Portal de Periódicos da CAPES

Double cone coil rTMS efficacy for treatment-resistant depression: A prospective randomized controlled trial

2019; Elsevier BV; Volume: 13; Issue: 1 Linguagem: Inglês

10.1016/j.brs.2019.09.009

1935-861X

Maud Tastevin, Karine Baumstarck, Florence Groppi, Michel Cermolacce, Guillaume Lagrange, Christophe Lançon, Raphaëlle Richieri,

Pain Management and Treatment

Major depressive disorder is the first cause of ill health and disability worldwide and more than 300 million people are affected according to World Health Organization. Moreover, it has been estimated that 30–50% of patients are resistant to antidepressants and cognitive behavioral treatment. In this regard, the development of repetitive transcranial magnetic stimulation (rTMS) as an alternative approach is interesting [[1]Perera T. George M.S. Grammer G. Janicak P.G. Pascual-Leone A. Wiercki T.S. The clinical TMS society consensus review and treatment recommendations for TMS therapy for major depressive disorder.Brain Stimul. 2016; 9: 336-346https://doi.org/10.1016/j.brs.2016.03.010Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar]. Indeed, rTMS consists of a non-invasive cerebral stimulation not requiring general anesthesia. In treatment resistant depression (TRD), the usual technique using figure-in 8 (or butterfly) coils is currently efficient in 30–40% of cases [[2]Berlim M.T. van den Eynde F. Tovar-Perdomo S. Daskalakis Z.J. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.Psychol Med. 2014; 44: 225-239https://doi.org/10.1017/S0033291713000512Crossref PubMed Scopus (332) Google Scholar,[3]Brunoni A.R. Chaimani A. Moffa A.H. Razza L.B. Gattaz W.F. Daskalakis Z.J. et al.Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis.JAMA Psychiatry. 2017; 74: 143-152https://doi.org/10.1001/jamapsychiatryCrossref PubMed Scopus (258) Google Scholar]. Recent development of rTMS called deep-rTMS provides several coils with different shapes which could stimulate deeper in the brain (H1-coils, double cone coils, C-shaped, crown coils…) [[4]Lu M. Ueno S. Comparison of the induced fields using different coil configurations during deep transcranial magnetic stimulation.PLoS One. 2017; 12e0178422https://doi.org/10.1371/journal.pone.0178422Crossref PubMed Scopus (81) Google Scholar]. However, the lack of comparative studies between conventional coils and deep coils, does not permit to conclude about the safest and the most efficient one. In this context, we conducted a double blind randomized rTMS controlled trial to investigate the therapeutic effectiveness of the Magventure cool D-B80 coil (DC coil), applied daily during an acute phase of 4 weeks in TRD. Patients suffering a TRD were recruited between October 2015 and March 2018 from the Department of Psychiatry at Sainte Marguerite University Hospital, in Marseille, France. This study was approved by the institutional Ethics Committee, and registered at ClinicalTrials.gov (NCT02559466). Inclusion criteria were participants over the age of 18 who met the DSM-5 criteria of major depressive episode and treatment resistant criteria (failure of two successive trials of antidepressants at an adequate dose for six weeks each). Exclusion criteria were psychotic symptoms, schizophrenia or bipolar disorder, ECT during the current episode, r-TMS contraindications and pregnancy. The patients enrolled were randomized by electronic group allocation to receive either conventional r-TMS (r-TMS group) or double cone r-TMS (DC-TMS group). The left dorsolateral prefrontal cortex (DLPFC) was targeted according to the Beam F3 algorithm [[5]Beam W.1 Borckardt J.J. Reeves S.T. George M.S. An efficient and accurate new method for locating the F3 position for prefrontal TMS applications.Brain Stimul. 2009; 2: 50-54https://doi.org/10.1016/j.brs.2008.09.006Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar]. Conventional rTMS was applied daily during an acute phase of 4 weeks (20 sessions), at 10 Hz frequency with a figure-of-eight coil (Cool-B65, Magventure A/S) at an angle of 45° from the midsagittal plane (Fig. 1A). 2000 stimuli by session were delivered at 120% resting motor threshold in trains of 5 s stimulation followed by 25 s rest. DC coil rTMS was performed at equal location, duration and frequency sagittaly (Cool-D-B80, Magventure A/S) (Fig. 1B). All two devices were realized by a MagPro 100 stimulator (Magventure A/S). TMS was performed as add-on treatment. Pre-treatment medication had to be stable for at least 4 weeks prior to entry in the study and to have remained unchanged throughout the course of the study. Treatment was carried out by paramedical personnel not involved in rating procedures. The primary outcome was the change of Montgomery-Åsberg Depression Rating Scale score (MADRS) (from baseline to 4-weeks post-inclusion). Secondary outcomes measures were the proportion of patients achieving response defined as a reduction of 50% MADRS score, remission defined as a MADRS score < 10, changes in the Quick Inventory of Depressive Symptomatology Self-Report-16 items (QIDS-SR16) and the Medical Outcome Study Short Form (SF-12). The sample size was determined to detect, between groups, a 5-point difference (standard deviation: 5) in MADRS change defined as clinically pertinent. With a significant p-value of 0.05, a 80% power, a potential 5% lost to follow-up, a total of 18 patients per group were needed. The analysis was performed on the intention-to-treat (ITT) population. The MADRS change was compared between groups using Mann-Whitney test. The secondary endpoints were compared between the 2 groups: using χ2 test or Fisher's exact test for binary variables; using Student t-test or Mann-Whitney test for continuous variables as appropriate. Adjustment for unbalanced baseline characteristics was performed. We randomly assigned 45 patients to the r-TMS group (n = 22) and the DC-TMS group (n = 23). Finally, 36 patients achieved the treatment (n = 18 in each group), 9 patients discontinued (not stable psychotropic regimen n = 3; withdrawn consent n = 2; drop out n = 4). Baseline characteristics were the same in the two groups except from the age (Table 1). In ITT population, the MADRS change did not differ between groups (11.2 ± 10.6 vs. 7.7 ± 10.3, respectively for r-TMS group and DC-TMS, p = 0.584). Eight patients (44.4%) were responders in the r-TMS group versus 6 patients (33.3%) in the DC-TMS group with no significant differences between two groups (p = 0,494). Moreover, there was no difference in terms of remission and score changes with MADRS between the two groups after treatment. Secondary outcome measures involving other assessments of depression severity (QIDS SR-16) and quality of life (SF-12) did not differ between groups after treatment (Table 2). Adjustment for age did not change these results. Overall tolerability was good without spontaneous reported side-effects except for 4 patients who dropped out after pain at the application site (r-TMS group: 1; DC-TMS: 1), panic attack (r-TMS group) and induction of hypomanic episode (DC-TMS).Table 1Baseline characteristics.All (n = 45)r-TMS group (n = 23)DC-TMS group (n = 22)p-valueDemographic characteristicsGender (male)13 (28.9%)8 (34.8%)5 (22.7%)0.372Gender (female)32 (71.1%)15 (65.2%)17 (77.3%)0.372Age (years), mean ± SD47.9 ± 12.642.9 ± 11.553.1 ± 11.90.012Education level (>12 years)20 (65.2%)10 (43.5%)10 (45.5%)0.735Marital status Single28 (66.7%)12 (52.2%)16 (72.7%)0.155 Couple17 (37.8%)11(47.8%)6 (27.3%)Clinical characteristicsDepression duration (Years)13.8 ± 12.911.7 ± 8.615.9 ± 16.10.759Number of depressive episodes1.6 ± 1.31.4 ± 0.81.8 ± 1.60.556Current episode chronicity33 (73.3%)18 (78.3%)15 (68.2%)0.420MAUDSLEY Staging method9.4 ± 1.89.6 ± 1.69.2 ± 1.90.510Comorbid anxiety disorder19 (42.2%)12 (52.2%)7 (31.8%)0.167Treatments AntidepressantSSRI15 (33.3%)8 (30.4%)7 (36.4%)0.673SNRI13 (33.3%)9 (39.1%)4 (18.2%)0.121tricyclics3 (6.7%)1 (4.3%)2 (9.1%)0.608 Others15 (33.3%)7 (30.4%)8 (36.4%)0.673Antipsychoticfirst generation1 (2.2%)0 (0.0%)1 (4.5%)0.489second generation8 (17.8%)6 (26.1%)2 (9.1%)0.243Mood stabilizerslamotrigine1 (2.2%)0 (0.0%)1 (4.5%)0.489lithium1 (2.2%)0 (0.0%)1 (4.5%)0.489Baseline symptoms scores (mean ± SD) MADRS score31.8 ± 11.032.9 ± 11.430.8 ± 10.90.311 QIDS-SR16 score17.4 ± 5.018.1 ± 4.616.7 ± 5.50.480 SF-12 physical score38.7 ± 10.739.6 ± 8.937.7 ± 12.50.332 SF-12 mental score45.2 ± 7.444.4 ± 6.046.0 ± 8.80.521 Open table in a new tab Table 2Post-treatment characteristics.All (n = 36)r-TMS group (n = 18)DC-TMS group (n = 18)p-valueMADRSMean change (mean ± SD)−9.4 ± 10.5−11.2 ± 10.6−7.7 ± 10.30.584Responder n (%)14 (38.9%)8 (44.4%)6 (33.3%)0.494Remitter n (%)6 (16.7%)3 (16.7%)3 (16.7%)1.000QIDS-SR16 mean change(mean ± SD)−4.3 ± 5.8−4.8 ± 5.4−3.8 ± 6.20.610SF-12 mean changeMental composite (mean ± SD)8.9 ± 11.110.7 ± 10.97.2 ± 11.30.364Physical composite (mean ± SD)2.1 ± 7.62.1 ± 5.52.2 ± 9.10.936 Open table in a new tab Although no significant differences between two groups were detected, the response rates were in line with the usual rTMS treatment response outcome for TRD patient in both protocols [[3]Brunoni A.R. Chaimani A. Moffa A.H. Razza L.B. Gattaz W.F. Daskalakis Z.J. et al.Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis.JAMA Psychiatry. 2017; 74: 143-152https://doi.org/10.1001/jamapsychiatryCrossref PubMed Scopus (258) Google Scholar]. Likewise, our remission rate was in line with previous studies using conventional rTMS [[2]Berlim M.T. van den Eynde F. Tovar-Perdomo S. Daskalakis Z.J. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.Psychol Med. 2014; 44: 225-239https://doi.org/10.1017/S0033291713000512Crossref PubMed Scopus (332) Google Scholar], but rather low regarding other reports using DC-TMS (34.7–47.6%) [[6]Monteiro D.C. Cantilino A. Use of a double-cone coil in transcranial magnetic stimulation for depression treatment.Neuromodulation Soc. 2018; https://doi;org/10.1111/ner.12896Crossref PubMed Scopus (2) Google Scholar]. The follow-up duration and assessments were insufficient to evaluate potential time impact and delayed effects on remission or response rates. In addition, our study targeted the same area in both groups. Other promising targets are currently proposed with deep-TMS, in particular the medial region of the prefrontal cortex [[7]Downar J. Daskalakis Z.J. New targets for rTMS in depression: a review of convergent evidence.Brain Stimul. 2013; 6: 231-240https://doi.org/10.1016/j.brs.2012.08.006Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]. Deep-rTMS trials were most often associated with H1-coils, which obtained FDA approval [[7]Downar J. Daskalakis Z.J. New targets for rTMS in depression: a review of convergent evidence.Brain Stimul. 2013; 6: 231-240https://doi.org/10.1016/j.brs.2012.08.006Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar,[8]Kisely S. Li A. Warren N. Siskind D. A systematic review and meta-analysis of deep brain stimulation for depression.Depress Anxiety. 2018; 35: 468-480https://doi.org/10.1002/da.22746Crossref PubMed Scopus (62) Google Scholar]. DC-TMS trials are very few and only one comparative study has been published [[7]Downar J. Daskalakis Z.J. New targets for rTMS in depression: a review of convergent evidence.Brain Stimul. 2013; 6: 231-240https://doi.org/10.1016/j.brs.2012.08.006Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar,[9]Kreuzer P.M. Downar J. de Ridder D. Schwarzbach J. Schecklmann M. Langguth B. A comprehensive review of dorsomedial prefrontal cortex rTMS utilizing a double cone coil. Neuromodulation.https://doi.org/10.1111/ner.12874Date: 2018Google Scholar]. In this latter, DC-TMS was applied to the anterior cingulate cortex and showed a significant group × time interaction effect regarding the change in depression score. DC-TMS at 3 weeks was significantly superior than conventional rTMS, but this effect was transient lasting in between 3 and 12 weeks [[10]Kreuzer P.M. Schecklmann M. Lehner A. Wetter T.C. Poeppl T.B. Rupprecht R. et al.The ACDC pilot trial: targeting the anterior cingulate by double cone coil rTMS for the treatment of depression.Brain Stimul. 2015; 8: 240-246https://doi.org/10.1016/j.brs.2014.11.014Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. Overall, our trial confirmed the safety and the efficiency of DC coils but did not conclude to a significant superiority compared to figure-in-8 coils. Other variables such as cost-effectiveness, time-effect, stimulation targets and parameters should be systematically considered in future comparative studies to better discriminate the most interesting stimulation protocol. This study was supported by the Public Assistance Marseille Hospitals (AORC junior 2014) and a research grant from a French foundation for health research and innovation "Fondation de l'Avenir".