|Year : 2022 | Volume
| Issue : 4 | Page : 129-148
Insights and future directions on the combined effects of mind-body therapies with transcranial direct current stimulation: An evidence-based review
Ingrid Rebello-Sanchez1, Karen Vasquez-Avila1, Joao Parente1, Kevin Pacheco-Barrios2, Paulo S De Melo1, Paulo E P Teixeira1, Kian Jong3, Wolnei Caumo4, Felipe Fregni1
1 Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, 96-13th Street, Charlestown, Boston, MA, USA
2 Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, 96-13th Street, Charlestown, Boston, MA, USA; Research Unit for the Generation and Synthesis of Evidence in Health, San Ignacio de Loyola University, Lima, Peru
3 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
4 Department of Surgery, School of Medicine, Federal University of Rio Grande do Sul (UFRGS); Laboratory of Pain and Neuromodulation at Hospital das Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
|Date of Submission||16-Jun-2022|
|Date of Decision||31-Aug-2022|
|Date of Acceptance||06-Sep-2022|
|Date of Web Publication||13-Dec-2022|
Dr. Felipe Fregni
Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, 96 13th Street, Charlestown, Boston, MA
Source of Support: None, Conflict of Interest: None
Mind-body therapies (MBTs) use mental abilities to modify electrical neural activity across brain networks. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that modulates neuronal membrane potentials to enhance neuroplasticity. A combination of these treatment strategies may generate synergistic or additive effects and thus has been more commonly tested in clinical trials, fostering a novel yet promising field of research. We conducted a literature search in four different databases including only randomized clinical trials (RCTs) that tested the combination of MBTs with tDCS. Ten studies (n = 461) were included. Combined protocols included meditation/mindfulness (8/10), biofeedback (1/10), and hypnosis (1/10). The RCTs were heterogeneous with regard to population, design, and types of outcomes. Based on the findings of this search, we provide here a content description, methodological and practical insights, and future directions for the field. We hope this review will provide future authors with information to facilitate the development of trials with improved protocols.
Keywords: Biofeedback, hypnosis, meditation, mind-body therapies, mindfulness, transcranial direct current stimulation
|How to cite this article:|
Rebello-Sanchez I, Vasquez-Avila K, Parente J, Pacheco-Barrios K, De Melo PS, Teixeira PE, Jong K, Caumo W, Fregni F. Insights and future directions on the combined effects of mind-body therapies with transcranial direct current stimulation: An evidence-based review. J Int Soc Phys Rehabil Med 2022;5:129-48
|How to cite this URL:|
Rebello-Sanchez I, Vasquez-Avila K, Parente J, Pacheco-Barrios K, De Melo PS, Teixeira PE, Jong K, Caumo W, Fregni F. Insights and future directions on the combined effects of mind-body therapies with transcranial direct current stimulation: An evidence-based review. J Int Soc Phys Rehabil Med [serial online] 2022 [cited 2023 May 28];5:129-48. Available from: https://www.jisprm.org/text.asp?2022/5/4/129/363467
| Introduction|| |
Mind-body therapies (MBTs) are a group of interventions strengthened on the premise that the relationship between the mind and the body can positively influence an individual's overall health. The examples include meditation, yoga, tai chi, qigong, breathing exercises, biofeedback, hypnosis, and acupuncture and evidence shows their usefulness in different neuropsychiatry diseases.,,,,,,,,
Transcranial direct current stimulation (tDCS) is a low-cost, safe, noninvasive neuromodulation technique. In its machinery, it modulates the neural membrane resting potentials. Clinically, it has shown to reduce symptomology and improve motor, sensory, and cognitive processing in many neuropsychiatric disorders.
Since tDCS modulates and facilitates underlying neural activity, its optimal effect should be achieved when combined with another behavioral therapy.,, On the other hand, there are data evidencing the direct effect of MBTs in the central nervous system and the recruitment of complex brain networks.,,,,, Therefore, the combination with tDCS could augment neuroplasticity in brain networks primed by the MBT and increase the effect of these interventions. A few randomized controlled trials have been performed in that matter, marking the emergence of a growing field.,,,,,,,,,,
Our objective is to provide a discussion concerning the different perspectives, limitations, and challenges of combining tDCS with MBTs, backed on the findings of a systematic literature search. We intend to aid future researchers interested in this topic by supplying a broad overview of the published literature and consistently suggesting future directions for the field.
| Methods|| |
In May 2021, we searched in online US-based databases (PubMed/Medline, Cochrane CENTRAL, and American Psychological Association [APA] PsycNet), and in December 2021 in a non-US database (LILACS), using terms to identify tDCS studies with meditation/mindfulness therapies, hypnotherapy, biofeedback, yoga, acupuncture, qigong, and tai chi. These therapies were selected based on the most common MBTs used by patients and those studied in the neurology field. We also checked the cited references in each one of the included articles for related studies.
PubMed, Cochrane and LILACS
("transcranial direct current stimulation" OR tdcs) AND ("mind-body therapy" OR "mind-body therapies" OR meditation OR mindfulness OR mindful OR hypnosis OR biofeedback OR yoga OR tai chi OR qigong OR acupuncture OR "acupuncture therapy" OR "breathing exercises").
American Psychological Association PsycNet
("transcranial direct current stimulation" OR tdcs) AND ("mind-body therapy" OR "mind-body therapies" OR meditation OR mindfulness OR mindful OR hypnosis OR biofeedback OR yoga OR tai chi OR qigong OR acupuncture OR "acupuncture therapy" OR "breathing exercises") filtered by a clinical trial.
The inclusion criteria were as follows: (i) being a randomized controlled trial; (ii) having at least one arm of combined MBT and tDCS; (iii) article available in English, Portuguese, Spanish, or French. We did not include case report, case series, reviews, and studies performed on animals.
Study selection, data extraction, and critical appraisal
Abstract screening, full-text screening, and data extraction were performed by three independent authors (KV-A, JP, and IR-S) and discrepancies were resolved by a third reviewer (KP-B). In the cases where data were reported in graphs and not in numerical values, the WebPlotDigitizer-Copyright-2010-2020 Ankit Rohatgi was used to acquire the means and the upper limit values which were later transformed into standard error and standard deviation (SD) using mathematical equations. If the results were reported in other forms, we excluded the study from the effect size calculation. To help illustrate the current findings, we calculated the within-and between-effect sizes of the included studies, using Hedges' g statistic due to the small sample sizes. For each outcome, we used the mean and the SD pre-and postintervention, as well as the mean difference, with the MAVIS v1.1.3 effect size calculator. In the cases where only the change of the difference was reported and we had the values of preintervention, we calculated the postintervention mean and SD using mathematical equations. The effect sizes of the main effects were calculated for factorial trials when possible. Moreover, to have an overall evaluation of the current methodological rigor of published articles, we used Version 2 of the Cochrane risk-of-bias tool for randomized trials 2.
| Results|| |
We identified 366 articles, 301 in the initial search in May and 59 from an additional search done in December 2021. Six titles were identified through manual and citation searching [Figure 1]. After abstract and full-text review, ten studies were included and twelve reports analyzed (2 articles were secondary analyses [Pollinini et al. 2020 and Brown et al. 2019] of two other trials [Ahn et al. 2019 and Witkiewitz et al. 2019, respectively]). We did not find published RCTs that combined tDCS with qigong, tai-chi, or acupuncture, although we did find three abstracts of yoga studies, but with no published results. We also found 12 ongoing trials, ten of which were of tDCS combined with meditation/mindfulness, one with acupuncture, and one with biofeedback [[Appendix 1] for the complete list,,,,,,,,,,,].
[Table 1] summarizes the information regarding the study design, population characteristics, and interventions of each one of the studies. The studies' populations were healthy subjects, patients with major depressive disorder, alcohol use disorder, or pain due to knee osteoarthritis. The articles were composed mostly of small to moderate sample sizes (95 subjects being the largest) or over-stratified samples, as is the case of Robinson et al. which conducted a 2 × 2 × 2 factorial design with 87 participants. Most of the studies were outpatient, aside from Ahn et al. which used home-based tDCS concurrently with home-guided mindfulness-based meditation. They evaluated subjects' satisfaction with the devices used and the way the procedure occurred and found great responses in terms of confidence, easiness, and helpfulness, with no important differences between intervention groups. [Table 2] summarizes the tDCS and MBT protocols of each study.
Tables summarizing the calculated within-and between-effect sizes are available on [Appendix 2], according to different categories of outcome: Pain [Table S1], cognitive [Table S2], addiction [Table S3], mindfulness state, and emotional intelligence outcomes [Table S4], psychological [Table S5]. Regarding safety, there was no report of important adverse events, although Witkiewitz et al. described having patients that dropped out of the study due to not tolerating sensations of tDCS. Only three out of ten trials collected mechanistic data, i.e., electroencephalogram (EEG) patterns (Hunter et al. and Guleken et al.) and quantitative sensory testing (QST) measures (Ahn et al.). The overall risk of bias ranged from moderate to high [Appendix 3].
Combination with mindfulness
Eight out of ten trials combined tDCS with meditation/mindfulness. Due to the lack of consensus regarding its definition, we accepted the definitions established by the authors themselves. Mindfulness and meditation have been used interchangeably on several occasions, although they are subtle different terms. Mindfulness means a nonjudgmental awareness to the present moment, while meditation is a mindfulness technique that consists of formal practice of self-regulated attention to enhance the awareness of ourselves and the environment.,, However, the consensual definition of mindfulness/meditation practice is not defined, and there are no conventional treatment guidelines available, allowing multiple technique variants to be implemented. In this review, none of the eight articles that studied meditation therapies used the same protocol. They varied in terminology, number and duration of sessions, and administration mode (self or group guided). The number of tDCS sessions ranged from 1 to 12, with an average of 6.5 sessions. Most of the sample populations were healthy individuals (4/8), but the combination was also tested on treatment-resistant depressive disorder (2/8) and chronic knee OA (1/10). Significant between-group differences were found in mindfulness associated with tDCS in pain-related outcomes, such as pain scales (Numeric Rating Scale for pain, Western Ontario and McMaster Universities Osteoarthritis index, and QST (pain thresholds and conditioned pain modulation) in knee OA population; l the Digit Span Forward measure in patients with treatment-resistant major depressive disorder; and specifically in the inhibitory control measured by the Stop Signal Test in alcohol users.
Most studies did not specify how the training was performed or accounted for the therapy training or previous experience effects. While most of the trials were performed on healthy individuals, only Hunter et al. screened subjects considering their previous experience with meditation. Not only it might be harder to detect improvements in healthy individuals, but there seem to be structural and functional connectivity differences between the brains of experienced meditators and the average population.,,, Selecting nonnaïve individuals might increase even more the likelihood of a ceiling effect, especially if studying outcomes such as mindfulness state, given that we would expect these subjects to reach the ceil of improvement more easily.
On top of that, considering that experienced meditators don't need as much instruction to reach a mindfulness state as would a naïve meditator, it might also be that they benefited from sham meditation in control groups, jeopardizing the detection of between-group differences. It is crucial that trials applying MBT interventions have at least a reasonable level of uniformed practice between groups. What adds concern is that most of the trials did not report the MBT training strategy or its timeline, when we expect these skills to be laborious to develop (e.g., reaching a mindfulness state).
Combination with hypnotherapy
Hypnotherapy is the psychotherapeutic use of hypnotic induction to achieve better clinical outcomes. Hypnosis is defined by the APA as a state of consciousness with focused attention, reduction of peripheral awareness, and an increased response to suggestion. The only study in this review assessing the combination of hypnotherapy and tDCS was Beltran Serrano et al. The study compared four different healthy groups: (1) active tDCS; (2) hypnotic suggestion (HS); (3) active tDCS and HS; and (4) sham tDCS and HS. The authors identified within group differences some pain outcomes for the hypnotherapy and sham tDCS group on the heat pain threshold and the cold pressor thresholds, and in the hypnotherapy and active tDCS, only differences on the heat pain threshold.
Hypnotherapy effects, on the contrary of meditation, don't seem to be related to the amount of practice done by the subject, but rather to his/her inner susceptibility. Interestingly, research in the field has far identified that there is variability in the competence to respond to hypnotic induction and/or suggestion between different individuals. Currently, there are scales to identify different hypnotizability levels, which have been associated with different EEG and neuroimaging metrics,,,, and clinical response. The study of Beltran Serrano et al. did apply a screening hypnotizability scale and chose a cutoff point to select individuals according to their capability to respond to HS. Although much still is discussed over the applicability of these scales, in this matter, there seems to be an advantage for hypnotherapy research.
Combination with biofeedback
Biofeedback was defined as a loop intervention that involves the measurement of a physiological parameter and its transformation into an auditory and/or visual signal – monitored with the purpose of teaching the patient how to modify it. In accordance, motor imagery, visual mirror feedback, and brain-computer interface were not considered biofeedback interventions in our review, and only one study of biofeedback plus tDCS was found. Guleken et al. conducted a single-blinded, randomized trial with 16 healthy young individuals to analyze the supportive effects of tDCS when added to neurofeedback (NFB) in cognitive outcomes of selective attention, response time, and suppression. The participants were assigned to either NFB (i.e., electroencephalography feedback through visual representations on a screen) or NFB plus tDCS, with no full control group. The calculated averaged effect sizes are reported in [Table S2] and show significant within-group differences but no between-group differences on continuous performance task sub-items. However, the authors reported that the EEG frequency bands between the NFB plus tDCS group when compared to only NFB, had a statistically significant increase in alpha (F [3.21] = 3.807, P = 0.025) beta2 (F [3.21] =3.570, P = 0.031) and theta/beta (F [3.21] =4.270, P = 0.017).
Guleken et al. did not report addressing the effects of training practice. Again, techniques such as interpreting physiological surrogates in biofeedback can be laborious to develop. It is important to consider that using biofeedback techniques in a trial usually requires the use of complex devices that can be unintuitive to the participant. Therefore, it is necessary to consider the exposure of each participant to similar devices and software, since familiarity to the technique can predict better performance. For this to be addressed, it is necessary a training phase, where every individual must undergo a few practice sessions with a brief test, in the end, to assure that everyone starts the intervention in the same level of expertise. These test scores could be used to adjust the analysis to the level of expertise at baseline.
Mind-body therapies combined with transcranial direct current stimulationt: A growing field
The prevalence of chronic pain and psychiatry conditions (i.e., major depressive disorder and anxiety disorders) are escalating globally, as well as the incidence of opioid and antianxiety drugs dependence., As supported by the findings of this search, we consider the combination of MBT and tDCS promising as a safe, nonaddicting, and unexpensive alternative for the treatment of neuropsychiatry conditions. Furthermore, based on our search, the first articles combining tDCS with MBTs were published in 2017, and since then, we have observed an exponential increase of publications [Figure 2], with 12 on-going trials. This points to a novel yet growing and expandable field, especially due to the need for more remote treatments to reach rural and underrepresented populations, and to fit the new requirements of postpandemic world. The combination of MBTs with tDCS in home-based protocols seems feasible, as supported by the feasibility reports of the included study of Ahn et al. and the numerous trials applying home-based biofeedback, meditation, hypnotherapy, or tDCS.,,, This is largely facilitated by the evolution of portable user-friendly tDCS devices, and health software compatible to smartphones.
|Figure 2: Scientific production of mind-body therapies and tDCS combination This graph represents the scientific records to date related to the combination of tDCS and mind-body therapies, including ongoing clinical trials and published articles. tDCS: Transcranial direct current stimulation|
Click here to view
| Discussion|| |
The combination of tDCS with MBTs is feasible and safe, with mindfulness apparently being the most feasible adjunct therapy. Most likely that is due to its low cost, easy implementation (guided recordings and no need for an in-person therapist), and increased evidence in the literature compared to other MBTs. Nonetheless, the lack of studies on therapies such as tai-chi, qigong, and acupuncture may be partially due to high costs related to the need for personalized guidance and moderate infrastructure (i.e., materials and equipped spaces). The concomitant association of tDCS with MBTs that demand physical movement (e.g., tai-chi, qigong) requires higher complexity.
However, the data for combined tDCS and MBTs – even for mindfulness/meditation– come mostly from the pilot and proof-of-concept studies testing clinical outcomes in healthy subjects, still far from impacting real clinical practice. Assessments of neurophysiological correlates (including multimodal neuroimaging [EEG and functional magnetic resonance imaging], autonomic response [heart rate variability], and cortical excitability studies with TMS) are still scarce and certainly missed. These surrogates are essential to better explore MBTs' mechanisms of action and neural signatures. Therefore, there is a need for more mechanistic trials in the field. Data from mechanistic trials could help the development of biomarkers or monitoring tools for the subjects' state of engagement to the MBT and thus allow for it to be controlled for in the analysis. Furthermore, they could serve the purpose of identifying different patterns of susceptibility of response across different subjects and help foster more individually-tailored approaches. In fact, researchers should build prediction models of response, including both clinical and physiological covariates, to identify the subset of individuals that benefit the most from the combined therapy and the factors associated with it. In that matter, the rationale for sample selection should also be revisited. If not added as sample selection criteria, the previous experience with the MBT needs to be accounted for in the design or in the analysis, especially for studies combining tDCS with meditation/mindfulness.
Furthermore, mechanistic data will serve in the development of optimized targeted protocols with tDCS, since a fully comprehension of the physiological framework that underlie the MBT is essential to propose any mechanism of synergism with tDCS. This is a brain stimulation technique that does not induce action potentials, rather it changes the neuronal membranes' excitability and modulates circuits' response to different stimuli. Thus, a spatial correlation between the tDCS target area (electrode placement) and brain circuits primed by the MBT in question is needed., For this reason, we suggest categorizing the MBTs in cognitive/emotional oriented (e.g., meditation/mindfulness, biofeedback, and hypnosis) and sensory-motor oriented MBTs (e.g., Yoga, qigong, tai-chi), based on the hypothesis that certain MBTs may activate similar neural networks according to the predominant tasks associated with their practice. Cognitive/emotional-oriented MBTs, such as meditation and hypnosis, might use neural networks associated with emotional and executive processing such as prefrontal networks. Therefore, the association of cognitive/emotional oriented MBTs with tDCS may strengthen the modulation of its respective networks. Sensory-motor oriented MBTs would involve body movement (such as Yoga, qigong, and tai-chi) and movement representation techniques (such as motor imagery), and we could infer that they would activate predominantly areas that are also activated during the specific exercises, as the primary motor cortex (M1) and supplementary motor areas. Therefore, the previously mentioned areas could be used to explore the best location for the tDCS stimulation when combined with MBTs.
It is also essential that the trials optimize the number of tDCS sessions and follow current evidence on the montage and current density for each health condition. For example, we found an average of 6.3 tDCS sessions overall, lower than those used in previous positive trials, ranging from ten to even 60.,, It has been suggested that an extended number of tDCS sessions is fundamental to inducing long-lasting neuroplasticity., In fact, findings from a dose-response RCT suggest that a minimum of 15 daily sessions is needed to achieve a clinically meaningful result (50% decrease in reported pain) in patients with fibromyalgia using high-definition tDCS. To compare, only three out of ten trials performed ≥ 10 tDCS sessions (Ahn et al. 2019, Guleken et al. 2020, Galen et al. 2019). However, many studies were feasibility pilot trials, as the state of the evidence at this point requires.
A final suggestion for future researchers is that the study design should consider a further exploration of the main and combined effects. Therefore to (i) explore the potential placebo effect; (ii) detangle main effects; and (iii) investigate synergistic or additive effects of the interventions, the ideal is to use a full-factorial design, which should be considered parallel to feasibility issues of conducting such trials.
| Conclusion|| |
The combination of tDCS and MBTs is a growing field that needs further research with larger sample sizes, standardized, evidence-based tDCS and MBTs protocols, and better study reporting. We hope this review will provide future authors with information to facilitate the development of improved trials' protocols.
Financial support and sponsorship
This work was financially supported by National Center for Complementary and Alternative Medicine (R01 AT009491-01A1).
Conflicts of interest
There are no conflicts of interest.
| Supplementary Material|| |
| APPENDIX 1: Ongoing Clinical Trials|| |
| APPENDIX 2: Within- and Between- Effect Sizes for Pain, cognitive, addiction, mindfulness state and emotional intelligence, and psychological outcomes.|| |
| APPENDIX 3: Detailed analysis of risk of bias using RoB2 tool|| |
Domain 01 - Randomization process: We considered articles that had well-defined designs, detailed description of the method of randomization and an innocent rate of differences in baseline characteristics (or well addressed) as having low risk of bias for this domain (Hunter et al., Witkiewitz et al. Ahn et al.). Still, none of the articles mentioned who was responsible for generating the random allocation sequence. In concern to randomization, aside from Clarke et al., the other articles were at least described as having a random allocation, (Monnart et al., Robinson et al., Chin-Lu Hung et al., Guleken et al., Badran et al.). However, the description was not appropriate, so they were consequently checked as some concerns. Although Beltran Serrano et al. did not properly define the method of randomization, we considered as low risk due to the detailed description of allocation concealment, elsewhere mentioned only by Hunter et al. Since Badran et al. also did not report baseline characteristics adequately, we considered that their article had a high risk of bias for this domain.
Domain 02 - Deviations from intended interventions: Most articles had at least the subjects unaware of their intervention group allocation, aside from Monnart et al. that conducted an open-label trial and Chin-Lu Hung et al. that do not mention blinding. Clarke et al. and Guleken et al. did not blind staff members, while Robinson et al., Witkiewitz et al. and Badran et al. describe their trials as double-blinded, however using nonspecific terms like "experimenters", "careers", "research staff", making the information of who was masked imprecise. Beltran Serrano et al. did not perform sham hypnotherapy, and due to the crossover design, we had some concerns. Robinson et al. and Witkiewitz et al. report that the active group presented a considerably higher rate of sensations like itching, heat, and tingling, which might have jeopardized the success of blinding. Regarding the intention to treat effect, many articles excluded subjects already randomized that were outliers or that dropped out of the study from the final analysis. Those were not considered as an appropriate ITT (Clarke et al., Robinson et al., Hunter et al.). Monnart et al. report having 15 dropouts that were not well-defined in terms of their temporal relation to the randomization procedure, which turned our conclusion difficult. Although Witkiewitz et al. report they use an intention-to-treat analysis, aside from the non-eligible subjects excluded after the randomization, many eligible ones were excluded for other reasons, and we did not consider this to be an ITT approach either. Chin-Lu Hung et al., Guleken et al. and Badran et al. provide no information of any deviations from intended interventions or whether the analysis was made by the original assigned groups.
Domain 03 - Missing outcome data: Ahn et al., Clarke et al., Beltran Serrano et al. and Witkiewitz et al. adequately report the rate of missing data. Of those, Witkiewitz et al. had the most important rate of missingness, but also were the only to report having accounted for this issue in the analysis and described sensitivity analysis for missing data. Ahn et al. had all the assessments complete, and Clarke et al. had outcome measurements available for nearly all subjects. The three of them were considered to have low risk of bias for this domain. Furthermore, we concluded that Beltran Serrano et al. had a lower risk of bias than other trials that also failed to specifically report missing data (Hunter et al., Monnart et al., Chin-Lu Hung et al., Guleken et al., Badran et al., Robinson et al.), because they mentioned there were no dropouts, and this was a short protocol with assessment of neurophysiological outcomes happening at the same moment as the intervention sessions. Consequently, it is less likely that there were missing outcomes, and if there were, that they depended on their true value.
Domain 04 - Measurement of the outcome: None of the articles was judged as having an inappropriate method of measuring the outcome. Active and control groups had similar protocols, and outcome assessments happened at the same conditions. However, aside from Beltran Serrano et al., none of the authors specifies if the outcome assessor was blinded. Therefore, we also considered to have low risk of bias the trials that provided more detailed information of blinding (Ahn et al., Hunter et al.) instead of only defining the trial as "double-blind" (Badran et al.). Robinson et al. and especially Witkiewitz et al. were exceptions to that rule because they had higher rates of tDCS-related sensations on the active arms, making the success of blinding questionable. Although Beltran Serrano et al. did not perform sham hypnotherapy, they had reliable neurophysiological assessments with blinded assessors. Likewise, even though Guleken et al. study was only single-blind, we did not define it as having a high risk of bias for this domain because the primary outcome was based on performance, making it less likely that the assessment was influenced by knowledge of intervention received. Although Clark et al. opted for a computerized assessment method, which minimized the likelihood of assessment bias, the extent to which the unblinded assessors were involved is not clear. Due to the considerable amount of missing information and to the open-label design, Chin-Lu Hung et al. and Monnart et al., respectively, were defined as having a high risk of bias for this domain.
Domain 05 - Selection of the reported result: Witkiewitz et al. report outcome measurements and statistical procedures that are in accordance with pre-specified intentions available on ClinicalTrials.gov. We could also find the trial's project of Beltran Serrano et al. on ClinicalTrials.Gov, and it evidenced that the planned primary outcome was changed, which raised some concerns. We could not find protocols for any of the other trials, however, we still considered as having a low risk of bias for this domain those articles that had a clear primary outcome and well-explained analysis, including assumptions needed for different statistical plans. That was the case of Witkiewitz et al. and Hunter et al. Badran et al. do not provide any information regarding statistical analysis.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]