.E.H.). Nine items or subitems were defined as core items corresponding to those strictly required to replicate the signal at the right spot. These items are the type of coil (3.b), stimulation frequency (4.a), percentage of resting motor threshold (RMT) (4.b), targeted area (4.c), angle of the coil with the patient head (4.f), number of sessions (8.a), number of weeks (8.b), number of pulses (8.c), and session duration (8.d).

TABLE 1

TABLE 1

Completeness of reporting was assessed for each rTMS intervention in the original full-text article. Then, all written additional information sources such as supplementary data, reference lists, clinical trial registration records, or trial protocols were explored. Items were rescored when relevant with information obtained in additional sources.

If some items were still incompletely reported, corresponding authors of the original trials were contacted by e-mail. The author's most recent available e-mail address was identified by the contact address in their most recently referenced publication. If no valid e-mail was found, the author's name was entered in Google to search for an e-mail address. If the first author or corresponding author e-mail address was not available, we searched for any co-author e-mail address. One reminder e-mail was sent after 14 days. Items were rescored according to authors' responses.

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Data Analysis

Data are summarized by frequency (percentage) for categorical data and means (SD) or median (interquartile range) for quantitative data. R v3.2.3 was used for analysis.

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RESULTS

After title, abstract, and full-text screening and removing duplicates, the final sample comprised 98 trials reporting 134 interventions (Fig. 1A). Of the 98 trials, 67 evaluated 1 experimental rTMS intervention group, 27 evaluated 2 experimental rTMS interventions, 3 evaluated 3 experimental rTMS interventions, and 1 evaluated 4 experimental interventions with sham rTMS as a control. Those trials were published between 1995 and 2016 (median year of publication = 2008). All eligible studies were published in English. The sample size of RCTs ranged from 10 to 325 patients. The median sample size was 40 patients (interquartile range = 22–60). Six of the 98 articles were short reports (no more than 3 pages not counting the bibliography); the remaining were full-length articles. Figure 2 provides the number and percentage of interventions for which each checklist item was assessed as complete in the original article, after searching additional sources, and after contacting authors by e-mail.

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

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Completeness of rTMS Intervention Description in Full Texts

None of the interventions provided an exhaustive report of rTMS intervention according to our checklist (25 items or subitems). A brief presentation description (item 1) and rationale (item 2) were reported for all 134 interventions. Intervention materials (item 3) were fully described for only 19 interventions (14.2%) due to the poor reporting of head support or seat. For item 4, related to the description of the procedure, subitems for stimulation frequency, percentage of RMT, and targeted area were reported for 133 (99.3%), 130 (97.0%), and 131 (97.8%) interventions, respectively, but mental activity of patients during rTMS was reported in only 10 studies (7.5%). The angle of the coil with the head (subitem 4.f) was reported for 67 interventions (50.0%). The description of intervention providers (subitem 5a) was available for 43 (32.1%) of 134 interventions, but their training (subitem 5b) was reported for only 18 interventions (13.4%). The place where the intervention took place was described for 72 interventions (53.7%). Item 8 (when and how much) was fully described for 121 interventions (90.3%). Management of missing sessions was described for only 2 interventions; the description of how the targeted area was validated was provided for 124 interventions (92.5%) and how the percentage of RMT was validated for 97 (72.4%). The description of intervention modification during the trial (item 10) was found for only 4 interventions (3.0%). Planned assessment of adherence (item 11) was less reported (1/134 interventions, 0.7%) than the actual assessment of adherence (108/134 interventions, 80.6%). The description of our defined core items was complete for 61 interventions (45.5%).

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Completeness of rTMS Intervention Description With Additional Sources

Additional sources of data were found for 12 trials reporting 19 interventions (14.2%). Improvement in description concerned items 4 (4a and 4f), 5a, and 9 (9a, 9b, and 9d), but it did not increase the proportion of interventions with complete descriptions for all items or for our predefined core items.

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Completeness of rTMS Intervention Description After E-mail Communication

For 13 trials, we did not find any authors' e-mail addresses. Thus, we sent e-mails to 85 authors. We received 15 responses to complete the data for 19 interventions (Fig. 1B). After considering information obtained from author responses, rTMS was fully described for 14 interventions (10.4%). The core items were exhaustively described in 74 interventions (55.2%). If we excluded from the core items, the subitem 4.f related to the coil angle description, 115 interventions (85.8%) were completely reported for the remaining core items.

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DISCUSSION

This methodological systematic review of RCTs aimed to assess the completeness of reporting of rTMS interventions for MDD. Our results showed that no intervention was completely reported according to our predefined items based on the TIDieR checklist. A search of additional sources allowed us to obtain the description of some further items, but complete description of 10.4% of rTMS interventions was obtained only after an e-mail contact with authors. Our predefined core items, which are essential procedural components needed for intervention replication, were completely described in the full text for 45.5% interventions, increased to 55.2% interventions after contacting authors.

These results provide valuable information and have several implications. First, incomplete descriptions of rTMS impedes correct implementation of research results into clinical practice.15,16 Lack of some intervention components can prevent intervention replication or cause inadequate or ineffective rTMS use. When trying to synthesize available evidence for rTMS in a systematic review, it can also limit interpretation of the results.

Our results are consistent with other studies that evaluated the completeness of descriptions of nonpharmacological interventions in other areas such as cardiac rehabilitation,13 speech language intervention,17 or telehealth-delivered dietary interventions.18

As in other studies, we found that the intervention brief name and rationale were well described,13,19 whereas intervention tailoring, modifications, and planification of the assessment of fidelity were consistently incompletely described.17,20

Incomplete description of rTMS interventions in RCTs might be explained by several factors. First, those who write the protocol and the trial report may be unaware of the recent reporting guidelines CONSORT and TIDieR, and this can be reinforced by the fact that not all the journals endorsed those guidelines in their editorial policy. Some could also argue that incomplete description is due to word count limitation in research articles, but this can be resolved by the use of online supplemental material without this limitation issue. Journals have an important role to play to improve completeness of intervention description in requiring authors to comply with reporting guidelines and in supporting unlimited online supplementary data.

Second, incomplete reporting of the angle of the coil with the head could be explained by the fact that the angle used by convention is a 90-degree angle to the ground.21 The angle differs only in sham rTMS, in some trials, in which an ineffective angle of 45 degrees and misplacement of the coil could be used to mimic rTMS procedures. After analyzing our results, we found two items describing the angle, the 4.f angle and the 9.a description of the targeted area. We consider that the item 4.f. angle can be removed from the checklist for a future evaluation of the rTMS description because it is a part of the description of the “how targeted area.”

Third, rTMS is a complex nonpharmacological intervention requiring the description of a large number of components to provide a complete description of some TIDieR items. This point has been raised previously.10 In our study, we found a high proportion of complete descriptions for the “when” and “how much” items as compared with previous studies assessing the reporting of nonpharmacological interventions.13 Descriptions of the number of rTMS sessions, number of pulses, duration of one session, and total duration of treatment were complete in more than 95% interventions. Nevertheless, we acknowledge that the number of pulses could be more precisely defined and suggest that future protocols or reports of RCTs should also include the description of the number of pulses per train, the number of trains, and the time between each train.10

The Peterchev recommendations do not mention the description of environmental factors that could influence rTMS efficacy and focus on the description of coil or electrode configuration parameters and stimulus waveform parameters. One component of our checklist was the description of mental activity during rTMS; it was described in the full text for 10 of 134 interventions and obtained after contacting authors for 18 further interventions. The importance of reporting guided mental activity or, in contrast, reporting of the absence of indications provided to participants regarding their mental activity can be discussed. However, recent studies show that some kinds of mental activities such as day dreaming,22 hypnosis,23 or internal speaking24 may be correlated with spontaneous electrical activity of the brain. This spontaneous electrical activity may interact with the cortex stimulation and modify the rTMS efficiency.25 We thus consider that mental activity is a component of the rTMS intervention that needs to be reported for an accurate replication and a better understanding of their relation with rTMS efficacy.

This is the first study to provide an assessment of the completeness of the description of the rTMS intervention in RCTs. Strengths of this study include the use of a systematic search of trials evaluating rTMS in MDD without limitations on date or database, data assessment performed by two independent raters, and use of the TIDieR checklist. We further adapted the TIDieR checklist to accurately assess the rTMS characteristics. Our poor response rate (16.5%) to our author survey might be explained by a lack of interest or sensitization of authors to the issue or difficulties in recalling some intervention details for older trials.

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CONCLUSIONS

Components of rTMS interventions delivered in RCTs are incompletely reported, which prevents their adequate implementation in clinical practice and limits the correct interpretation of their efficacy. Our findings encourage authors, editors, and reviewers to use and spread the existing reporting guidelines, specifically the TIDieR checklist. Our adapted-to-rTMS TIDieR checklist could be used to help in the reporting of future trials.

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Keywords:

repetitive transcranial magnetic stimulation; major depression disorder; intervention description

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