A systematic literature review of the clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) in non-treatment resistant patients with major depressive disorder

Background The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) in treatment resistant patients (at least 4 medication trials) appears to be well accepted and forms the coverage policies and rTMS’s use in many of the largest US payers. However, less is known about rTMS’s use in patients who have undergone ≤1 failed medication trial. The purpose of this analysis was to determine the clinical efficacy of rTMS in patients after ≤1 medication trials. Methods A systematic review of the literature was undertaken to identify all articles which addressed the use of rTMS in ≤1 medication trial. All types of study designs were included and assessed for quality and strength of evidence using: GRADE and CEBM. Searches of peer reviewed articles were undertaken for the year 2000 to the present. All languages were considered. Electronic databases were searched and included: PubMed and EBSCO. Evidence assessment websites were also searched and included: Cochrane, NICE, AHRQ, and ICER. Additionally, the clinical guidelines for specialty societies which use rTMS was searched. Hand searches of the reference sections of identified articles was also undertaken. Results Electronic and other sources identified 165 after duplicates were removed. Twenty two articles were assessed for eligibility and ultimately 10 articles were included in the systematic review and graded. Six articles were graded high quality (CEBM/GRADE: 1c/B) demonstrating that the use of rTMS was clinically efficacious in patients after ≤1 medication trial. Four additional trials demonstrated a positive effect of rTMS in patients after ≤1 medication trial but were of a lower quality. Conclusion The use of rTMS in patients after ≤1 medication trial should be considered. US payers should consider revising their coverage policies to include the use of rTMS in these patients. Electronic supplementary material The online version of this article (10.1186/s12888-018-1989-z) contains supplementary material, which is available to authorized users.


Background
Repetitive transcranial magnetic stimulation (rTMS) is an FDA cleared therapy for use in treating major depressive disorder (MDD). All products cleared for market use are indicated for: "Treatment of major depressive disorder in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode [1][2][3][4][5]". The clinical efficacy of rTMS has been demonstrated in numerous randomized controlled clinical trials in patients who have failed 1-4 pharmacologic treatment regimens [6][7][8]. Additionally, medical specialty guidance documents support its use, including a whitepaper from the Clinical Transcranial Magnetic Stimulation (TMS) Society [9] and consensus recommendations published by a group of rTMS experts in the National Network of Depression Centers (NNDC) the American Psychiatric Association (APA) Council on Research [10].
Current medical policy coverage guidelines for the largest US payers call for coverage of rTMS if the following condition is met: "….inability to tolerate psychopharmacologic agents (at least 3-4 trials of agents with distinct side effects) [11][12][13][14][15]". Unfortunately as patients move through the depression treatment paradigm they become more resistant to any therapy [16][17][18][19]. The American Psychiatric Council further states: "A consistent predictor of antidepressant response across most therapeutic modalities is the degree of treatment resistance. Thus, rTMS is like other known antidepressant treatments in this respect with greater treatment resistance generally predicting poorer response [10]." Recently a local Medicare carrier has allowed for rTMS use after at most 1 failed pharmacologic therapy [20]. Additionally a lifetime cost effectiveness analysis examining the use of rTMS after one failed therapy and comparing it to standard therapy (i.e. multiple trials of pharmacologic agents) demonstrated that rTMS can be cost saving and improve upon the quality of life in the various age cohorts examined [21].
Based on the above, it is the purpose of this analysis to further examine the evidence on the use of rTMS in patients major depressive disorder who have failed ≤1 vs. ≥2 pharmacologic trials (as a comparison) to determine if there is clinical efficacy (and if clinical efficacy improves in patients who have undergone ≤1 failed medication trial vs. ≥2 failed medication trials [hereafter defined as treatment resistant]) when used after ≤1 failed medication trials. As well, it is the intention to examine patients who were treated with rTMS ± pharmacotherapy vs. pharmacotherapy as the first therapy in treatment naïve patients in order to determine rTMS's clinical effect. This analysis appears not to have been done previously and may offer payers an alternative for cost savings and improved outcomes vs. numerous trials of pharmacologic agents.

Methods
A systematic review of the literature was undertaken using the following sources and search terms: Search terms: ((((Predict*) AND response) AND rTMS)) AND depress*. As well, search terms used were: ((((((rTMS) AND major) AND depress*) AND controlled) AND trial)) AND response.
Electronic searches were undertaken using both PubMed and EBSCO.
Other searches were made of the following websites: Hand searches of the reference sections of all articles obtained were undertaken.
Articles which addressed the issue of the number of medication trials and rTMS outcomes in patients with MDD were included. More specifically, those trials which defined non-treatment resistant patients as ≤1 medication trial and evaluated rTMS outcomes were also included. Those trials that defined non-treatment resistance as ≤2 medication trials were excluded. The clinical outcome evaluated was clinical response to rTMS in treatment naïve or after 1 failed medication trial.
The level and quality of the evidence was assessed using the Center for Evidence Based Medicine (CEBM) [22] and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [23] criteria. (See Additional file 1: Appendix 1 for the criteria used for each.) Electronic and hand searches were performed by JV and adjudicated by LC. Assessment of the evidence was first performed by JV and confirmed by AL.
Lastly a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was utilized to ensure the manuscript adhered to minimum accepted guidelines for systematic reviews (Additional file 2: Appendix 2).

Electronic searches
Electronic databases were searched for the years: 2000 to the present. The year 2000 was chosen as rTMS began to be evaluated in patients about this time.
PubMed searched on January 20, 2018 using the search terms: ((((Predict*) AND response) AND rTMS)) AND depress* -91 hits; 10 records obtained PubMed searched on January 31, 2018 using the search terms: ((((((rTMS) AND major) AND depress*) AND controlled) AND trial)) AND response -85 hits; 6 records identified; 3 duplicates; 2 new record obtained. EBSCO searched on January 21, 2018 using the search terms: ((((Predict*) AND response) AND rTMS)) AND depress* -59 hits; 4 records identified; 3 duplicates; 1 new record obtained EBSCO searched on January 31, 2018 using the search terms: ((((((rTMS) AND major) AND depress*) AND controlled) AND trial)) AND response -50 hits; 4 records identified. 4 duplicates; 0 new records obtained.  Figure 1 depicts the flow diagram of articles screened, identified, eligible and excluded from the analysis. In total there were 10 articles identified which addressed the issue of rTMS efficacy based on the number of medication trials and which; focused on patients who were not defined as treatment resistant (≤1 medication failure), that a patient with MDD had undergone prior to use of rTMS. These studies are identified in Table 1. Table 2 shows those studies that were excluded with reasons.

Consensus recommendations by specialty societies
As can be seen in Table 1, there were six studies that would be considered of high quality as evaluated by CEBM/GRADE criteria which demonstrated a statistically significant and positive effect of rTMS in patients with low medication resistance (≤1 trial) prior [24][25][26][27][28][29]. The other trials were of lower quality but again, all demonstrated a positive effect of rTMS in patients with low medication resistance (≤ 1 trial) [30][31][32][33] , . Two studies related to treatment resistance were excluded for the following reasons: Lefkovitz [8] was excluded as it compared ≤2 medication trials to ≥3 trials. It did however find that patients treated with rTMS who failed ≤2 medication trials were significantly more responsive (P = 0.032) vs. those with ≥3 medication trials. Mitchell [34] was excluded as it did not specify the number of medication trials but did state that the number of medication trials affected rTMS's efficacy.  Adverse events (where identified) included Table 3 and mainly consisted of headache and scalp pain [24,25,[27][28][29]32]. These adverse events were transitory in nature.
Based on the heterogeneity of the included studies, a further breakdown of the clinical response to rTMS was undertaken based on the number of medication trials prior to its use (Table 4). What can be seen in Table 4 are the following findings: the lower the number of medication trials, the better the response rate to rTMS; in patients with a ≤ 1 medication trial, the use of rTMS plus medication resulted in a response that was significantly higher vs. medication only; and in patients with ≤1 medication trial vs. ≥2 medication trials the use of rTMS provided an improved response.

Discussion
We present results of the first systematic examination of published clinical trial data to specifically demonstrate that the use of rTMS therapy in patients with ≤1 failed medication trials produces superior outcomes compared to those observed in patients who exhibit higher levels of medication resistance. It is known that the use of rTMS in treating MDD has demonstrated clinical efficacy in high quality studies and in patients who have previously failed 1-4 medication trials [35,36]. This systematic review/analysis extends the understanding of the scope of rTMS' therapeutic potential, and identified several clinical trials which show improved clinical efficacy of rTMS when used in depressed patients characterized by less pharmacoresistance (≤1 medication trials). The effect of increased treatment resistance in patients as medication trials increase is also a consistent finding with other therapeutic modalities [16][17][18][19]. It is also known that 20-40% of patients do not benefit from, or cannot tolerate adverse effects from, serial adequate trials of antidepressant medications [37]. It is thus important to identify treatments that can provide clinical benefit to the patient as early on as possible. Patients treated with rTMS who failed ≤2 treatments significantly more responsive (P = 0.032) than those with ≥3 treatments (P = 0.057).
Fitzgerald PB, et al. Depression Anxiety. 2016 [50] Patients treated with rTMS who responded/did not respond had on average 5.7-6.1 failed medication trials.
Could not break out low vs. high medication treatment resistance.
In a recent cost effective analysis, it has been found that the introduction of rTMS therapy after one failed medication therapy may cost less and provide for similar or even better outcomes when compared with serial medication trials over the life of the patient [21]. The findings from this cost effectiveness analysis are in line with other cost effectiveness analyses which examined patients over 9 weeks [38], and 3 years [39]. However, the main methodological difference between these prior reports and that of the Voigt et al. analysis [21] is the examination of cost effectiveness in patients who are not treatment resistant patients (i.e. after only one failed therapy). As rTMS is more clinically efficacious in patients who have failed ≤1 failed medication trial, and the likelihood that it will cost less in a less pharmacoresistant population, may be reason for payers to re-think coverage policies which restrict rTMS coverage to only depressed patients who present after 4 failed medication trials. The present findings support consideration of rTMS coverage after only one failed medication therapy, consistent with at least one Medicare local coverage determination policy which covers rTMS services for appropriate candidates after only one failed antidepressant medication therapy [20].
The 2016 Clinical TMS Society Consensus review of rTMS for MDD did not address the issue of treatment resistance [9]. While the results of the present analysis are in agreement with comments in a recent consensus recommendations paper [10], the current analysis differs with regard to the conclusions summarized by McClintock et al. [10]. They included data from a large, multisite, an open case series which was excluded from the current analysis due to the fact that it did not break out treatment resistance [40]. Additionally, further scrutiny of a large naturalistic study [33] that shaped the general conclusions of McClintock et al. [10] shows that while there was not a statistically significant difference in outcomes between non-treatment/treatment resistant subgroups, there was also an identified trend favoring the clinical efficacy of rTMS in patients who have undergone ≤1 failed medication trial.
While a direct comparison of response and remission rates based on degree of treatment resistance cannot be made, comparing response and remission rates from different studies may provide some insights. As it relates to the response and remission rates after failed therapies for both medication and rTMS, the literature shows that with medication the remission and response rates were: 30.6 and 28.5% after one failed medication therapy; 13.7 and 16.8% after 2 failed medication therapies and; 13 and 16.3% after 3 failed medication therapies [41]. The response and remission rates for rTMS were noted to be Active rTMS: eye pain (n = 10); GI & toothache (n = 12); site discomfort (n = 18); site pain (n = 59); facial pain (n = 11); muscle twitching (n = 334); pain of skin (n = 14). as follows: 95% response and 63% remission rate in treatment naïve patients [28]; 43% response rate after one failed medication trial [31]; 36.6% remission after one to two failed medication therapies [18] and; 28.9% remission after 3-4 failed medication therapies [18]. The types of patients in each of these studies appear to be comparable when evaluating the baseline characteristics [18,31,41]. Based on the data, it appears rTMS may provide at least comparable remission and response outcomes to antidepressant pharmacotherapy, based on treatment resistance. Lastly, based on the results in Table 4, there appears to be a durable and improved response to the use of rTMS plus medication vs. medication only in patients who have failed ≤1 medication trials. These trials were well designed (i.e. RCTs). The use of rTMS as augmentative therapy to medication in treatment resistant patients (≥2 medication trials) has also demonstrated an improved response in a systematic review and meta-analysis [42]. The fact that similar results are demonstrated in patients who have failed ≤1 failed medication trial likely holds promise for rTMS as augmentative therapy in these types of patients.

Limitations
The use of PubMed, EBSCO, and English language journals may have missed non-English language publications.
The risk of bias in each study was not assessed. However, CEBM and GRADE assessments were evaluated. Four of the studies identified were randomized controlled trials [27][28][29]43]. In each of these trials it was identified that the GRADE quality of evidence was moderate (level B).

Conclusion
High quality evidence exists supporting the clinical efficacy of rTMS in patients who have failed ≤1 medication therapies. This evidence also appears to be in line with remission and response rates of patients who have undergone additional medication trials after one failed medication trial. High quality evidence also exists that rTMS used solely or in combination with antidepressants for first-episode major depressive disorder may be more effective than antidepressants alone. Thus the use of rTMS may shorten the treatment odyssey for patients with MDD. Further, cost-effectiveness has been demonstrated in patients with one failed rTMS therapy. Lastly, payers are beginning to cover rTMS after one failed medication trialwith one Medicare payer out of 7 doing so -Novitas [20]. Private payers in the US are not. Therefore rTMS should be considered for coverage with patients who have failed ≤1 failed medication trials.