- Email: [email protected]
Comparative efficacy and acceptability of electroconvulsive therapy versus repetitive transcranial magnetic stimulation for major depression: A systematic review and multiple-treatments meta-analysis
Accepted Manuscript Title: Comparative Efficacy and Acceptability of Electroconvulsive Therapy versus Repetitive Transcranial Magnetic Stimulation for Major Depression: a Systematic Review and Multiple-Treatments Meta-Analysis Author: Jian-jun Chen Li-bo Zhao Yi-yun Liu Song-hua Fan Peng Xie PII: DOI: Reference:
S0166-4328(16)30805-1 http://dx.doi.org/doi:10.1016/j.bbr.2016.11.028 BBR 10568
To appear in:
Behavioural Brain Research
Received date: Revised date: Accepted date:
10-10-2016 11-11-2016 15-11-2016
Please cite this article as: Chen Jian-jun, Zhao Li-bo, Liu Yi-yun, Fan Songhua, Xie Peng.Comparative Efficacy and Acceptability of Electroconvulsive Therapy versus Repetitive Transcranial Magnetic Stimulation for Major Depression: a Systematic Review and Multiple-Treatments Meta-Analysis.Behavioural Brain Research http://dx.doi.org/10.1016/j.bbr.2016.11.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Comparative Efficacy and Acceptability of Electroconvulsive Therapy versus Repetitive Transcranial Magnetic Stimulation for Major Depression: a Systematic Review and Multiple-Treatments Meta-Analysis
Jian-jun Chen1,2,3,4,5,6, Li-bo Zhao6,7, Yi-yun Liu1,2,6,8, Song-hua Fan1,2,6,8, Peng Xie1,2,6,7,8,#
1Institute
of Neuroscience, Chongqing Medical University
2Chongqing 3Institute
Key Laboratory of Neurobiology, Chongqing Medical University
of Life Sciences, Chongqing Medical University
4Department 5Canada
of Obstetrics and Gynecology, the First Affiliated Hospital of Chongqing Medical University
- China -New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University
6Institute
of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University
7Department
of Neurology, Yongchuan Hospital of Chongqing Medical University
8Department
of Neurology, the First Affiliated Hospital of Chongqing Medical University,
#corresponding
author:
Professor Peng Xie Department of Neurology The First Affiliated Hospital at Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China Tel.: +86-23-68485490 Fax: +86-23-68485111 E-mail: [email protected]
Highlights 1. ECT was the most efficacious, but least tolerated. 2. R-rTMS was the best tolerated treatment for MDD. 3. B-rTMS appears to have the most favorable balance between efficacy and acceptability.
ABSTRACT Backgrounds: The effects of electroconvulsive therapy (ECT) and bilateral, left prefrontal, and right prefrontal repetitive transcranial magnetic stimulation (rTMS) on major depressive disorder (MDD) have not been adequately addressed by previous studies. Here, a multiple-treatments meta-analysis, which incorporates evidence from direct and indirect comparisons from a network of trials, was performed to assess the efficacy and acceptability of these four treatment modalities on MDD. Method: The literature was searched for randomized controlled trials (RCTs) on ECT, bilateral rTMS, and unilateral rTMS for treating MDD up to May 2016. The main outcome measures were response and drop-out rates. Results: Data were obtained from 25 studies consisting of 1288 individuals with MDD. ECT was non-significantly more efficacious than B-rTMS, R-rTMS, and L-rTMS. Left prefrontal rTMS was non -significantly less efficacious than all other treatment modalities. In terms of acceptability, R-rTMS was non-significantly better tolerated than ECT, BrTMS, and L-rTMS. ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B-rTMS (25%), R-rTMS (8%), and L-rTMS (2%). R-rTMS was the besttolerated treatment with the cumulative probabilities of being the best-tolerated treatment being: R-rTMS (52%), BrTMS (17%), L-rTMS (16%), and ECT (14%). Coherence analysis detected no statistically significant incoherence in any comparisons of direct with indirect evidence for the response rate and drop-out rate. Conclusions: ECT was the most efficacious, but least tolerated, treatment, while R-rTMS was the best tolerated treatment for MDD. B-rTMS appears to have the most favorable balance between efficacy and acceptability. Key words: depression, MDD; meta-analysis; transcranial magnetic stimulation, TMS, rTMS, electroconvulsive therapy, ECT
INTRODUCTION Major depressive disorder (MDD, major depression) is a debilitating mental disorder affecting up to 15% of the general population and accounting for 12.3% of the global burden of disease (1). To date, increasing evidence from biochemical, neuropsychological, postmortem, and neuroimaging studies indicates that MDD is not likely caused by a single brain region or neurotransmitter system, but rather is a system-level disorder affecting several integrated pathways (2, 3). Electroconvulsive therapy (ECT) is a well-established and effective treatment method for MDD superior to both placebo and sham ECT (anesthesia only) (4, 5). Some researchers even consider ECT to be the most effective treatment for MDD (6). Of MDD patients who receive ECT, approximately 70% to 80% show significant improvement (6), and ECT is effective in half of patients with treatment-resistant depression (TRD) (7). However, ECT is complicated by a number of side effects including cognitive impairment; so many patients are reluctant to engage in ECT treatment due to the risks and stigma associated with cognitive side effects, which has motivated attempts at developing treatment alternatives (8). Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive method of brain stimulation for the treatment of patients with serious neuropsychiatric disorders including MDD (9). Unlike ECT, rTMS does not require anesthesia or induction of seizures. RTMS is divided into bilateral rTMS (B-rTMS), left prefrontal rTMS (L-rTMS), and right prefrontal rTMS (R-rTMS) according to the stimulation location. Most studies of rTMS in MDD focus on highfrequency (5-20 Hz) stimulation to the left dorsolateral prefrontal cortex, and L-rTMS has been shown to have positive antidepressive effects (10, 11). Some randomized controlled trials (RCTs) have demonstrated that R-rTMS shows significantly greater improvement in depression scores compared with sham rTMS (12, 13), and our previous research has shown that L-rTMS and R-rTMS have a similar efficacy on MDD patients (14). Moreover, a 2012 systematic review showed that B-rTMS is a promising treatment for MDD (15), and our previous research also found that bilateral and unilateral rTMS had comparable efficacies on MDD patients (16). Hitherto, ECT has been traditionally viewed as the superior treatment modality vis-a-vis rTMS (17), but this conclusion has been primarily based on RCTs of ECT versus L-rTMS. There is still lack of quantitative data comparing the efficacy of ECT versus B-rTMS or R-rTMS in MDD. To this end, although standard meta-analyses are an effective tool, they can only compare two alternative treatments at a time; moreover, if no trials directly compare two interventions, it is impossible to compare their relative efficacies (18). In contrast, multiple treatments meta-analyses use a technique that incorporates evidence from both direct and indirect comparisons from a network of trials of different interventions to better estimate summary treatment effects. Our group used this method to compare the efficacy and tolerability of antidepressants for MDD in children and adolescents, and the results has been published in
Lancet in 2016 (19). Therefore, here we applied a multiple-treatments meta-analysis to compare the efficacy and acceptability of B-rTMS, R-rTMS, L-rTMS, and ECT in the treatment of MDD. METHODS Study Selection This systematic review and meta-analysis was conducted and reported according to the PRISMA statement (http://www.prisma-statement.org/). A comprehensive literature search of RCTs comparing ECT with rTMS was conducted up to May 2016 through the major scientific and medical databases, including international databases (PubMed, CCTR, Web of Science, and Embase) and two Chinese databases (CBM-disc and CNKI). The key search terms were “depression” AND (“transcranial magnetic stimulation” OR “TMS” OR “repetitive TMS” OR “rTMS”) AND (“electroconvulsive therapy” OR “ECT”). No language or publication year limitation was imposed. To avoid omitting relevant trials, conference summaries and reference documents listed in the obtained articles were checked. Among the identified studies, only those meeting the following criteria were selected for subsequent analyses: (i) RCTs comparing one treatment against another (B-rTMS, L-rTMS, R-rTMS, and ECT); (ii) assessing mood by the Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS), or Clinical Global Impression (CGI); (iii) patients over 18 years of age without metallic implants or foreign bodies, dementia, personal or family history of epileptic seizures, severe suicidal risk, organic brain damage, severe agitation or delirium, substance abuse, alcohol or drug dependence, and/or medically unfit for general anesthesia. Studies with pregnant patients were excluded because rTMS and ECT have unclear fetal side effects (20). Studies were excluded if they: (i) had no random allocation; (ii) enrolled subjects with ‘narrow’ depression diagnoses (e.g., postpartum depression) or secondary depression diagnoses (e.g., vascular depression); (iii) used rTMS and ECT concomitantly with a new antidepressant without wash out period; and (iv) case reports and reviews. Data Extraction Two reviewers independently verified all potentially suitable RCTs by the aforementioned inclusion and exclusion criteria and the completeness of data abstraction. Any disagreement was resolved by consensus and, if needed, a third reviewer was consulted. Data retrieved from the included RCTs were recorded in a structured fashion as follows: (i) sample characteristics: mean age, gender, mean depression score, treatment strategy used, presence of TRD; (ii) rTMS parameters: stimulation location, frequency, motor threshold, and duration; (iii) primary outcome measure: response was defined as at least a 50% reduction in the absolute HDRS or MADRS score from baseline, or significant improvement in the CGI, at the conclusion of therapy (21) with a preference for HDRS; and (iv) secondary outcome measure: overall drop-out rates at the study's end. For data that could not be directly retrieved, good faith efforts were applied to obtain the data by dispatching e-mails to the author, researching other studies citing the RCT in question, and
researching associated conference summaries. Bias Risk in Individual Studies Two reviewers independently assessed bias risk of the eligible studies according to the Cochrane handbook. We selected the following items to assess the bias risk: (1) did the authors conduct randomization? (2) did the authors conduct allocation concealment? (3) did the authors conduct blind treatment? and (4) were the baseline clinical characteristics matched between two groups. Studies with three or more ‘NO’ were still excluded. Statistical Analysis In order to make the interpretation of current results easier for clinicians (22), the response rate (a dichotomous primary outcome for efficacy) was used instead of a continuous symptom score. If the baseline scores, standard deviations (SD), and endpoint means were provided instead of the dichotomous efficacy outcomes, we estimated the number of responding patients through a validated imputation method. (23) To perform a clinically sound analysis, we used a worst-case scenario analysis of drop-out patients, assuming all such patients failed to respond to treatment. (24) First, with a random-effects model, we performed a meta-analysis of augmentation agents that had direct comparisons. For each analysis, we assessed heterogeneity using the Chi-square based Q test and I squared index (I2). (25) We performed the analyses using RevMan5.0 software (Cochrane Information Management System [IMS]). Second, we performed multiple-treatment meta-analysis using an arm-based, random-effects model within an empirical Bayes framework using Markov chain Monte Carlo method (26). The model allowed for estimating effect sizes for all possible pair-wise comparisons of augmentation agents. P-values of less than 0.05 were used to assess significance. We also computed and ranked the probabilities for each treatment's efficacy (27). The ranking of the competing treatments was assessed with the median of the posterior distribution for the rank of each treatment. We performed this analysis using WinBUGS (Imperial College and MRC, London, UK) and R v2.15.0 (R Development Core Team, Vienna, Austria). The coherence of an analyzed network – i.e., that indirect and direct evidence on the same comparisons do not disagree beyond chance – is the key assumption behind multiple-treatments meta-analysis. Whenever indirect estimates could be built with a single common comparator, the ratio of odds ratios for indirect vs. direct evidence is calculated to estimate incoherence. The disagreement between direct and indirect evidence with a 95% confidence interval excluding unity is defined as incoherent (24). RESULTS The electronic literature search resulted in 557 potentially relevant studies, of which 25 eligible articles were pooled for analysis (28-52) (Figure 1). Overall, 1288 individuals were randomly assigned to one of the four treatment modalities and were included in the multiple-treatments meta-analysis with all 1288 patients included in the efficacy
analysis (25 studies) and 820 patients included in the acceptability analysis (12 studies). The mean duration of the studies was 3.04 weeks, and the mean sample size was 25.7 participants per group (range: 6–147). The main characteristics of the included RCTs are described (Tables 1 and 2). All the 25 included studies conducted the randomization, two studies did not conduct allocation concealment, seven studies did not conduct blind treatment and the baseline clinical characteristics were matched between two groups in all included studies (Table 2). As these studies displayed minimal or no bias risk, all of them were included in the metaanalysis. Direct comparisons for the four treatment modalities showed no statistically significant differences in response rates between any two treatment modalities (Table 3). However, the odds ratio (OR) non-significantly favored ECT over LrTMS and R-rTMS with pooled ORs of 1.43 [95% confidence interval (CI), 0.92-2.22] and 2.19 (95% CI, 0.72-6.70), respectively. B-rTMS was non-significantly superior to L-rTMS, but non-significantly inferior to R-rTMS, with pooled ORs of 1.70 (95% CI, 0.74-3.92) and 0.93 (95% CI, 0.63-1.37), respectively. R-rTMS was comparably efficacious to LrTMS. These results obtained from 25 independent analyses without adjustment for multiple testing (i.e., about two CIs would be expected to exclude unity by chance alone). For drop-outs, statistically significant differences did not exist between the treatment modalities. Overall, heterogeneity was moderate. In the meta-analyses of direct comparisons, we found no I 2 values higher than 75%. From the multiple-treatments meta-analysis on response rates, ECT was non-significantly more efficacious than BrTMS, R-rTMS and L-rTMS with pooled ORs of 1.27 (95% CI, 0.58-2.61), 1.14 (95% CI, 0.63-1.94), and 1.65 (95% CI, 0.88-2.83), respectively. L-rTMS was non-significantly less efficacious than B-rTMS and R-rTMS with pooled ORs of 0.90 (95% CI, 0.46-1.52) and 0.96 (95% CI, 0.59-1.44), respectively. In terms of acceptability, R-rTMS was nonsignificantly better tolerated than ECT, B-rTMS, and L-rTMS with pooled ORs of 0.47 (95% CI, 0.05-1.39), 0.94 (95% CI, 0.15-2.45), and 0.57 (95% CI, 0.07-1.56), respectively. Coherence analysis detected no statistically significant incoherence in any comparisons of direct with indirect evidence for the response rate and drop-out rate. Figure 2 showed the distribution of probabilities of each treatment modality being ranked at each of four possible positions. ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B-rTMS (25%), R-rTMS (8%), and L-rTMS (2%) (Figure 2A). R-rTMS was the besttolerated treatment with the cumulative probabilities of being the best-tolerated treatment being: R-rTMS (52%), BrTMS (17%), L-rTMS (16%), and ECT (14%) (Figure 2B). DISCUSSION Nowadays, metabolomics has been extensively used to identify potential biomarkers for psychiatric disorders (53, 54). Although many works has used metabolomics to identify biomarkers for MDD (55, 56), there are still no objective
methods to diagnose MDD. Besides, there are no treatment methods that could cure MDD with 100% response rate. Here, this multiple-treatments meta-analysis was based on 25 studies consisting of 1288 individuals randomly assigned to ECT, B-rTMS, R-rTMS or L-rTMS for MDD. We retrieved almost all relevant RCTs, and the overlooked literature that were not indexed by international databases were likely to be of low quality and would not significantly affect the results of this review (57). Although the results were statistically non-significant, ECT and L-rTMS were the most efficacious and least efficacious treatments, respectively, and in terms of drop-outs, R-rTMS and ECT were the most tolerated and least tolerated, respectively. These results suggested that the most efficacious treatment, ECT, may not be the best in terms of overall acceptability. Although important outcomes, such as discontinuation symptoms and sideeffects, were not investigated here, B-rTMS appears to be the best choice among the four modalities, as it had the most favorable possible balance between efficacy and acceptability. Interestingly, recent multimodal neuroimaging data showed that B-rTMS might have synergistic therapeutic effects by reversing both the hypo-function in the right DLPFC and the hyper-function in the left DLPFC (58, 59). That being said, the therapeutic application of rTMS involves several parameters (e.g., frequency, resting motor threshold, number of stimuli per day) (60); however, the optimum rTMS protocol based on these parameters has yet to be determined. Therefore, future RCTs should seek to identify and optimize clinically relevant stimulation parameters in order to improve the antidepressant effects of rTMS. Moreover, other subsidiary technologies, such as baseline electrophysiological and/or neuroimaging evaluations, can be used to predict which patient subgroups can particularly benefit from rTMS (61). Although we did not perform a formal cost-effective analysis here, there are studies stating that ECT is more costeffective than rTMS in the treatment of MDD (62, 63). However, in the absence of a complete economic model, this conclusion should not be made unequivocally because several cost components are associated with the use of ECT or rTMS (64). Limitations First, as the ‘5 cm method' for locating the DLPFC has been recently criticized for its inaccuracy (9), future rTMS studies should take advantage of neuronavigation approaches (65). Second, this review only examined efficacy at study end, and thus our conclusion cannot be applied to medium-term or long-term outcomes. Third, patients in the selected RCTs were over 18 years of age, so it is inappropriate to apply these findings to adolescents. Finally, several metaanalyses have been criticized for the inclusion of poor-quality trials and for combining heterogeneous studies. However, our comprehensive and systematic literature search combined with the use of stringent inclusion and exclusion criteria aided in mitigating these concerns. Conclusions
This multiple-treatments meta-analysis comparing the efficacy and acceptability of B-rTMS, R-rTMS, L-rTMS, and ECT in the treatment of MDD showed that: (i) ECT was the most efficacious, but least tolerated, treatment method; (ii) R-rTMS was the best tolerated treatment method; and (iii) B-rTMS appeared to have the most favorable balance between efficacy and acceptability. Further studies, such as well-designed, large-scale, multi-center RCTs directly comparing B-rTMS, R-rTMS, L-rTMS, and ECT, are needed to draw more definitive conclusions. Acknowledgements We thank Dr N. D. Melgiri for editing and proofreading the manuscript. This work was supported by the Natural Science Foundation Project of China (81601208, 31271189, 81200899, 31300917, and 81401140), the National Basic Research Program of China (973 Program, grant no. 2009CB918300), the Fund for Outstanding Young Scholars in Chongqing Medical University (CYYQ201502), and the Chongqing Science & Technology Commission (cstc2014jcyjA10102). Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
REFERENCES 1. Reynolds EH. Brain and mind: a challenge for WHO. The Lancet, 2003, 361(9373): 1924-1925. 2. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nature medicine, 2001, 7(5): 541547. 3. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, Jian-jun Chen, et al. Altered gut microbiome induces depressivelike behaviors through a pathway mediated by the host's metabolism. Molecular Psychiatry 2016; 21(6):786-96. 4. Fink M. ECT has proved effective in treating depression. Nature, 2000, 403(6772): 826-826. 5. UK ECT review group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet, 2003; 361:799-808. 6. Rasmussen K G. Some considerations in choosing electroconvulsive therapy versus transcranial magnetic stimulation for depression. The journal of ECT, 2011, 27(1): 51-54. 7. Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Archives of General Psychiatry, 2000, 57(5): 425-434. 8. Fitzgerald PB, Hoy KE, Herring SE, et al. Pilot study of the clinical and cognitive effects of high-frequency magnetic seizure therapy in major depressive disorder. Depression and anxiety, 2013, 30(2): 129-136. 9. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology, 2012, 37(1): 102-116. 10. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. a sham-controlled randomized trial. Arch Gen Psychiatry. 2010; 67(5):507-516. 11. Schutter DJ. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med. 2009; 39(1):65-75. 12. Klein E, Kreinin I, Chistyakov A, et al. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Archives of general psychiatry, 1999, 56(4): 315-320. 13. Kauffmann CD, Cheema MA, Miller BE. Slow right perfrontal transcranial magnetic stimulation as a reatment for medication‐resistant depression: A double‐blind, placebo‐controlled study. Depression and anxiety, 2004, 19(1): 59-62. 14. Chen J, Zhou C, Wu B, et al. Left versus right repetitive transcranial magnetic stimulation in treating major depression: a meta-analysis of randomised controlled trials. Psychiatry research, 2013, 210(3): 1260-1264. 15. Berlim MT, Van den Eynde F, Daskalakis ZJ. A systematic review and meta-analysis on the efficacy and acceptability of bilateral repetitive transcranial magnetic stimulation (rTMS) for treating major depression. Psychol Med, 2013, 43(11): 2245-2254.
16. Chen J, Liu Z, Zhu D, et al. Bilateral vs. unilateral repetitive transcranial magnetic stimulation in treating major depression: a meta-analysis of randomized controlled trials. Psychiatry research, 2014, 219(1): 51-57. 17. Minichino¹ A, Bersani¹ F S, Capra¹ E, et al. ECT, rTMS, and deepTMS in pharmacoresistant drug-free patients with unipolar depression: a comparative review. Neuropsychiatric disease and treatment, 2012, 8: 55-64. 18. Cipriani A, Barbui C, Rizzo C, Salanti G. What is a multiple treatments meta-analysis? Epidemiology and psychiatric sciences 2012; 21(2):151-3. 19. Cipriani A, Zhou X, Del Giovane C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet, 2016; 388(10047):881-90. 20. Chabrol H, Teissedre F, Saint-Jean M, Teisseyre N, Roge B, Mullet E. Prevention and treatment of post-partum depression: a controlled randomized study on women at risk. Psychological medicine 2002; 32(6):1039-47. 21. Hamilton M. A rating scale for depression. Journal of Neurology, Neurosurgery & Psychiatry, 1960, 23(1): 56-62. 22. Guyatt GH, Juniper EF, Walter SD, et al. Interpreting treatment effects in randomised trials. Brit Med J (BMJ).1998; 316:690–93. 23. Furukawa TA, Cipriani A, Barbui C,et al. Imputing response rates from means and standard deviations in metaanalysis. Int Clin Psychopharm. 2005; 20:49–52. 24. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009; 373: 746-58. 25. Higgins J P T, Thompson S G, Deeks J J, et al. Measuring inconsistency in meta-analyses. Bmj, 2003, 327(7414): 557-560. 26. Ades AE, Sculpher M, Sutton A, et al. Bayesian methods for evidence synthesis in cost-eff ectiveness analysis. Pharmacoeconomics, 2006; 24: 1–19. 27. Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. Journal of clinical epidemiology, 2011, 64(2): 163-171. 28. Eche J, Mondino M, Haesebaert F, Saoud M, Poulet E, Brunelin J. Low- vs High-Frequency Repetitive Transcranial Magnetic Stimulation as an Add-On Treatment for Refractory Depression. Front Psychiatry. 2012; 3:13. 29. Fitzgerald PB, Brown TL, Marston NAU, et al. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Archives of General Psychiatry, 2003, 60(10): 1002-1008. 30. Fitzgerald PB, Hoy K, Daskalakis ZJ, et al. A randomized trial of the anti‐depressant effects of low‐and high‐ frequency transcranial magnetic stimulation in treatment‐resistant depression. Depression and anxiety, 2009, 26(3): 229-234. 31. Fitzgerald PB, Sritharan A, Daskalakis ZJ, et al. A functional magnetic resonance imaging study of the effects of
low frequency right prefrontal transcranial magnetic stimulation in depression. Journal of clinical psychopharmacology, 2007, 27(5): 488-492. 32. Höppner J, Schulz M, Irmisch G, et al. Antidepressant efficacy of two different rTMS procedures. European archives of psychiatry and clinical neuroscience, 2003, 253(2): 103-109. 33.Rossini D, Lucca A, Magri L, et al. A symptom-specific analysis of the effect of high-frequency left or lowfrequency right transcranial magnetic stimulation over the dorsolateral prefrontal cortex in major depression. Neuropsychobiology, 2010, 62(2): 91-97. 34. Stern WM, Tormos JM, Press DZ, et al. Antidepressant effects of high and low frequency repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex: a double-blind, randomized, placebo-controlled trial. The Journal of neuropsychiatry and clinical neurosciences, 2007, 19(2): 179-186. 35. Triggs WJ, Ricciuti N, Ward HE, et al. Right and left dorsolateral pre-frontal rTMS treatment of refractory depression: a randomized, sham-controlled trial. Psychiatry research, 2010, 178(3): 467-474. 36. Rosa MA, Gattaz WF, Pascual-Leone A, Fregni F, Rosa MO, et al. Comparison of repetitive
transcranial
magnetic stimulation and electroconvulsive therapy in unipolar non-psychotic refractory depression: a randomized, single-blind study. Int J Neuropsychopharmacol, 2006, 9:667–676. 37. Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, et al. Repetitive Transcranial Magnetic Stimulation versus Electroconvulsive Therapy for Major Depression: Preliminary Results of a Randomized Trial. Biol Psychiatry, 2002, 51(8): 659-67. 38. Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M. Comparison
of
unlimited
transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major
numbers
depressive
of
rapid
episode.
Int J
Neuropsychopharmacol, 2000, 3:129–134. 39. Grunhaus L, Dannon PN, Schreiber S, Dolberg OH, Amiaz R, et al. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Biol Psychiatry, 2000, 47:314–324. 40. Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN. A randomized electroconvulsive therapy and repetitive transcranial magnetic
stimulation
controlled
comparison
of
in severe and resistant nonpsychotic
major depression. Biol Psychiatry, 2003, 53: 324–331. 41. Eranti S, Mogg A, Pluck G, Landau S, Purvis R, et al. A randomized, controlled trial with 6-month follow up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry, 2007, 164: 73–81. 42. Hansen PE, Ravnkilde B, Videbech P, Clemmensen K, Sturlason R, et al. Low-Frequency Repetitive Transcranial
Magnetic Stimulation Inferior to Electroconvulsive Therapy in Treating Depression. J ECT, 2011, 27(1):26-32. 43. Fitzgerald PB, Hoy KE, Singh A, et al. Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment-resistant major depression. International Journal of Neuropsychopharmacology, 2013, 16(9): 1975-1984. 44. Blumberger DM, Mulsant BH, Fitzgerald PB, Rajji TK, Ravindran AV, Young LT, Levinson AJ, Daskalakis ZJ. A randomized double-blind sham-controlled comparison of unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant major depression. World J Biol Psychiatry. 2012; 13(6): 423- 435. 45. Fitzgerald PB, Hoy KE, Herring SE, McQueen S, Peachey AV, Segrave RA, Maller J, Hall P, Daskalakis ZJ. A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression. J Affect Disord. 2012; 139(2):193-198. 46. Conca A, Di Pauli J, Beraus W, Hausmann A, Peschina W, Schneider H, König P, Hinterhuber H. Combining high and low frequencies in rTMS antidepressive treatment: preliminary result. Hum Psychopharmacol. 2002; 17(7):353356. 47. M. Rybak, R. Bruno, Y. Turnier-Shea, S. Pridmore. An Attempt to Increase the Rate and Magnitude of the Antidepressant Effect of Transcranial Magnetic Stimulation (TMS). German Journal of Psychiatry. 2005; 8: 59-65. 48. Fitzgerald PB, Hoy K, Gunewardene R, Slack C, Ibrahim S, Bailey M, Daskalakis ZJ. A randomized trial of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in treatment-resistant major depression. Psychol Med. 2011; 41: 1187-1196. 49. Pallanti S, Bernardi S, Di Rollo A, Antonini S, Quercioli L. Unilateral low frequency versus sequential bilateral repetitive transcranial magnetic stimulation: is simpler better for treatment of resistant depression? Neuroscience. 2010; 167(2): 323- 328. 50. Xiaoming Wang, Deben Yang, Yuanfeng, Hui Huang, Xiaoqiang Zhao. A controlled study of the treatment of repetitive transcranial magnetic stimulation in patients with major depression. Chinese Journal of Clinical Rehabilitation. 2004; 8(9):1770-1 51. Jianjuo Wan, Sanmei Hu, Meiying Chen, Xiangkun Chen, Lihua Yu, Yongmei Zhang, Qiongfang Wu. A control study of sertraline plus RTMS in the treatment of treatment-resistant depression. J Clin Psychosom Dis, 2011, 17(3): 202-204. 52. Isenberg K, Downs D, Pierce K, et al. Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment-resistant depressed patients. Ann Clin Psychiatry, 2005, 17(3):153-9. 53. Chen J, Huang H, Zhao L, et al. Sex-specific urinary biomarkers for diagnosing bipolar disorder. PloS one, 2014,
9(12): e115221. 54. Chen J, Liu Z, Fan S, et al. Combined application of NMR-and GC-MS-based metabonomics yields a superior urinary biomarker panel for bipolar disorder. Scientific reports, 2014, 4: 5855. 55. Chen J, Zhou C, Liu Z, et al. Divergent urinary metabolic phenotypes between major depressive disorder and bipolar disorder identified by a combined GC–MS and NMR spectroscopic metabonomic approach. Journal of proteome research, 2015, 14(8): 3382-3389. 56. Zheng P, Wang Y, Chen L, et al. Identification and validation of urinary metabolite biomarkers for major depressive disorder. Molecular & Cellular Proteomics, 2013, 12(1): 207-214. 57. Deeks JJ, Altman DG, & Bradburn MJ. Statistical Methods for Examining Heterogeneity and Combining Results from Several Studies in Meta‐Analysis. Systematic Reviews in Health Care: Meta-Analysis in Context, Second Edition, 2008; 285-312. 58. Kito S, Hasegawa T, Koga Y. Neuroanatomical correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression. Psychiatry and Clinical Neurosciences, 2011, 65, 175–182. 59. Martinot ML, Martinot JL, Ringuenet D, Galinowski A,Gallarda T, Bellivier F, Lefaucheur JP, Lemaitre H,Artiges E. Baseline
brain
metabolism
in
resistant
depression
and
response
to
transcranial
magneticstimulation.
Neuropsychopharmacology, 2011, 36, 2710–2719. 60. Xie J, Jianjun Chen, Wei Q. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a meta-analysis of stimulus parameter effects. Neurol Res. 2013; 35(10):1084-91. 61. Arns M, Drinkenburg W H, Fitzgerald P B, et al. Neurophysiological predictors of non-response to rTMS in depression. Brain stimulation, 2012, 5(4): 569-576. 62. Knapp M, Romeo R, Mogg A, et al. Cost-effectiveness of transcranial magnetic stimulation vs. electroconvulsive therapy for severe depression: a multi-centre randomised controlled trial. Journal of affective disorders, 2008, 109(3): 273-285. 63. McLoughlin D M, Mogg A, Eranti S, et al. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis. Health technology assessment (Winchester, England), 2007, 11(24): 1-54. 64. Le Lay A, Despiegel N, François C, Duru G. Can discrete event simulation be of use in modelling major depression? Cost Effectiveness and Resource Allocation, 2006; 4(1):19. 65. Schönfeldt-Lecuona C, Lefaucheur JP, Cardenas-Morales L, Wolf R, Kammer T, & Herwig U. The value of neuronavigated rTMS for the treatment of depression. Neurophysiologie Clinique/ Clinical Neurophysiology, 2010; 40: 37-43.
Figure 1 Flow Chart of Study Selection The electronic literature search resulted in 557 potentially relevant studies, of which 25 eligible articles were pooled for analysis.
Figure 2 Rankings for Efficacy and Acceptability The distribution of probabilities of each treatment modality was ranked at each of four possible positions. (A) ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B-rTMS (25%), R-rTMS (8%), and L-rTMS (2%). (B) R-rTMS was the best-tolerated treatment with the cumulative probabilities of being the best-tolerated treatment being: R-rTMS (52%), B-rTMS (17%), L-rTMS (16%), and ECT (14%).
TABLE LEGENDS
Table 1 Demographic and Clinical characteristics of Included Subjects Female/
Mean age,
Mean MDD
Primary
male, n
yrs (S.D.)
score (S.D.)
diagnosis
48.9 (13.4) vs.
26.0 (3.3) vs. 25.1
All MDD
Yb
58.0 (12.5)
(3.8)a
43.4 (12.7) vs.
23.7 (3.8) vs. 24.3
All MDD
Yb Yc
Study
Pairs
n
Blumberger et
L vs. B
22 vs.
12/10
26
14/12
24 vs.
15/9
al., 2012 Fitzgerald
et
L vs. B
al., 2012 Rybak et al.,
L vs. B
vs. vs.
22
14/8
40.4 (15.5)
(3.6)a
9/9
6/3 vs. 6/3
47.0 (12.3) vs.
23.8 (2.4) vs. 23.0
17%
53.4 (13.3)
(4.0)a
83% MDD
45.8 (12.5) vs.
30.8 (6.0) vs. 29.4
48.2 (16.1)
(4.3)d
47.4 (14.1) vs.
21.8 (2.6) vs. 21.5
15%BD,85% MDD All MDD
2005 Conca et al., 2002 Fitzgerald
et
al., 2011 Pallanti et al.,
L vs. B
R vs. B R vs. B
2010 Fitzgerald
et
al., 2013 Hansen et al., 2011
R vs. B R
vs.
ECT
24 vs. 12 71 vs.
16/8 vs. 9/3 47/24
147
vs. 100/47
46.8 (13.7)
20 vs.
12/8
51.2
27.9 (5.9) vs. 28.7
20
11/9
91 vs.
59/32
88
66/22
30 vs.
23/7
30
vs. vs.
19/11
(12.5) vs.
BD,
25% OP
Part
58% MDD
(2.9)a
vs.
17%
BD,
47.6 (12.3)
(6.0)a
46.7 (14.2) vs.
19.5 (4.4) vs. 19.8
22%
48.5 (15.9)
(5.0)a
78% MDD
46.0 (N.A.) vs.
24.0 (N.A.) vs.
52.0 (N.A.)
24.0
TRD
(N.A.)a
BD,
13%
Yb Yb
Yb Y
BD,87% MDD
Eranti et al., 2007 Rosa
L ECT
et
al.
L
2006
ECT
Wang et al.,
L
2004
vs.
et
L
al., 2003
ECT
Janicak et al.,
L
2002
vs.
et
al., 2000 Pridmore
vs. vs.
et
vs. vs.
ECT al.,
2011 Fitzgerald
L
et
L
vs.
al., 2009 Rossini et al.,
2007
et
al.,
8% BD, 92% MDD All MDD
Yb
All MDD
N
All MDD
Yc
68.0 (13.4)
20 vs.
12/8 vs. 7/8
41.8 (10.2) vs.
30.1 (4.7) vs. 32.1
46.0 (10.6)
(5.0) a
18 vs.
N.A.
31.0
20 vs.
14/6
20
15/5
15 vs.
vs.
11/4 vs. 6/5 vs.
(5.0)
vs.
27.8 (3.2) vs. 26.7
32.0 (6.0)
(2.8)a
57.6 (13.7) vs.
24.4 (3.9) vs. 25.5
61.4 (16.6)
(5.9) a
42.8 (12.9) vs.
32.5(6.4)vs.33.4(9
30%
42.7 (14.0)
.0)f
70% MDD
58.4 (15.7) vs.
25.8
20 vs.
12/8
20
14/6
63.6 (15.0)
28.4 (9.3)a
16 vs.
N.A.
44.0 (11.9) vs.
45 vs.
15/30
vs.
(6.1) vs.
25.3 (4.1) vs. 25.8
18%
Yc
41.5 (12.9)
(3.6)a
82% MDD
36.2 (18.8) vs.
26.3 (12) vs. 28.1
43
15/28
35.7 (15.3)
L vs. R
15 vs.
8/7 vs. 5/6
42.4 (11.2) vs.
34.5 (4.9) vs. 33.3
39.6 (10.0)
(3.8)e
L vs. R L vs. R
16 vs. 11
8/7 vs. 3/8
42.1
(9.3)
vs.
33.6 (3.9) vs. 34.3
BD,
All MDD
Y
All MDD
Yb
All MDD
Yb Yc
46.5 (11.4)
(4.9)e
53.6 (11.3) vs.
24.6 (4.5) vs. 24.3
54%
32 vs.
23/9
42
30/12
54.5 (11.8)
(4.4)d
46% MDD
20 vs.
12/8 vs. 7/3
52.7 (10.6) vs.
27.7 (3.5) vs. 27.9
All MDD
52.8 (9.5)
(3.8)d
10
vs.
N Part
ECT
L vs. R
BD,
N
All MDD
(16)d
2010 Stern
23.9 (7.0) vs. 24.8
16/6
11 et
63.6 (17.3) vs.
22
16
al., 2007 Fitzgerald
vs.
(5.0)a
11
ECT
al., 2000 et
L
16/8
18
ECT
Grunhaus,
24 vs.
15
ECT
Grunhaus
Wan
vs.
BD,
Yc
Triggs et al.,
L vs. R
2010
18 vs.
14/4 vs. 9/7
16
Höppner et al.,
L vs. R
2003
10 vs.
7/3 vs. 8/2
10
Eche
et
al.,
L vs. R
6 vs. 8
L vs. R
2005
14 vs.
2/4 vs. 6/2 6/8 vs. 6/8
14
Fitzgerald
et
L vs. R
al., 2003 a17-item
28.2 (6.0) vs. 27.2
48.5 (10.8)
(4.8)f
59.5
(6.8)
Yb
vs.
N.A.
All MDD
N
50.8
(9.4)
vs.
29.8 (6.9) vs. 32.0
All MDD
Yc Yb
46.1 (16.3)
(8.0)e
43.4
25.1 (4.9) vs. 23.9
10%
(6.2)d
90% MDD
36.1 (7.5) vs. 37.7
3% BD, 97%
(8.4)e
MDD
(9.7) vs.
55.6 (9.7)
20 vs.
12/8
20
13/7
vs.
42.2
(9.8)
45.5 (11.5)
vs.
BD,
Yb
Hamilton Depression Rating Scale.
bFailure
to respond to 2 antidepressants in the current major depressive episode.
cFailure
to respond to 1 antidepressants in the current major depressive episode.
d21-item
Hamilton Depression Rating Scale.
eMontgomery–Asberg f24-item
All MDD
52.0 (11.7)
2012 Isenberg et al.,
46.7 (15.3) vs.
Depression Rating Scale.
Hamilton Depression Rating Scale.
Abbreviations: rTMS, repetitive transcranial magnetic stimulation; L, left rTMS; R, right rTMS; B, bilateral rTMS; TRD, treatment-resistant depression; ECT, electroconvulsive therapy; BD, bipolar depression; MDD, major depressive disorder; N.A., information not available; S. D., standard deviation; and OP, other psychosis
Table 2 rTMS Parameters of Included Randomized Controlled Trials Study
Pairs
Blumberger
et
al., 2012 Fitzgerald et al., 2012 Rybak
et
al.,
2005 Conca
et
al.,
2002 Fitzgerald et al., 2011 Pallanti et al., 2010 Fitzgerald et al., 2013 Hansen
et
L vs. B L vs. B R vs. B R vs. B R vs. B
et
al., L
et
L
2004 2003
al., L
2002 2000 2000
Fitzgerald et al., 2007 Fitzgerald et al., 2009 et
al.,
2010
L
vs.
2010
et
al.,
10 Hz vs. 10 Hz L (S) 1 Hz R 1 Hz vs. 1 Hz L (S) 1 Hz R 1 Hz vs. 10 Hz L (S) 1 Hz R 1 Hz vs. 1 Hz R+10 Hz L 1 Hz vs. right
20 Hz vs. N.A
vs.
ECT
Duration
110 vs. 100a 6 weeks 120 vs. 120 3 weeks 110 vs. 110 2 weeks 100 vs. 100 1 weeks 110 vs. 110 4 weeks 110 vs. 110 3 weeks 110 vs. 110 4 weeks
TPPS 1450 vs. 1215 NA 1200 vs. 1200 1300 vs. 1300 900
Y
Y
Y
Y
Augmentation
Y
NA Y
Y
Augmentation
Y
NA Y
Y
Augmentation
Y
NA NA Y
Y
Y
Y
Y
vs.
Y
Y
Y
Y
Y
Y
Y
Y
Augmentation
vs. 84% augmentation,
900
16% monotherapy Augmentation
Y
Y
N
Y
110
2 weeks
1000
Augmentation
Y
Y
N
Y
100
4 weeks
2500
Monotherapy
Y
NA N
Y
70
2 weeks
500
Monotherapy
Y
NA NA Y
90
4 weeks
1200
Monotherapy
Y
N
4 weeks
1000
Y
NA NA Y
Y
NA NA Y
Monotherapyb
Y
Y
N
1500
Augmentation
Y
N
NA Y
Augmentation
Y
NA Y
Y
Y
Y
Y
Augmentation
Y
NA NA Y
100
2 weeks
10 Hz vs. N.A
100
4 weeks
9%
augmentation,
91% monotherapy
400
or 78% augmentation,
1200
22% monotherapy
12001400
L vs. R 10 Hz vs. 1 Hz
100 vs. 110 3 weeks
NA
L vs. R 10 Hz vs. 1 Hz
100 vs. 110 3 weeks
NA
L vs. R 15 Hz vs. 1 Hz
100 vs. 100 2 weeks
L vs. R 5 Hz vs. 5 Hz
Augmentation
NA
20 Hz vs. N.A
Hz
RD AC BT BL
3 weeks
4 weeks
1 Hz or 10 Hz vs. 1
strategy
15% monotherapy
1420 900
Methodology
vs. 85% augmentation,
900 420
Treatment
110
90
bilateral vs.
% rMT
10 Hz vs. bilateral 110
vs. 10 Hz vs. right or
Stern et al., 2007 L vs. R Triggs
(S)10 Hz L
bilateral
ECT
Wan et al., 2011
10 Hz vs. 1 Hz R
vs. 10 Hz vs. right or
ECT
Pridmore et al., L
Rossini
vs.
ECT
Grunhaus, et al., L
(S)10 Hz L
bilateral
ECT et
10 Hz vs. 1 Hz R
vs. 10 Hz vs. right or
ECT
Grunhaus et al., L
(S)10 Hz L
bilateral
ECT
al., L
10 Hz vs. 1 Hz R
vs. 10 Hz vs. right or
ECT
Rosa et al., 2006
Janicak
vs.
ECT
2007
Wang
L vs. B
al., R
2011 Eranti
L vs. B
Frequency
600 600
64% augmentation, 37% monotherapy vs.
N
Y
Y
Y
110 vs. 110 2 weeks
NA
Monotherapy
Y
NA Y
Y
100 vs. 100 2 weeks
NA
Augmentation
Y
NA Y
Y
Höppner et al.,
L vs. R 20 Hz vs. 1 Hz
90 vs. 110 2 weeks
Eche et al., 2012 L vs. R 10 Hz vs. 1 Hz
100 vs. 100 2 weeks
2003
Isenberg et al., 2005 Fitzgerald et al., 2003 a
L vs. R 20 Hz vs. 1 Hz
80 vs. 110 4 weeks
L vs. R 10 Hz vs. 1 Hz
100 vs. 100 4 weeks
NA 2000 vs. 120 NA 1000 vs. 300
Augmentation
Y
Y
NA Y
Augmentation
Y
NA N
Y
Monotherapy
Y
NA N
Yc
Augmentation
Y
Y
Y
Y
120% of the rMT in subjects older than 60 years old.
b Medication
was tapered and ceased where possible; no new medication was commenced in the two weeks before entry
into the study. c Subjects
receiving rTMS treatment on the right side were notably older.
Abbreviations: rTMS, repetitive transcranial magnetic stimulation; TPPS, total pulse per session in rTMS; RD, randomized; AC, allocation concealment; BT, blind treatment; and BL, baseline; L, left rTMS; R, right rTMS; B, bilateral rTMS; ECT, electroconvulsive therapy; rMT, resting motor threshold; (S), sequential; Y, yes; N, no; and NA, not available.
Table 3 Response and dropout rates for efficacy and acceptability in meta-analyses of direct comparisons between each pair of treatment modality Number
Number
Efficacy
Acceptability
of studies
of patients
Response rate
OR (95% CI)
Dropout rate
OR (95% CI)
R
8
265
53/137vs53/128
0.99(0.58,1.69)
7/46vs0/31
3.97(0.63,25.1)
B
4
150
24/81vs23/69
0.52(0.09,3.06)
4/72vs7/60
0.52(0.12,2.15)
ECT
7
262
67/135vs78/127
0.64(0.30,1.38)
4/37vs7/31
0.42(0.11,1.65)
L
8
265
53/128vs53/137
1.01(0.59,1.73)
0/31vs7/46
0.25(0.04,1.59)
B
2
258
46/91vs81/167
1.21(0.72,2.06)
23/71vs36/147
1.48(0.79,2.76)
ECT
1
60
7/30vs12/30
0.46(0.15,1.40)
10/30vs8/30
1.38(0.45,4.17)
L
4
150
23/69vs24/81
1.93(0.33,11.4)
7/60vs4/72
1.94(0.46,8.11)
R
2
258
81/167vs46/91
0.82(0.49,1.40)
36/147vs23/71
0.68(0.36,1.26)
L
7
262
78/127vs67/135
1.55(0.72,3.34)
7/31vs4/37
2.37(0.61,9.27)
R
1
60
12/30vs7/30
2.19(0.72,6.70)
8/30vs10/30
0.73(0.24,2.21)
L vs.
R vs.
B vs.
ECT vs.
rTMS, repetitive transcranial magnetic stimulation; L, left rTMS; R, right rTMS; B, bilateral rTMS; ECT, electroconvulsive therapy; OR, odds ratio; vs., versus; CI, confidence interval.
S0166-4328(16)30805-1 http://dx.doi.org/doi:10.1016/j.bbr.2016.11.028 BBR 10568
To appear in:
Behavioural Brain Research
Received date: Revised date: Accepted date:
10-10-2016 11-11-2016 15-11-2016
Please cite this article as: Chen Jian-jun, Zhao Li-bo, Liu Yi-yun, Fan Songhua, Xie Peng.Comparative Efficacy and Acceptability of Electroconvulsive Therapy versus Repetitive Transcranial Magnetic Stimulation for Major Depression: a Systematic Review and Multiple-Treatments Meta-Analysis.Behavioural Brain Research http://dx.doi.org/10.1016/j.bbr.2016.11.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Comparative Efficacy and Acceptability of Electroconvulsive Therapy versus Repetitive Transcranial Magnetic Stimulation for Major Depression: a Systematic Review and Multiple-Treatments Meta-Analysis
Jian-jun Chen1,2,3,4,5,6, Li-bo Zhao6,7, Yi-yun Liu1,2,6,8, Song-hua Fan1,2,6,8, Peng Xie1,2,6,7,8,#
1Institute
of Neuroscience, Chongqing Medical University
2Chongqing 3Institute
Key Laboratory of Neurobiology, Chongqing Medical University
of Life Sciences, Chongqing Medical University
4Department 5Canada
of Obstetrics and Gynecology, the First Affiliated Hospital of Chongqing Medical University
- China -New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University
6Institute
of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University
7Department
of Neurology, Yongchuan Hospital of Chongqing Medical University
8Department
of Neurology, the First Affiliated Hospital of Chongqing Medical University,
#corresponding
author:
Professor Peng Xie Department of Neurology The First Affiliated Hospital at Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China Tel.: +86-23-68485490 Fax: +86-23-68485111 E-mail: [email protected]
Highlights 1. ECT was the most efficacious, but least tolerated. 2. R-rTMS was the best tolerated treatment for MDD. 3. B-rTMS appears to have the most favorable balance between efficacy and acceptability.
ABSTRACT Backgrounds: The effects of electroconvulsive therapy (ECT) and bilateral, left prefrontal, and right prefrontal repetitive transcranial magnetic stimulation (rTMS) on major depressive disorder (MDD) have not been adequately addressed by previous studies. Here, a multiple-treatments meta-analysis, which incorporates evidence from direct and indirect comparisons from a network of trials, was performed to assess the efficacy and acceptability of these four treatment modalities on MDD. Method: The literature was searched for randomized controlled trials (RCTs) on ECT, bilateral rTMS, and unilateral rTMS for treating MDD up to May 2016. The main outcome measures were response and drop-out rates. Results: Data were obtained from 25 studies consisting of 1288 individuals with MDD. ECT was non-significantly more efficacious than B-rTMS, R-rTMS, and L-rTMS. Left prefrontal rTMS was non -significantly less efficacious than all other treatment modalities. In terms of acceptability, R-rTMS was non-significantly better tolerated than ECT, BrTMS, and L-rTMS. ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B-rTMS (25%), R-rTMS (8%), and L-rTMS (2%). R-rTMS was the besttolerated treatment with the cumulative probabilities of being the best-tolerated treatment being: R-rTMS (52%), BrTMS (17%), L-rTMS (16%), and ECT (14%). Coherence analysis detected no statistically significant incoherence in any comparisons of direct with indirect evidence for the response rate and drop-out rate. Conclusions: ECT was the most efficacious, but least tolerated, treatment, while R-rTMS was the best tolerated treatment for MDD. B-rTMS appears to have the most favorable balance between efficacy and acceptability. Key words: depression, MDD; meta-analysis; transcranial magnetic stimulation, TMS, rTMS, electroconvulsive therapy, ECT
INTRODUCTION Major depressive disorder (MDD, major depression) is a debilitating mental disorder affecting up to 15% of the general population and accounting for 12.3% of the global burden of disease (1). To date, increasing evidence from biochemical, neuropsychological, postmortem, and neuroimaging studies indicates that MDD is not likely caused by a single brain region or neurotransmitter system, but rather is a system-level disorder affecting several integrated pathways (2, 3). Electroconvulsive therapy (ECT) is a well-established and effective treatment method for MDD superior to both placebo and sham ECT (anesthesia only) (4, 5). Some researchers even consider ECT to be the most effective treatment for MDD (6). Of MDD patients who receive ECT, approximately 70% to 80% show significant improvement (6), and ECT is effective in half of patients with treatment-resistant depression (TRD) (7). However, ECT is complicated by a number of side effects including cognitive impairment; so many patients are reluctant to engage in ECT treatment due to the risks and stigma associated with cognitive side effects, which has motivated attempts at developing treatment alternatives (8). Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive method of brain stimulation for the treatment of patients with serious neuropsychiatric disorders including MDD (9). Unlike ECT, rTMS does not require anesthesia or induction of seizures. RTMS is divided into bilateral rTMS (B-rTMS), left prefrontal rTMS (L-rTMS), and right prefrontal rTMS (R-rTMS) according to the stimulation location. Most studies of rTMS in MDD focus on highfrequency (5-20 Hz) stimulation to the left dorsolateral prefrontal cortex, and L-rTMS has been shown to have positive antidepressive effects (10, 11). Some randomized controlled trials (RCTs) have demonstrated that R-rTMS shows significantly greater improvement in depression scores compared with sham rTMS (12, 13), and our previous research has shown that L-rTMS and R-rTMS have a similar efficacy on MDD patients (14). Moreover, a 2012 systematic review showed that B-rTMS is a promising treatment for MDD (15), and our previous research also found that bilateral and unilateral rTMS had comparable efficacies on MDD patients (16). Hitherto, ECT has been traditionally viewed as the superior treatment modality vis-a-vis rTMS (17), but this conclusion has been primarily based on RCTs of ECT versus L-rTMS. There is still lack of quantitative data comparing the efficacy of ECT versus B-rTMS or R-rTMS in MDD. To this end, although standard meta-analyses are an effective tool, they can only compare two alternative treatments at a time; moreover, if no trials directly compare two interventions, it is impossible to compare their relative efficacies (18). In contrast, multiple treatments meta-analyses use a technique that incorporates evidence from both direct and indirect comparisons from a network of trials of different interventions to better estimate summary treatment effects. Our group used this method to compare the efficacy and tolerability of antidepressants for MDD in children and adolescents, and the results has been published in
Lancet in 2016 (19). Therefore, here we applied a multiple-treatments meta-analysis to compare the efficacy and acceptability of B-rTMS, R-rTMS, L-rTMS, and ECT in the treatment of MDD. METHODS Study Selection This systematic review and meta-analysis was conducted and reported according to the PRISMA statement (http://www.prisma-statement.org/). A comprehensive literature search of RCTs comparing ECT with rTMS was conducted up to May 2016 through the major scientific and medical databases, including international databases (PubMed, CCTR, Web of Science, and Embase) and two Chinese databases (CBM-disc and CNKI). The key search terms were “depression” AND (“transcranial magnetic stimulation” OR “TMS” OR “repetitive TMS” OR “rTMS”) AND (“electroconvulsive therapy” OR “ECT”). No language or publication year limitation was imposed. To avoid omitting relevant trials, conference summaries and reference documents listed in the obtained articles were checked. Among the identified studies, only those meeting the following criteria were selected for subsequent analyses: (i) RCTs comparing one treatment against another (B-rTMS, L-rTMS, R-rTMS, and ECT); (ii) assessing mood by the Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS), or Clinical Global Impression (CGI); (iii) patients over 18 years of age without metallic implants or foreign bodies, dementia, personal or family history of epileptic seizures, severe suicidal risk, organic brain damage, severe agitation or delirium, substance abuse, alcohol or drug dependence, and/or medically unfit for general anesthesia. Studies with pregnant patients were excluded because rTMS and ECT have unclear fetal side effects (20). Studies were excluded if they: (i) had no random allocation; (ii) enrolled subjects with ‘narrow’ depression diagnoses (e.g., postpartum depression) or secondary depression diagnoses (e.g., vascular depression); (iii) used rTMS and ECT concomitantly with a new antidepressant without wash out period; and (iv) case reports and reviews. Data Extraction Two reviewers independently verified all potentially suitable RCTs by the aforementioned inclusion and exclusion criteria and the completeness of data abstraction. Any disagreement was resolved by consensus and, if needed, a third reviewer was consulted. Data retrieved from the included RCTs were recorded in a structured fashion as follows: (i) sample characteristics: mean age, gender, mean depression score, treatment strategy used, presence of TRD; (ii) rTMS parameters: stimulation location, frequency, motor threshold, and duration; (iii) primary outcome measure: response was defined as at least a 50% reduction in the absolute HDRS or MADRS score from baseline, or significant improvement in the CGI, at the conclusion of therapy (21) with a preference for HDRS; and (iv) secondary outcome measure: overall drop-out rates at the study's end. For data that could not be directly retrieved, good faith efforts were applied to obtain the data by dispatching e-mails to the author, researching other studies citing the RCT in question, and
researching associated conference summaries. Bias Risk in Individual Studies Two reviewers independently assessed bias risk of the eligible studies according to the Cochrane handbook. We selected the following items to assess the bias risk: (1) did the authors conduct randomization? (2) did the authors conduct allocation concealment? (3) did the authors conduct blind treatment? and (4) were the baseline clinical characteristics matched between two groups. Studies with three or more ‘NO’ were still excluded. Statistical Analysis In order to make the interpretation of current results easier for clinicians (22), the response rate (a dichotomous primary outcome for efficacy) was used instead of a continuous symptom score. If the baseline scores, standard deviations (SD), and endpoint means were provided instead of the dichotomous efficacy outcomes, we estimated the number of responding patients through a validated imputation method. (23) To perform a clinically sound analysis, we used a worst-case scenario analysis of drop-out patients, assuming all such patients failed to respond to treatment. (24) First, with a random-effects model, we performed a meta-analysis of augmentation agents that had direct comparisons. For each analysis, we assessed heterogeneity using the Chi-square based Q test and I squared index (I2). (25) We performed the analyses using RevMan5.0 software (Cochrane Information Management System [IMS]). Second, we performed multiple-treatment meta-analysis using an arm-based, random-effects model within an empirical Bayes framework using Markov chain Monte Carlo method (26). The model allowed for estimating effect sizes for all possible pair-wise comparisons of augmentation agents. P-values of less than 0.05 were used to assess significance. We also computed and ranked the probabilities for each treatment's efficacy (27). The ranking of the competing treatments was assessed with the median of the posterior distribution for the rank of each treatment. We performed this analysis using WinBUGS (Imperial College and MRC, London, UK) and R v2.15.0 (R Development Core Team, Vienna, Austria). The coherence of an analyzed network – i.e., that indirect and direct evidence on the same comparisons do not disagree beyond chance – is the key assumption behind multiple-treatments meta-analysis. Whenever indirect estimates could be built with a single common comparator, the ratio of odds ratios for indirect vs. direct evidence is calculated to estimate incoherence. The disagreement between direct and indirect evidence with a 95% confidence interval excluding unity is defined as incoherent (24). RESULTS The electronic literature search resulted in 557 potentially relevant studies, of which 25 eligible articles were pooled for analysis (28-52) (Figure 1). Overall, 1288 individuals were randomly assigned to one of the four treatment modalities and were included in the multiple-treatments meta-analysis with all 1288 patients included in the efficacy
analysis (25 studies) and 820 patients included in the acceptability analysis (12 studies). The mean duration of the studies was 3.04 weeks, and the mean sample size was 25.7 participants per group (range: 6–147). The main characteristics of the included RCTs are described (Tables 1 and 2). All the 25 included studies conducted the randomization, two studies did not conduct allocation concealment, seven studies did not conduct blind treatment and the baseline clinical characteristics were matched between two groups in all included studies (Table 2). As these studies displayed minimal or no bias risk, all of them were included in the metaanalysis. Direct comparisons for the four treatment modalities showed no statistically significant differences in response rates between any two treatment modalities (Table 3). However, the odds ratio (OR) non-significantly favored ECT over LrTMS and R-rTMS with pooled ORs of 1.43 [95% confidence interval (CI), 0.92-2.22] and 2.19 (95% CI, 0.72-6.70), respectively. B-rTMS was non-significantly superior to L-rTMS, but non-significantly inferior to R-rTMS, with pooled ORs of 1.70 (95% CI, 0.74-3.92) and 0.93 (95% CI, 0.63-1.37), respectively. R-rTMS was comparably efficacious to LrTMS. These results obtained from 25 independent analyses without adjustment for multiple testing (i.e., about two CIs would be expected to exclude unity by chance alone). For drop-outs, statistically significant differences did not exist between the treatment modalities. Overall, heterogeneity was moderate. In the meta-analyses of direct comparisons, we found no I 2 values higher than 75%. From the multiple-treatments meta-analysis on response rates, ECT was non-significantly more efficacious than BrTMS, R-rTMS and L-rTMS with pooled ORs of 1.27 (95% CI, 0.58-2.61), 1.14 (95% CI, 0.63-1.94), and 1.65 (95% CI, 0.88-2.83), respectively. L-rTMS was non-significantly less efficacious than B-rTMS and R-rTMS with pooled ORs of 0.90 (95% CI, 0.46-1.52) and 0.96 (95% CI, 0.59-1.44), respectively. In terms of acceptability, R-rTMS was nonsignificantly better tolerated than ECT, B-rTMS, and L-rTMS with pooled ORs of 0.47 (95% CI, 0.05-1.39), 0.94 (95% CI, 0.15-2.45), and 0.57 (95% CI, 0.07-1.56), respectively. Coherence analysis detected no statistically significant incoherence in any comparisons of direct with indirect evidence for the response rate and drop-out rate. Figure 2 showed the distribution of probabilities of each treatment modality being ranked at each of four possible positions. ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B-rTMS (25%), R-rTMS (8%), and L-rTMS (2%) (Figure 2A). R-rTMS was the besttolerated treatment with the cumulative probabilities of being the best-tolerated treatment being: R-rTMS (52%), BrTMS (17%), L-rTMS (16%), and ECT (14%) (Figure 2B). DISCUSSION Nowadays, metabolomics has been extensively used to identify potential biomarkers for psychiatric disorders (53, 54). Although many works has used metabolomics to identify biomarkers for MDD (55, 56), there are still no objective
methods to diagnose MDD. Besides, there are no treatment methods that could cure MDD with 100% response rate. Here, this multiple-treatments meta-analysis was based on 25 studies consisting of 1288 individuals randomly assigned to ECT, B-rTMS, R-rTMS or L-rTMS for MDD. We retrieved almost all relevant RCTs, and the overlooked literature that were not indexed by international databases were likely to be of low quality and would not significantly affect the results of this review (57). Although the results were statistically non-significant, ECT and L-rTMS were the most efficacious and least efficacious treatments, respectively, and in terms of drop-outs, R-rTMS and ECT were the most tolerated and least tolerated, respectively. These results suggested that the most efficacious treatment, ECT, may not be the best in terms of overall acceptability. Although important outcomes, such as discontinuation symptoms and sideeffects, were not investigated here, B-rTMS appears to be the best choice among the four modalities, as it had the most favorable possible balance between efficacy and acceptability. Interestingly, recent multimodal neuroimaging data showed that B-rTMS might have synergistic therapeutic effects by reversing both the hypo-function in the right DLPFC and the hyper-function in the left DLPFC (58, 59). That being said, the therapeutic application of rTMS involves several parameters (e.g., frequency, resting motor threshold, number of stimuli per day) (60); however, the optimum rTMS protocol based on these parameters has yet to be determined. Therefore, future RCTs should seek to identify and optimize clinically relevant stimulation parameters in order to improve the antidepressant effects of rTMS. Moreover, other subsidiary technologies, such as baseline electrophysiological and/or neuroimaging evaluations, can be used to predict which patient subgroups can particularly benefit from rTMS (61). Although we did not perform a formal cost-effective analysis here, there are studies stating that ECT is more costeffective than rTMS in the treatment of MDD (62, 63). However, in the absence of a complete economic model, this conclusion should not be made unequivocally because several cost components are associated with the use of ECT or rTMS (64). Limitations First, as the ‘5 cm method' for locating the DLPFC has been recently criticized for its inaccuracy (9), future rTMS studies should take advantage of neuronavigation approaches (65). Second, this review only examined efficacy at study end, and thus our conclusion cannot be applied to medium-term or long-term outcomes. Third, patients in the selected RCTs were over 18 years of age, so it is inappropriate to apply these findings to adolescents. Finally, several metaanalyses have been criticized for the inclusion of poor-quality trials and for combining heterogeneous studies. However, our comprehensive and systematic literature search combined with the use of stringent inclusion and exclusion criteria aided in mitigating these concerns. Conclusions
This multiple-treatments meta-analysis comparing the efficacy and acceptability of B-rTMS, R-rTMS, L-rTMS, and ECT in the treatment of MDD showed that: (i) ECT was the most efficacious, but least tolerated, treatment method; (ii) R-rTMS was the best tolerated treatment method; and (iii) B-rTMS appeared to have the most favorable balance between efficacy and acceptability. Further studies, such as well-designed, large-scale, multi-center RCTs directly comparing B-rTMS, R-rTMS, L-rTMS, and ECT, are needed to draw more definitive conclusions. Acknowledgements We thank Dr N. D. Melgiri for editing and proofreading the manuscript. This work was supported by the Natural Science Foundation Project of China (81601208, 31271189, 81200899, 31300917, and 81401140), the National Basic Research Program of China (973 Program, grant no. 2009CB918300), the Fund for Outstanding Young Scholars in Chongqing Medical University (CYYQ201502), and the Chongqing Science & Technology Commission (cstc2014jcyjA10102). Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
REFERENCES 1. Reynolds EH. Brain and mind: a challenge for WHO. The Lancet, 2003, 361(9373): 1924-1925. 2. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nature medicine, 2001, 7(5): 541547. 3. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, Jian-jun Chen, et al. Altered gut microbiome induces depressivelike behaviors through a pathway mediated by the host's metabolism. Molecular Psychiatry 2016; 21(6):786-96. 4. Fink M. ECT has proved effective in treating depression. Nature, 2000, 403(6772): 826-826. 5. UK ECT review group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet, 2003; 361:799-808. 6. Rasmussen K G. Some considerations in choosing electroconvulsive therapy versus transcranial magnetic stimulation for depression. The journal of ECT, 2011, 27(1): 51-54. 7. Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Archives of General Psychiatry, 2000, 57(5): 425-434. 8. Fitzgerald PB, Hoy KE, Herring SE, et al. Pilot study of the clinical and cognitive effects of high-frequency magnetic seizure therapy in major depressive disorder. Depression and anxiety, 2013, 30(2): 129-136. 9. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology, 2012, 37(1): 102-116. 10. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. a sham-controlled randomized trial. Arch Gen Psychiatry. 2010; 67(5):507-516. 11. Schutter DJ. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med. 2009; 39(1):65-75. 12. Klein E, Kreinin I, Chistyakov A, et al. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Archives of general psychiatry, 1999, 56(4): 315-320. 13. Kauffmann CD, Cheema MA, Miller BE. Slow right perfrontal transcranial magnetic stimulation as a reatment for medication‐resistant depression: A double‐blind, placebo‐controlled study. Depression and anxiety, 2004, 19(1): 59-62. 14. Chen J, Zhou C, Wu B, et al. Left versus right repetitive transcranial magnetic stimulation in treating major depression: a meta-analysis of randomised controlled trials. Psychiatry research, 2013, 210(3): 1260-1264. 15. Berlim MT, Van den Eynde F, Daskalakis ZJ. A systematic review and meta-analysis on the efficacy and acceptability of bilateral repetitive transcranial magnetic stimulation (rTMS) for treating major depression. Psychol Med, 2013, 43(11): 2245-2254.
16. Chen J, Liu Z, Zhu D, et al. Bilateral vs. unilateral repetitive transcranial magnetic stimulation in treating major depression: a meta-analysis of randomized controlled trials. Psychiatry research, 2014, 219(1): 51-57. 17. Minichino¹ A, Bersani¹ F S, Capra¹ E, et al. ECT, rTMS, and deepTMS in pharmacoresistant drug-free patients with unipolar depression: a comparative review. Neuropsychiatric disease and treatment, 2012, 8: 55-64. 18. Cipriani A, Barbui C, Rizzo C, Salanti G. What is a multiple treatments meta-analysis? Epidemiology and psychiatric sciences 2012; 21(2):151-3. 19. Cipriani A, Zhou X, Del Giovane C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet, 2016; 388(10047):881-90. 20. Chabrol H, Teissedre F, Saint-Jean M, Teisseyre N, Roge B, Mullet E. Prevention and treatment of post-partum depression: a controlled randomized study on women at risk. Psychological medicine 2002; 32(6):1039-47. 21. Hamilton M. A rating scale for depression. Journal of Neurology, Neurosurgery & Psychiatry, 1960, 23(1): 56-62. 22. Guyatt GH, Juniper EF, Walter SD, et al. Interpreting treatment effects in randomised trials. Brit Med J (BMJ).1998; 316:690–93. 23. Furukawa TA, Cipriani A, Barbui C,et al. Imputing response rates from means and standard deviations in metaanalysis. Int Clin Psychopharm. 2005; 20:49–52. 24. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009; 373: 746-58. 25. Higgins J P T, Thompson S G, Deeks J J, et al. Measuring inconsistency in meta-analyses. Bmj, 2003, 327(7414): 557-560. 26. Ades AE, Sculpher M, Sutton A, et al. Bayesian methods for evidence synthesis in cost-eff ectiveness analysis. Pharmacoeconomics, 2006; 24: 1–19. 27. Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. Journal of clinical epidemiology, 2011, 64(2): 163-171. 28. Eche J, Mondino M, Haesebaert F, Saoud M, Poulet E, Brunelin J. Low- vs High-Frequency Repetitive Transcranial Magnetic Stimulation as an Add-On Treatment for Refractory Depression. Front Psychiatry. 2012; 3:13. 29. Fitzgerald PB, Brown TL, Marston NAU, et al. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Archives of General Psychiatry, 2003, 60(10): 1002-1008. 30. Fitzgerald PB, Hoy K, Daskalakis ZJ, et al. A randomized trial of the anti‐depressant effects of low‐and high‐ frequency transcranial magnetic stimulation in treatment‐resistant depression. Depression and anxiety, 2009, 26(3): 229-234. 31. Fitzgerald PB, Sritharan A, Daskalakis ZJ, et al. A functional magnetic resonance imaging study of the effects of
low frequency right prefrontal transcranial magnetic stimulation in depression. Journal of clinical psychopharmacology, 2007, 27(5): 488-492. 32. Höppner J, Schulz M, Irmisch G, et al. Antidepressant efficacy of two different rTMS procedures. European archives of psychiatry and clinical neuroscience, 2003, 253(2): 103-109. 33.Rossini D, Lucca A, Magri L, et al. A symptom-specific analysis of the effect of high-frequency left or lowfrequency right transcranial magnetic stimulation over the dorsolateral prefrontal cortex in major depression. Neuropsychobiology, 2010, 62(2): 91-97. 34. Stern WM, Tormos JM, Press DZ, et al. Antidepressant effects of high and low frequency repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex: a double-blind, randomized, placebo-controlled trial. The Journal of neuropsychiatry and clinical neurosciences, 2007, 19(2): 179-186. 35. Triggs WJ, Ricciuti N, Ward HE, et al. Right and left dorsolateral pre-frontal rTMS treatment of refractory depression: a randomized, sham-controlled trial. Psychiatry research, 2010, 178(3): 467-474. 36. Rosa MA, Gattaz WF, Pascual-Leone A, Fregni F, Rosa MO, et al. Comparison of repetitive
transcranial
magnetic stimulation and electroconvulsive therapy in unipolar non-psychotic refractory depression: a randomized, single-blind study. Int J Neuropsychopharmacol, 2006, 9:667–676. 37. Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, et al. Repetitive Transcranial Magnetic Stimulation versus Electroconvulsive Therapy for Major Depression: Preliminary Results of a Randomized Trial. Biol Psychiatry, 2002, 51(8): 659-67. 38. Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M. Comparison
of
unlimited
transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major
numbers
depressive
of
rapid
episode.
Int J
Neuropsychopharmacol, 2000, 3:129–134. 39. Grunhaus L, Dannon PN, Schreiber S, Dolberg OH, Amiaz R, et al. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Biol Psychiatry, 2000, 47:314–324. 40. Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN. A randomized electroconvulsive therapy and repetitive transcranial magnetic
stimulation
controlled
comparison
of
in severe and resistant nonpsychotic
major depression. Biol Psychiatry, 2003, 53: 324–331. 41. Eranti S, Mogg A, Pluck G, Landau S, Purvis R, et al. A randomized, controlled trial with 6-month follow up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry, 2007, 164: 73–81. 42. Hansen PE, Ravnkilde B, Videbech P, Clemmensen K, Sturlason R, et al. Low-Frequency Repetitive Transcranial
Magnetic Stimulation Inferior to Electroconvulsive Therapy in Treating Depression. J ECT, 2011, 27(1):26-32. 43. Fitzgerald PB, Hoy KE, Singh A, et al. Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment-resistant major depression. International Journal of Neuropsychopharmacology, 2013, 16(9): 1975-1984. 44. Blumberger DM, Mulsant BH, Fitzgerald PB, Rajji TK, Ravindran AV, Young LT, Levinson AJ, Daskalakis ZJ. A randomized double-blind sham-controlled comparison of unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant major depression. World J Biol Psychiatry. 2012; 13(6): 423- 435. 45. Fitzgerald PB, Hoy KE, Herring SE, McQueen S, Peachey AV, Segrave RA, Maller J, Hall P, Daskalakis ZJ. A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression. J Affect Disord. 2012; 139(2):193-198. 46. Conca A, Di Pauli J, Beraus W, Hausmann A, Peschina W, Schneider H, König P, Hinterhuber H. Combining high and low frequencies in rTMS antidepressive treatment: preliminary result. Hum Psychopharmacol. 2002; 17(7):353356. 47. M. Rybak, R. Bruno, Y. Turnier-Shea, S. Pridmore. An Attempt to Increase the Rate and Magnitude of the Antidepressant Effect of Transcranial Magnetic Stimulation (TMS). German Journal of Psychiatry. 2005; 8: 59-65. 48. Fitzgerald PB, Hoy K, Gunewardene R, Slack C, Ibrahim S, Bailey M, Daskalakis ZJ. A randomized trial of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in treatment-resistant major depression. Psychol Med. 2011; 41: 1187-1196. 49. Pallanti S, Bernardi S, Di Rollo A, Antonini S, Quercioli L. Unilateral low frequency versus sequential bilateral repetitive transcranial magnetic stimulation: is simpler better for treatment of resistant depression? Neuroscience. 2010; 167(2): 323- 328. 50. Xiaoming Wang, Deben Yang, Yuanfeng, Hui Huang, Xiaoqiang Zhao. A controlled study of the treatment of repetitive transcranial magnetic stimulation in patients with major depression. Chinese Journal of Clinical Rehabilitation. 2004; 8(9):1770-1 51. Jianjuo Wan, Sanmei Hu, Meiying Chen, Xiangkun Chen, Lihua Yu, Yongmei Zhang, Qiongfang Wu. A control study of sertraline plus RTMS in the treatment of treatment-resistant depression. J Clin Psychosom Dis, 2011, 17(3): 202-204. 52. Isenberg K, Downs D, Pierce K, et al. Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment-resistant depressed patients. Ann Clin Psychiatry, 2005, 17(3):153-9. 53. Chen J, Huang H, Zhao L, et al. Sex-specific urinary biomarkers for diagnosing bipolar disorder. PloS one, 2014,
9(12): e115221. 54. Chen J, Liu Z, Fan S, et al. Combined application of NMR-and GC-MS-based metabonomics yields a superior urinary biomarker panel for bipolar disorder. Scientific reports, 2014, 4: 5855. 55. Chen J, Zhou C, Liu Z, et al. Divergent urinary metabolic phenotypes between major depressive disorder and bipolar disorder identified by a combined GC–MS and NMR spectroscopic metabonomic approach. Journal of proteome research, 2015, 14(8): 3382-3389. 56. Zheng P, Wang Y, Chen L, et al. Identification and validation of urinary metabolite biomarkers for major depressive disorder. Molecular & Cellular Proteomics, 2013, 12(1): 207-214. 57. Deeks JJ, Altman DG, & Bradburn MJ. Statistical Methods for Examining Heterogeneity and Combining Results from Several Studies in Meta‐Analysis. Systematic Reviews in Health Care: Meta-Analysis in Context, Second Edition, 2008; 285-312. 58. Kito S, Hasegawa T, Koga Y. Neuroanatomical correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation in treatment-resistant depression. Psychiatry and Clinical Neurosciences, 2011, 65, 175–182. 59. Martinot ML, Martinot JL, Ringuenet D, Galinowski A,Gallarda T, Bellivier F, Lefaucheur JP, Lemaitre H,Artiges E. Baseline
brain
metabolism
in
resistant
depression
and
response
to
transcranial
magneticstimulation.
Neuropsychopharmacology, 2011, 36, 2710–2719. 60. Xie J, Jianjun Chen, Wei Q. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a meta-analysis of stimulus parameter effects. Neurol Res. 2013; 35(10):1084-91. 61. Arns M, Drinkenburg W H, Fitzgerald P B, et al. Neurophysiological predictors of non-response to rTMS in depression. Brain stimulation, 2012, 5(4): 569-576. 62. Knapp M, Romeo R, Mogg A, et al. Cost-effectiveness of transcranial magnetic stimulation vs. electroconvulsive therapy for severe depression: a multi-centre randomised controlled trial. Journal of affective disorders, 2008, 109(3): 273-285. 63. McLoughlin D M, Mogg A, Eranti S, et al. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis. Health technology assessment (Winchester, England), 2007, 11(24): 1-54. 64. Le Lay A, Despiegel N, François C, Duru G. Can discrete event simulation be of use in modelling major depression? Cost Effectiveness and Resource Allocation, 2006; 4(1):19. 65. Schönfeldt-Lecuona C, Lefaucheur JP, Cardenas-Morales L, Wolf R, Kammer T, & Herwig U. The value of neuronavigated rTMS for the treatment of depression. Neurophysiologie Clinique/ Clinical Neurophysiology, 2010; 40: 37-43.
Figure 1 Flow Chart of Study Selection The electronic literature search resulted in 557 potentially relevant studies, of which 25 eligible articles were pooled for analysis.
Figure 2 Rankings for Efficacy and Acceptability The distribution of probabilities of each treatment modality was ranked at each of four possible positions. (A) ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B-rTMS (25%), R-rTMS (8%), and L-rTMS (2%). (B) R-rTMS was the best-tolerated treatment with the cumulative probabilities of being the best-tolerated treatment being: R-rTMS (52%), B-rTMS (17%), L-rTMS (16%), and ECT (14%).
TABLE LEGENDS
Table 1 Demographic and Clinical characteristics of Included Subjects Female/
Mean age,
Mean MDD
Primary
male, n
yrs (S.D.)
score (S.D.)
diagnosis
48.9 (13.4) vs.
26.0 (3.3) vs. 25.1
All MDD
Yb
58.0 (12.5)
(3.8)a
43.4 (12.7) vs.
23.7 (3.8) vs. 24.3
All MDD
Yb Yc
Study
Pairs
n
Blumberger et
L vs. B
22 vs.
12/10
26
14/12
24 vs.
15/9
al., 2012 Fitzgerald
et
L vs. B
al., 2012 Rybak et al.,
L vs. B
vs. vs.
22
14/8
40.4 (15.5)
(3.6)a
9/9
6/3 vs. 6/3
47.0 (12.3) vs.
23.8 (2.4) vs. 23.0
17%
53.4 (13.3)
(4.0)a
83% MDD
45.8 (12.5) vs.
30.8 (6.0) vs. 29.4
48.2 (16.1)
(4.3)d
47.4 (14.1) vs.
21.8 (2.6) vs. 21.5
15%BD,85% MDD All MDD
2005 Conca et al., 2002 Fitzgerald
et
al., 2011 Pallanti et al.,
L vs. B
R vs. B R vs. B
2010 Fitzgerald
et
al., 2013 Hansen et al., 2011
R vs. B R
vs.
ECT
24 vs. 12 71 vs.
16/8 vs. 9/3 47/24
147
vs. 100/47
46.8 (13.7)
20 vs.
12/8
51.2
27.9 (5.9) vs. 28.7
20
11/9
91 vs.
59/32
88
66/22
30 vs.
23/7
30
vs. vs.
19/11
(12.5) vs.
BD,
25% OP
Part
58% MDD
(2.9)a
vs.
17%
BD,
47.6 (12.3)
(6.0)a
46.7 (14.2) vs.
19.5 (4.4) vs. 19.8
22%
48.5 (15.9)
(5.0)a
78% MDD
46.0 (N.A.) vs.
24.0 (N.A.) vs.
52.0 (N.A.)
24.0
TRD
(N.A.)a
BD,
13%
Yb Yb
Yb Y
BD,87% MDD
Eranti et al., 2007 Rosa
L ECT
et
al.
L
2006
ECT
Wang et al.,
L
2004
vs.
et
L
al., 2003
ECT
Janicak et al.,
L
2002
vs.
et
al., 2000 Pridmore
vs. vs.
et
vs. vs.
ECT al.,
2011 Fitzgerald
L
et
L
vs.
al., 2009 Rossini et al.,
2007
et
al.,
8% BD, 92% MDD All MDD
Yb
All MDD
N
All MDD
Yc
68.0 (13.4)
20 vs.
12/8 vs. 7/8
41.8 (10.2) vs.
30.1 (4.7) vs. 32.1
46.0 (10.6)
(5.0) a
18 vs.
N.A.
31.0
20 vs.
14/6
20
15/5
15 vs.
vs.
11/4 vs. 6/5 vs.
(5.0)
vs.
27.8 (3.2) vs. 26.7
32.0 (6.0)
(2.8)a
57.6 (13.7) vs.
24.4 (3.9) vs. 25.5
61.4 (16.6)
(5.9) a
42.8 (12.9) vs.
32.5(6.4)vs.33.4(9
30%
42.7 (14.0)
.0)f
70% MDD
58.4 (15.7) vs.
25.8
20 vs.
12/8
20
14/6
63.6 (15.0)
28.4 (9.3)a
16 vs.
N.A.
44.0 (11.9) vs.
45 vs.
15/30
vs.
(6.1) vs.
25.3 (4.1) vs. 25.8
18%
Yc
41.5 (12.9)
(3.6)a
82% MDD
36.2 (18.8) vs.
26.3 (12) vs. 28.1
43
15/28
35.7 (15.3)
L vs. R
15 vs.
8/7 vs. 5/6
42.4 (11.2) vs.
34.5 (4.9) vs. 33.3
39.6 (10.0)
(3.8)e
L vs. R L vs. R
16 vs. 11
8/7 vs. 3/8
42.1
(9.3)
vs.
33.6 (3.9) vs. 34.3
BD,
All MDD
Y
All MDD
Yb
All MDD
Yb Yc
46.5 (11.4)
(4.9)e
53.6 (11.3) vs.
24.6 (4.5) vs. 24.3
54%
32 vs.
23/9
42
30/12
54.5 (11.8)
(4.4)d
46% MDD
20 vs.
12/8 vs. 7/3
52.7 (10.6) vs.
27.7 (3.5) vs. 27.9
All MDD
52.8 (9.5)
(3.8)d
10
vs.
N Part
ECT
L vs. R
BD,
N
All MDD
(16)d
2010 Stern
23.9 (7.0) vs. 24.8
16/6
11 et
63.6 (17.3) vs.
22
16
al., 2007 Fitzgerald
vs.
(5.0)a
11
ECT
al., 2000 et
L
16/8
18
ECT
Grunhaus,
24 vs.
15
ECT
Grunhaus
Wan
vs.
BD,
Yc
Triggs et al.,
L vs. R
2010
18 vs.
14/4 vs. 9/7
16
Höppner et al.,
L vs. R
2003
10 vs.
7/3 vs. 8/2
10
Eche
et
al.,
L vs. R
6 vs. 8
L vs. R
2005
14 vs.
2/4 vs. 6/2 6/8 vs. 6/8
14
Fitzgerald
et
L vs. R
al., 2003 a17-item
28.2 (6.0) vs. 27.2
48.5 (10.8)
(4.8)f
59.5
(6.8)
Yb
vs.
N.A.
All MDD
N
50.8
(9.4)
vs.
29.8 (6.9) vs. 32.0
All MDD
Yc Yb
46.1 (16.3)
(8.0)e
43.4
25.1 (4.9) vs. 23.9
10%
(6.2)d
90% MDD
36.1 (7.5) vs. 37.7
3% BD, 97%
(8.4)e
MDD
(9.7) vs.
55.6 (9.7)
20 vs.
12/8
20
13/7
vs.
42.2
(9.8)
45.5 (11.5)
vs.
BD,
Yb
Hamilton Depression Rating Scale.
bFailure
to respond to 2 antidepressants in the current major depressive episode.
cFailure
to respond to 1 antidepressants in the current major depressive episode.
d21-item
Hamilton Depression Rating Scale.
eMontgomery–Asberg f24-item
All MDD
52.0 (11.7)
2012 Isenberg et al.,
46.7 (15.3) vs.
Depression Rating Scale.
Hamilton Depression Rating Scale.
Abbreviations: rTMS, repetitive transcranial magnetic stimulation; L, left rTMS; R, right rTMS; B, bilateral rTMS; TRD, treatment-resistant depression; ECT, electroconvulsive therapy; BD, bipolar depression; MDD, major depressive disorder; N.A., information not available; S. D., standard deviation; and OP, other psychosis
Table 2 rTMS Parameters of Included Randomized Controlled Trials Study
Pairs
Blumberger
et
al., 2012 Fitzgerald et al., 2012 Rybak
et
al.,
2005 Conca
et
al.,
2002 Fitzgerald et al., 2011 Pallanti et al., 2010 Fitzgerald et al., 2013 Hansen
et
L vs. B L vs. B R vs. B R vs. B R vs. B
et
al., L
et
L
2004 2003
al., L
2002 2000 2000
Fitzgerald et al., 2007 Fitzgerald et al., 2009 et
al.,
2010
L
vs.
2010
et
al.,
10 Hz vs. 10 Hz L (S) 1 Hz R 1 Hz vs. 1 Hz L (S) 1 Hz R 1 Hz vs. 10 Hz L (S) 1 Hz R 1 Hz vs. 1 Hz R+10 Hz L 1 Hz vs. right
20 Hz vs. N.A
vs.
ECT
Duration
110 vs. 100a 6 weeks 120 vs. 120 3 weeks 110 vs. 110 2 weeks 100 vs. 100 1 weeks 110 vs. 110 4 weeks 110 vs. 110 3 weeks 110 vs. 110 4 weeks
TPPS 1450 vs. 1215 NA 1200 vs. 1200 1300 vs. 1300 900
Y
Y
Y
Y
Augmentation
Y
NA Y
Y
Augmentation
Y
NA Y
Y
Augmentation
Y
NA NA Y
Y
Y
Y
Y
vs.
Y
Y
Y
Y
Y
Y
Y
Y
Augmentation
vs. 84% augmentation,
900
16% monotherapy Augmentation
Y
Y
N
Y
110
2 weeks
1000
Augmentation
Y
Y
N
Y
100
4 weeks
2500
Monotherapy
Y
NA N
Y
70
2 weeks
500
Monotherapy
Y
NA NA Y
90
4 weeks
1200
Monotherapy
Y
N
4 weeks
1000
Y
NA NA Y
Y
NA NA Y
Monotherapyb
Y
Y
N
1500
Augmentation
Y
N
NA Y
Augmentation
Y
NA Y
Y
Y
Y
Y
Augmentation
Y
NA NA Y
100
2 weeks
10 Hz vs. N.A
100
4 weeks
9%
augmentation,
91% monotherapy
400
or 78% augmentation,
1200
22% monotherapy
12001400
L vs. R 10 Hz vs. 1 Hz
100 vs. 110 3 weeks
NA
L vs. R 10 Hz vs. 1 Hz
100 vs. 110 3 weeks
NA
L vs. R 15 Hz vs. 1 Hz
100 vs. 100 2 weeks
L vs. R 5 Hz vs. 5 Hz
Augmentation
NA
20 Hz vs. N.A
Hz
RD AC BT BL
3 weeks
4 weeks
1 Hz or 10 Hz vs. 1
strategy
15% monotherapy
1420 900
Methodology
vs. 85% augmentation,
900 420
Treatment
110
90
bilateral vs.
% rMT
10 Hz vs. bilateral 110
vs. 10 Hz vs. right or
Stern et al., 2007 L vs. R Triggs
(S)10 Hz L
bilateral
ECT
Wan et al., 2011
10 Hz vs. 1 Hz R
vs. 10 Hz vs. right or
ECT
Pridmore et al., L
Rossini
vs.
ECT
Grunhaus, et al., L
(S)10 Hz L
bilateral
ECT et
10 Hz vs. 1 Hz R
vs. 10 Hz vs. right or
ECT
Grunhaus et al., L
(S)10 Hz L
bilateral
ECT
al., L
10 Hz vs. 1 Hz R
vs. 10 Hz vs. right or
ECT
Rosa et al., 2006
Janicak
vs.
ECT
2007
Wang
L vs. B
al., R
2011 Eranti
L vs. B
Frequency
600 600
64% augmentation, 37% monotherapy vs.
N
Y
Y
Y
110 vs. 110 2 weeks
NA
Monotherapy
Y
NA Y
Y
100 vs. 100 2 weeks
NA
Augmentation
Y
NA Y
Y
Höppner et al.,
L vs. R 20 Hz vs. 1 Hz
90 vs. 110 2 weeks
Eche et al., 2012 L vs. R 10 Hz vs. 1 Hz
100 vs. 100 2 weeks
2003
Isenberg et al., 2005 Fitzgerald et al., 2003 a
L vs. R 20 Hz vs. 1 Hz
80 vs. 110 4 weeks
L vs. R 10 Hz vs. 1 Hz
100 vs. 100 4 weeks
NA 2000 vs. 120 NA 1000 vs. 300
Augmentation
Y
Y
NA Y
Augmentation
Y
NA N
Y
Monotherapy
Y
NA N
Yc
Augmentation
Y
Y
Y
Y
120% of the rMT in subjects older than 60 years old.
b Medication
was tapered and ceased where possible; no new medication was commenced in the two weeks before entry
into the study. c Subjects
receiving rTMS treatment on the right side were notably older.
Abbreviations: rTMS, repetitive transcranial magnetic stimulation; TPPS, total pulse per session in rTMS; RD, randomized; AC, allocation concealment; BT, blind treatment; and BL, baseline; L, left rTMS; R, right rTMS; B, bilateral rTMS; ECT, electroconvulsive therapy; rMT, resting motor threshold; (S), sequential; Y, yes; N, no; and NA, not available.
Table 3 Response and dropout rates for efficacy and acceptability in meta-analyses of direct comparisons between each pair of treatment modality Number
Number
Efficacy
Acceptability
of studies
of patients
Response rate
OR (95% CI)
Dropout rate
OR (95% CI)
R
8
265
53/137vs53/128
0.99(0.58,1.69)
7/46vs0/31
3.97(0.63,25.1)
B
4
150
24/81vs23/69
0.52(0.09,3.06)
4/72vs7/60
0.52(0.12,2.15)
ECT
7
262
67/135vs78/127
0.64(0.30,1.38)
4/37vs7/31
0.42(0.11,1.65)
L
8
265
53/128vs53/137
1.01(0.59,1.73)
0/31vs7/46
0.25(0.04,1.59)
B
2
258
46/91vs81/167
1.21(0.72,2.06)
23/71vs36/147
1.48(0.79,2.76)
ECT
1
60
7/30vs12/30
0.46(0.15,1.40)
10/30vs8/30
1.38(0.45,4.17)
L
4
150
23/69vs24/81
1.93(0.33,11.4)
7/60vs4/72
1.94(0.46,8.11)
R
2
258
81/167vs46/91
0.82(0.49,1.40)
36/147vs23/71
0.68(0.36,1.26)
L
7
262
78/127vs67/135
1.55(0.72,3.34)
7/31vs4/37
2.37(0.61,9.27)
R
1
60
12/30vs7/30
2.19(0.72,6.70)
8/30vs10/30
0.73(0.24,2.21)
L vs.
R vs.
B vs.
ECT vs.
rTMS, repetitive transcranial magnetic stimulation; L, left rTMS; R, right rTMS; B, bilateral rTMS; ECT, electroconvulsive therapy; OR, odds ratio; vs., versus; CI, confidence interval.