TRANSCRANIAL MAGNETIC STIMULATION

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1 MEDICAL POLICY TRANSCRANIAL MAGNETIC STIMULATION Policy Number: 2013T0536F Effective Date: December 1, 2013 Table of Contents COVERAGE RATIONALE... BACKGROUND... CLINICAL EVIDENCE... U.S. FOOD AND DRUG ADMINISTRATION... CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS)... APPLICABLE CODES... REFERENCES... POLICY HISTORY/REVISION INFORMATION... INSTRUCTIONS FOR USE This Medical Policy provides assistance in interpreting UnitedHealthcare benefit plans. When deciding coverage, the enrollee specific document must be referenced. The terms of an enrollee's document (e.g., Certificate of Coverage (COC) or Summary Plan Description (SPD)) may differ greatly. In the event of a conflict, the enrollee's specific benefit document supersedes this medical policy. All reviewers must first identify enrollee eligibility, any federal or state regulatory requirements and the plan benefit coverage prior to use of this Medical Policy. Other Policies and Coverage Determination Guidelines may apply. UnitedHealthcare reserves the right, in its sole discretion, to modify its Policies and Guidelines as necessary. This Medical Policy is provided for informational purposes. It does not constitute medical advice. UnitedHealthcare may also use tools developed by third parties, such as the MCG Care Guidelines, to assist us in administering health benefits. The MCG Care Guidelines are intended to be used in connection with the independent professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice. COVERAGE RATIONALE Transcranial magnetic stimulation is unproven for treating all conditions including the following: Chronic neuropathic pain Depression and other psychiatric disorders Dystonia Epilepsy Headaches Parkinson s disease Stroke Tinnitus A review of the technology as a whole, inclusive of several devices and protocols that have been tested in scientific studies, suggests there is insufficient evidence that transcranial magnetic stimulation (TMS) is beneficial for health outcomes in patients with major depression. There is a Page Related Medical Policies: Deep Brain Stimulation Vagus Nerve Stimulation Related Behavioral Health Guideline: Repetitive Transcranial Magnetic Stimulation (rtms) for Major Depressive Disorder

2 lack of evidence of an enduring treatment effect. Furthermore, some of the randomized sham controlled trials failed to find any significant treatment effect. In addition, there is insufficient evidence demonstrating that TMS results in treatment effects equivalent or superior to electroconvulsive therapy (ECT), an established treatment alternative for patients with highly treatment resistant depression. Some methodological concerns have been raised about the studies of TMS for treating depression. These include small sample size, lack of adequately blinded sham comparison in randomized controlled trials, and variable use of outcome measures. Further well-designed clinical trials with long-term follow-up are required to establish that transcranial magnetic stimulation results in improved long-term health outcomes in patients with depression. Additional evidence is also needed to determine optimal patient selection criteria for TMS. Some studies have examined the use of transcranial magnetic stimulation for treating disorders other than depression. However, because of limited studies and small sample size there is insufficient data to conclude that transcranial magnetic stimulation is beneficial for treating these conditions. Navigated transcranial magnetic stimulation (ntms) is unproven for treatment planning or for diagnosing motor neuron diseases or neurological disorders. There is limited information from the peer-reviewed published medical literature to conclude that navigated transcranial magnetic stimulation is an effective clinical diagnostic test. Most published studies involve a small number of patients. Additional studies with larger populations are needed to evaluate how this test can reduce clinical diagnostic uncertainty or impact treatment planning. BACKGROUND Single-pulse transcranial magnetic stimulation (TMS) was originally introduced in 1985 as a noninvasive and safe way to stimulate the cerebral cortex. Activation of the motor cortex by transcranial magnetic stimulation produces contralateral muscular-evoked potentials (MEPs), thus providing a valuable tool for functional mapping of the motor cortex. Technological advances introduced generators capable of producing rapid, repetitive pulses of magnetic stimulation. The magnetic field pulses pass unimpeded through the hair, skin, and skull and into the brain where they induce an electrical current to flow inside the brain without seizures or need for anesthesia. The amount of electricity created is very small and cannot be felt by the patient, but the electric charges cause the neurons to become active and are thought to lead to the release of neurotransmitters such as serotonin, norepinephrine and dopamine. Repetitive TMS has been advanced as a monotherapy or adjunctive treatment for patients with major depression, but it is also currently under investigation as a treatment for several other disorders originating in the cerebral cortex. TMS is delivered by various available devices, and treatment has been tested using a variety of protocols, including high frequency delivered over the left dorsolateral prefrontal cortex, low frequency delivered over the right or left dorsolateral prefrontal cortex, bi-lateral delivery, and deep TMS in which deeper prefrontal regions are stimulated. Navigated transcranial magnetic stimulation (ntms) is being studied as a diagnostic tool to stimulate functional cortical areas at precise anatomical locations to induce measurable responses. This technology is being investigated to map functionally essential motor areas for diagnostic purposes and for treatment planning. CLINICAL EVIDENCE Therapeutic Transcranial Magnetic Stimulation High Frequency Left-Sided TMS for Depression Berlim et al. (2013a) systematically and quantitatively assessed the efficacy of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) for major depression (MD) based on randomized, double-blind and sham-controlled trials (RCTs) across multiple HF-rTMS devices. Data from 29 RCTs were included, totaling 1371 patients with MD. Following approximately 13 sessions, 29.3% and 18.6% of patients receiving HF-rTMS were classified as responders and 2

3 remitters, respectively (compared with 10.4% and 5% of those receiving sham rtms). HF-rTMS was found to be equally effective as an augmentation strategy or as a monotherapy for MD, and when used in samples with primary unipolar MD or in mixed samples with unipolar and bipolar MD. Also, alternative stimulation parameters were not associated with differential efficacy estimates. Moreover, baseline depression severity and drop-out rates at study end were comparable between the HF-rTMS and sham rtms groups. Finally, heterogeneity between the included RCTs was not statistically significant. The authors concluded that HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile. This review examined the efficacy of HF-rTMS immediately after study end, and thus cannot estimate the stability of its medium to long-term antidepressant effects. Future studies should include longer follow-up periods (e.g. greater than 6 12 months) in order to establish the medium- to long-term effectiveness of HF-rTMS. Berlim et al. (2013d) conducted a meta-analysis to evaluate the utility of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) used as a strategy to accelerate and improve clinical response to antidepressants. Data were obtained from 6 randomized controlled trials (RCTs), totaling 392 patients with major depression. Two time points were considered: the end of the addon HF-rTMS stimulation period (T1) and the end of the study (T2), which was, on average, roughly 7 weeks (M = 6.80 ± 3.11) following start of combined rtms + antidepressant treatment. For T1, 6 studies reported on response and 4 on remission rates. The authors found significantly higher response rates for active HF-rTMS (43.3%; 84/194) compared to sham rtms (26.8%; 53/198); however, remission rates did not differ between groups. For study end (T2), 5 studies reported on response and 4 on remission rates; overall, response rates at T2 were significantly higher for subjects receiving HF-rTMS in comparison to those receiving sham rtms (62% [104/168] and 46% [79/172], respectively). Also, 53.8% (57/106) and 38.64% (36/107) of subjects receiving active HF-rTMS and sham rtms, respectively, were in remission at T2. The authors concluded that HF-rTMS is a promising strategy for accelerating clinical response to antidepressants in major depression, providing clinically meaningful benefits that are comparable to those of other agents such as triiodothyronine and pindolol. Additional well designed, randomized controlled trials are needed to determine if combining TMS with antidepressants has a greater effect than when TMS or antidepressants are used alone. Schutter (2009) performed a meta-analysis that included 30 double-blind sham-controlled parallel studies of multiple high-frequency transcranial magnetic stimulation devices with 1164 patients comparing the percentage change in depression scores from baseline to endpoint of active versus sham treatment. A random effects meta-analysis was performed to investigate the clinical efficacy of fast-frequency rtms over the left dorsolateral prefrontal cortex (DLPFC) in depression. According to the authors, the findings of the meta-analysis showed that high-frequency rtms over the left DLPFC is superior to sham in the treatment of depression. The effect size is robust and comparable to at least a subset of commercially available antidepressant drug agents. However, at this point caution should be exercised because the integrity of blinding and the lack of a proper control condition are considered limitations of rtms trials. In addition, age bias, medication, suboptimal stimulation parameters, lack of biological information and follow-up assessments may stand in the way of understanding the effects of rtms. In a randomized, controlled study, George et al. (2010) compared sham to active high-frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (rtms) in 199 patients with major depressive disorder (MDD) who were anti-depressant free. In a 2-week lead in phase, no treatment or drugs were allowed other than minimal use of sedatives, hypnotics, or anxiolytics. In phase 1, active or sham TMS was delivered daily for three weeks, and patients achieving a reduction of 30% in the Hamilton Depression Rating Scale (HAMD)-24 score could continue assigned treatment for an additional three weeks. Compared with patients receiving shamtreatment, patients receiving active rtms demonstrated significantly greater improvement in mean scores for rating and improvement scales. Active rtms led to higher rates of response (15% versus 5%) and remission (14% versus 5%) than sham treatment. There was a 10.5% drop-out rate (12% in TMS group and 9% in Sham group). Drop-outs were due to adverse effects in 5.4% (all in TMS group). A limitation of this study is author affiliation with manufacturers of TMS 3

4 devices. In addition, the manufacturer provided equipment used in the study. It is also unclear from the study how long the clinical benefit lasts once achieved. O Reardon, et al. (2007) conducted a multi-site, randomized controlled study of 301 medication free patients with MDD who had not benefitted from prior treatment. The aim of the study was to evaluate whether rtms over the left dorsolateral prefrontal cortex is effective in the acute treatment of major depression. Patients were randomized in a double blind study to active HFLrTMS (n=155) or sham rtms (n=146). Patients received rtms sessions five times a week for 4 to 6 weeks as the initial primary study endpoint. Patients with less than 25% reduction in baseline symptoms based on the Hamilton Depression Rating Scale (HAMD) score were crossed-over to the open label two week acute treatment continuation at four weeks. The authors reported that improvements in HAMD and MADRS scores were superior to the sham group. A significant difference in remission rates was not detected at 4 weeks. However, the remission rate was higher for the active group at 6 weeks than for the sham group. Limitations of this study included the following: low number of patients at the 6 week time point due to high rate of patients electing to enter open-label study at the 4 week time period; no follow-up after end of treatment; complete randomization only through week 4; and the study was supported by manufacturer. Four follow-up reports and studies related to the O Reardon (2007) randomized controlled trial (RCT) were identified: an open-label extension study from the RCT (Avery et al. 2008); an analysis of clinical predictors of rtms outcome from the RCT and the open-label extension study (Lisanby et al. 2009), and an analysis of safety data from the RCT, the open-label extension study, and a 6-month durability-of-effect study (Janicak et al. 2008). All studies were funded by the manufacturer. A large number of patients left the RCT for the open-label study. This prevented making further valid efficacy comparisons from RCT data. Data from the open-label study are of limited value, because they provide no means for valid comparison to a control group. Lisanby et al. (2009) reported that a lower degree of medication resistance in the current episode was a strong predictor for positive response to treatment with rtms. Shorter duration of current major depressive episode (MDE) was associated with a better outcome in the RCT. No deaths or seizures occurred in the RCT or open-label extension trials. Janicak et al. (2010) assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. Three hundred one patients were randomly assigned to active TMS over the left dorsolateral prefrontal cortex or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening. Relapse was the primary outcome measure. Ten of 99 patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. The authors concluded that these initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse. A limitation of this study included the lack of a controlled comparison since the two groups were no longer fully randomized after entry in the long-term trial. Carpenter et al. (2012) conducted an observational study that included 42 US-based clinical TMS practice sites that treated 307 outpatients with major depressive disorder (MDD), and a failure to show satisfactory improvement from antidepressant medication (defined as an average of 2.5 antidepressant treatments of adequate dose and duration in the current episode). Treatment was based on the labeled procedures of the approved TMS device, which meant all clinicians initiated treatment with left-sided high-frequency stimulation, though this protocol could be later modified for tolerability or logistical reasons, or as a consequence of clinician-determined variation in practice technique. Assessments were performed at baseline, week 2, at the point of maximal 4

5 acute benefit, and at week 6 for those patients (22%) treated beyond 6 weeks. There was a significant change in clinician-assessed response rate (CGI-S) from baseline to end of treatment. CCGI-S was 58.0% and remission rate was 37.1%. Patient-reported response rate ranged from 56.4 to 41.5% and remission rate ranged from 28.7 to 26.5%. The authors concluded that outcomes demonstrated response and adherence rates similar to populations in published controlled trials despite the non-research population showing greater illness morbidity. According to the authors, these data indicate that TMS is an effective treatment for those unable to benefit from initial antidepressant medication. Though not studied specifically, the authors also suggest that the high adherence rate supports the relatively high tolerability of TMS treatment by patients in a non-research setting. The observational naturalistic study design, while having the strength of demonstrating TMS in real-world settings, also does not allow for definitive conclusions of the effectiveness of TMS compared to other treatments or sham treatments. Additional limitations of the study include that the majority of the patients receiving TMS treatment also received antidepressant medication, making it difficult to identify the relative benefits of each treatment. In addition, follow-up after the end of treatment in this population was not demonstrated. Low Frequency Right-Sided TMS for Depression Berlim et al. (2013c) conducted a meta-analysis to evaluate low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) for treating major depression (MD). Data were obtained from eight RCTs, totaling 263 patients with MD. After an average of 12.6±3.9 rtms sessions, 38.2% (50/131) and 15.1% (20/132) of subjects receiving active LF-rTMS and sham rtms, respectively, were classified as responders. Also, 34.6% (35/101) and 9.7% (10/103) of subjects receiving active LF-rTMS and sham rtms were classified as remitters. Sensitivity analyses have shown that protocols delivering >1200 magnetic pulses in total as well as those offering rtms as a monotherapy for MD were associated with higher rates of response to treatment. The authors concluded that LF-rTMS is a promising treatment for MD, as it provides clinically meaningful benefits that are comparable to those of standard antidepressants and high-frequency rtms. Additional research is needed to confirm this hypothesis. In a randomized, controlled, two-arm, clinical trial, Aguirre et al. (2011) evaluated 34 major depression patients who were randomly assigned to receive 20 sessions of real or sham TMS of the right dorsolateral prefrontal cortex as adjuvant treatment to pharmacotherapy. Blinded external evaluators administered the Hamilton Depression Rating Scale. Both treatment groups significantly improved, although there were no statistical differences between them. In the real TMS group patients age inversely correlated with improvement of depressive symptoms at the end of the study. The percentage of decrease in scores on the Hamilton Scale was greater in subjects younger than 45 years old vs. others. These real TMS subgroups did not differ significantly in their history of previous depressive disorders, or in the refractoriness indicators of the current episode. The authors concluded that only younger patients benefited from lowfrequency TMS as adjuvant treatment to antidepressants in this study. The extremely small sample size limits the conclusions that can be drawn from this study. Bilateral TMS for Depression Berlim et al. (2012) conducted a meta-analysis on the efficacy of bilateral repetitive transcranial magnetic stimulation (rtms) for treating major depression (MD). Data were obtained from seven RCTs, totaling 279 patients with MD. After an average of 12.9 sessions, 24.7% (40/162) of patients receiving active bilateral rtms and 6.8% (8/117) of patients receiving sham rtms were classified as responders. Also, 19% (23/121) and 2.6% (2/77) of subjects were remitters following active bilateral rtms and sham rtms, respectively. The authors did not find significant differences efficacy- and acceptability-wise between active bilateral and unilateral rtms at study end. The authors concluded that bilateral rtms is a promising treatment for MD as it provides clinically meaningful benefits that are comparable with those of standard antidepressants and unilateral rtms. Additional well designed, randomized controlled trials evaluating bilateral rtms are needed to further describe safety and clinical outcomes. Multiple or Unspecified TMS Protocols for Depression 5

6 Allan et al. (2011) conducted a meta-analysis of TMS in the treatment of depression. Thirty-one studies of multiple devices were included with a cumulative sample of 815 active and 716 sham TMS courses. The authors found a moderately sized effect of TMS compared to sham treatment, but with significant variability between study effect sizes. Including relevant study variables in meta-regressions did not find any predictors of treatment efficacy. Nine studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up and no heterogeneity in outcome, suggesting a short-term sustained effect. According to the authors, TMS appears to be an effective treatment but without further decrease in depression severity after a 4 week follow-up. The authors stated that problems with finding a suitably blinded and ineffective placebo condition may have confounded the published effect sizes and concluded that if the TMS effect is specific, only further large double-blind randomized controlled designs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen. Lam, et al. (2008) analyzed 24 studies which evaluated rtms as an intervention for treatmentresistant depression, and determined that rtms provided benefit during treatment lasting up to 4 weeks, but that the response rate as measured by Hamilton Depression Rating Scale (HAMD) and Montgomery-Asberg Depression Rating Scale (MADRS) scores was low as was the remission rate. The authors also noted that the reviewed studies failed to conduct adequate longer-term follow-up to confirm the persistence of therapeutic effect. They concluded that additional study was needed to determine whether rtms could be considered a first-line monotherapy. Mantovani et al. (2012) examined the long-term durability of TMS using a TMS taper protocol and either continuation pharmacotherapy or naturalistic follow-up. Patients were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension in patients who did not respond to the acute trial (n = 43). Long-term durability of TMS acute effect was examined in remitters over a 12-week follow-up. Of 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the TMS taper. Thirty-two patients completed TMS taper. At the 3-month visit, 29 of 50 (58%) were classified as in remission, two of 50 (4%) were classified as partial responders, and one of 50 (2%) met criteria for relapse. During the entire 3- month follow-up, five of the 37 patients relapsed, but four of them regained remission by the end of the study. The average time to relapse in these five patients was 7.2 ± 3.3 weeks. Patients who relapsed had higher depression scores at 1 month. The authors concluded that while one third of the sample was lost to follow-up, the results demonstrate that most patients contributing to observations experienced persistence of benefit from TMS followed by pharmacotherapy or no medication. According to the authors, longer follow-up and more rigorous studies are needed to explore the true long-term durability of remission produced by TMS. However, with such a high rate of individuals lost to follow-up, it is not known what the true durability of effect was in the entire treated population. TMS Compared to Electroconvulsive Therapy (ECT) for Depression Berlim et al. (2013b) conducted a meta-analysis to evaluate the efficacy of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) and electroconvulsive therapy (ECT) for treating major depression (MD). Data were obtained from 7 randomized trials, totalling 294 patients with MD. After an average of 15.2 HF-rTMS and 8.2 ECT sessions, 33.6% (38/113) and 52% (53/102) of subjects, respectively, were classified as remitters. The associated Number Needed to Treat (NNT) for remission was 6 and favored ECT. Also, reduction of depressive symptomatology was significantly more pronounced in the ECT group. No differences on dropout rates for HF-rTMS and ECT groups were found. The authors concluded that ECT seems to be more effective than HF-rTMS for treating MD, although they did not differ in terms of dropout rates. According to the authors, future comparative trials with larger sample sizes and better matching at baseline, longer follow-ups and more intense stimulation protocols are warranted. Slotema et al. (2010) conducted a meta-analysis using data from randomized, sham-controlled studies of repetitive transcranial magnetic stimulation (rtms) treatment for depression (34 studies). Studies of rtms versus electroconvulsive treatment (ECT, 6 studies) for depression 6

7 were meta-analyzed. Standardized mean effect sizes of rtms versus sham were computed based on pretreatment-posttreatment comparisons. The mean weighted effect size of rtms versus sham for depression was Monotherapy with rtms was more effective than rtms as adjunctive to antidepressant medication. ECT was superior to rtms in the treatment of depression. Side effects were mild, yet more prevalent with high-frequency rtms at frontal locations. The authors concluded that it is time to provide rtms as a clinical treatment method for depression. In a comparative review, Minichino et al. (2012) investigated and compared the efficacy and tolerability of electroconvulsive therapy (ECT), transcranial magnetic stimulation (rtms), and deep transcranial magnetic stimulation (deeptms) in drug-free patients with pharmacoresistant unipolar depression. Nine studies met the author s inclusion criteria and were evaluated: 4 studies of ECT (160 subjects), 5 studies of high frequency rtms delivered over the left dorsolateral prefrontal cortex (211 patients), 2 studies of deeptms (58 patients). Three independent reviewers extracted results and assessed the quality of methodological reporting of selected studies, evaluating clinical response on the Hamilton Depression Rating Scale (HDRS), neuropsychological effects measured using a variety of cognitive assessments, remission rate based on the HDRS, and tolerability based on drop-out rate. The comparative evaluation of (HDRS) percentage variations showed ECT to be the most effective method after 4 weeks of therapy, followed by deeptms and rtms. DeepTMS and rtms showed stable improvement in cognitive performance over 4 weeks, while ECT patients showed a decrease at 2 weeks and then a slight increase from 2-4 weeks. ECT treatment and deeptms showed equal percentages of remitted patients, with a percentage (29%) two times higher than that in the rtms group (14%). DeepTMS shows the poorest tolerability, with a drop-out rate of 19%, followed by ECT (13%) According to the authors, rtms seemed to provide a better tolerability (7% drop-out rate), but with lower therapeutic efficacy. According to the authors, lack of data on the long-term effects of rtms and deeptms limits the completeness of this investigation. Hansen et al. (2011) compared the antidepressant efficacy and adverse effects of right prefrontal low-frequency rtms with that of electroconvulsive therapy (ECT). Sixty inpatients with major depression were randomized to 15 days of rtms or 9 ECTs. The authors found that repetitive transcranial magnetic stimulation was significantly less effective than ECT, but ECT had more adverse effects on cognitive function. The authors stated that this outcome does not point to right frontal low-frequency rtms using the present stimulus design as a first-line substitute for ECT, but rather as a treatment option for patients with depression who are intolerant to other types of treatment or not accepting ECT. Agency Reviews A 2012 ECRI Institute Emerging Technology Report evaluated the evidence on repetitive transcranial magnetic stimulation (rtms) using the NeuroStar TMS Therapy System as a secondline treatment for adults with major depressive disorder (MDD) that have not responded adequately to one prior antidepressant given at or above the recommended minimal dose. According to the report, the available evidence is insufficient to definitively conclude whether rtms alone produces a clinically meaningful or statistically significant improvement in response, remission, or quality of life compared to sham for treatment of major depressive disorder (ECRI 2012). Hayes reviewed the literature through May 2010 and concluded that there is some evidence from a number of randomized, sham-controlled trials that TMS may have some short term antidepressive effect in adult patients with drug-resistant depression, with average response and remission rates of 36% and 24%. However, improvement was generally seen in some but not all outcome measures and assessment time points, and not all of the studies demonstrated a clear treatment effect. In addition, these studies were relatively small, may not have had adequate blinding, varied with respect to type of TMS and treatment protocol, and did not provide extended follow up after treatment. Multiple confounding factors may have played a role in what appears to be the treatment effect of TMS. In summary, Hayes reviewed 16 randomized, double-blind, shamcontrolled studies involving 1444 patients with major depression assessed low-frequency right- 7

8 sided TMS (LFR-TMS) (4 studies; 235 patients), high-frequency ( 1 Hz) left-sided TMS (HFL- TMS) (11 studies; 1077 patients), low-frequency left-sided TMS (LFL-TMS) (1 study; 45 patients) and/or bilateral TMS (3 studies; 172 patients). To evaluate the antidepressant effects of treatment, each study employed one to six depression measures, which varied among studies. Compared with sham TMS, at least one active TMS approach led to significantly greater improvement in scores on one or more depression measures in 14 studies (Klein et al., 1999; Fitzgerald et al., 2003; Koerselman et al., 2004; Rossini et al., 2005a; Rossini et al., 2005b; Rumi et al., 2005; Avery et al., 2006; Fitzgerald et al., 2006; McDonald et al., 2006; O Reardon et al., 2007; Stern et al., 2007; Jorge et al., 2008; George et al., 2010; Pallanti et al., 2010). However, in five of these 14 studies, improvement was similar between active TMS and sham TMS on one of three (Klein et al., 1999; McDonald et al., 2006), one of four (George et al., 2010), or three of six (Fitzgerald et al., 2003; O Reardon et al., 2007) depression measures. Thus, demonstrated improvement may depend at least partly on the particular depression measure(s) used. The remaining two studies found no significant difference in improvement between active HFLTMS and sham TMS on any depression measures (Herwig et al., 2007; Mogg et al., 2008). According to Hayes, additional research is needed to define optimal treatment protocols, identify definitive patient selection criteria, and establish the magnitude and durability of treatment effect of TMS (Hayes, Transcranial Magnetic Stimulation for Major Depression, 2010). According to the World Federation of Societies of Biological Psychiatry (WFSBP) which includes members from the Department of Psychiatry, University of Bonn, Germany; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University, Baltimore; Department of Psychiatry, Medical University of South Carolina, Charleston; and Department of Psychiatry, Emory University, Atlanta, there is sufficient class I evidence of acute efficacy for TMS in depression in medication-free unipolar depressed patients. The large body of evidence from single site small sample trials suggests that TMS may be useful clinically in moderately treatmentresistant patients, either alone or used adjunctively with medications. The WFSBP recommends that psychiatrists consider using TMS in non-psychotic adults with major depression. Typically patients will have tried and failed at least one attempt at medication therapy, although this is not required. There are only limited data about using it in a maintenance fashion after acute response (Schlaepfer, 2010). A Comparative Effectiveness Review was prepared for the Agency for Healthcare Research and Quality (AHRQ) on Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults. According to the report, there was limited direct evidence for rtms (defined as studies in which rtms is compared head-to-head to other available treatments) when examining Tier 1 studies [studies in which patients specifically had two or more failures of prior treatment with antidepressive medications (ADM)]. They reviewed two fair trials (both in MDD-only populations), one that compared ECT and rtms, and the other that compared ECT and ECT plus rtms. Their conclusion was that those studies showed, with low strength of evidence, no differences between treatment conditions for depressive severity, response rates, and remission rates between ECT and rtms. There was no evidence of comparative effectiveness compared to any other treatments. When examining indirect evidence (i.e. not head-to-head comparative effectiveness, but comparisons between treatment and sham), the report concluded that there was evidence for superiority of rtms versus sham in Tier 1 studies. Specifically: rtms was beneficial relative to controls receiving a sham procedure for all three outcomes (severity of depressive symptoms, response rate, and remission rate). The report indicated that the next steps for research are to apply a consistent definition of TRD, to conduct more head-to-head clinical trials comparing nonpharmacologic interventions to one another and to pharmacologic treatments, and to carefully delineate the number of adequate treatment failures in the current episode (Gaynes et al. 2011). In 2011, the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) published a Technology Assessment on TMS for depression. Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel stated that while metaanalyses and recent clinical trials have generally shown statistically significant effects of TMS on depression outcomes, there is insufficient evidence of long term effects beyond the end of the 8

9 TMS treatment period or compared to treatment alternatives. They also conclude that as TMS has not yet demonstrated improved health outcomes in the investigational setting. The report states that for the above reasons, transcranial magnetic stimulation for the treatment of depression does not meet the TEC criteria (BCBS, 2011). According to the National Institute for Health and Care Excellence (NICE) Guideline on the Treatment and Management of Depression in Adults (2010), current evidence suggests that there are no major safety concerns associated with transcranial magnetic stimulation (TMS) for severe depression. There is uncertainty about the procedure s clinical efficacy, which may depend on higher intensity, greater frequency, bilateral application and/or longer treatment durations than have appeared in the evidence to date. TMS should therefore be performed only in research studies designed to investigate these factors. Professional Societies The American Psychiatric Association (APA): In a clinical practice guideline for the treatment of patients with major depressive disorder, the APA states that electroconvulsive therapy (ECT) remains the treatment of best established efficacy against which other stimulation treatments (e.g., vagus nerve stimulation, deep brain stimulation, transcranial magnetic stimulation, other electromagnetic stimulation therapies) should be compared. According to the APA, for patients whose symptoms have not responded adequately to medication, ECT remains the most effective form of therapy and should be considered [I]. Magnetic stimulation could also be considered [II]. According to the APA, a substantial number of studies of TMS have been conducted, but most have had small sample sizes, and the studies overall have yielded heterogeneous results. Further complicating the interpretation of the TMS literature is the variability in stimulation intensities (relative to the motor threshold), stimulus parameters (e.g., pulses/second, pulses/session), anatomical localization of stimulation, and number of TMS sessions in the treatment course. The three APA rating categories represent varying levels of clinical confidence: I: Recommended with substantial clinical confidence II: Recommended with moderate clinical confidence III: May be recommended on the basis of individual circumstances (Gelenberg et al. 2010). The American Academy of Neurology (AAN): The AAN s evidence-based practice parameter for the evaluation and treatment of depression, psychosis, and dementia in Parkinson disease concludes that there is insufficient evidence to support or refute the efficacy of TMS in the treatment of depression associated with Parkinson disease (Miyasaki, et al., 2006). American Academy of Child and Adolescent Psychiatry (AACAP): In a practice parameter for the assessment and treatment of children and adolescents with depressive disorders, the AACAP suggests several approaches to treating MDD, including rtms (Birmaher and Brent, 2007). Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT): In , the Canadian Psychiatric Association and the CANMAT partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders. A section of the updated guidelines (Section IV) relates to neurostimulation therapies, including TMS, electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), for treating MDD in adults. The subsection for TMS notes that in 2002, Canada approved the use of TMS for treating depressed adults who fail to respond to at least one antidepressant drug. Most available evidence pertains to the use of high-frequency left-sided TMS (HFL-TMS) for this indication. However, direct comparisons among the many open-label studies and randomized controlled studies are hampered by variations in study design and stimulation parameters. The CANMAT states that the best evidence for TMS is the relatively large (n=301) randomized trial conducted by O Reardon et al. (2007), which found that HFL-TMS was significantly superior to sham TMS. A meta-analyses conducted by Lam et al. (2008) also demonstrates superior response and remission rates for active versus sham TMS. Study findings conflict regarding whether HFL-TMS is superior to low-frequency right-sided TMS (LFR-TMS) or whether TMS is equal to ECT for treating depression. Based on available data, the CANMAT recommended that, when using TMS for treatment-resistant MDD, the first TMS approach should 9

10 be HFL-TMS and the treatment duration should be 30 sessions (3 weeks) instead of 20 sessions (2 weeks). The CANMAT noted that there was minimal evidence regarding the use of TMS for maintaining response/preventing relapse and drew no conclusions regarding TMS for this indication (Kennedy et al., 2009). Other Conditions While the majority of clinical trials have evaluated transcranial magnetic stimulation for treating depression, the use of transcranial magnetic stimulation has also been studied for treating other conditions including psychiatric disorders (other than depression), chronic neuropathic pain, dystonia, epilepsy, headaches, Parkinson s disease, stroke, and tinnitus. Slotema et al. (2012) conducted a meta-analysis that included 17 randomized double blind shamcontrolled trials of the effect of rtms on auditory hallucinations. When measured at the end of treatment, the mean effect size of rtms directed at the left temporoparietal area was moderate and the effect size of rtms directed at all brain regions was small. The authors concluded that more research is needed in order to optimize parameters and further evaluate the clinical relevance of this intervention. Berlim et al. (2013e) conducted a systematic review and meta-analysis to assess the efficacy of rtms for obsessive-compulsive disorder (OCD) and to generate hypotheses for more robustly powered RCTs. Data were obtained from 10 RCTs, totaling 282 subjects with OCD. The analyses showed that active rtms seemed to be efficacious for treating OCD. Nevertheless, according to the authors, future RCTs on rtms for OCD should include larger sample sizes and be more homogeneous in terms of demographic/clinical variables as well as stimulation parameters and brain targets. Freitas et al. (2011) performed a systematic search of studies using noninvasive stimulation in Alzheimer's disease (AD). The authors concluded that TMS/tDCS can induce acute and shortduration beneficial effects on cognitive function, but the therapeutic clinical significance in AD is unclear. According to the authors, TMS/tDCS may have therapeutic utility in AD, though the evidence is still very preliminary and cautious interpretation is warranted. In a systematic review, Elahi et al. (2009) evaluated the effects of rtms on motor signs in Parkinson's disease (PD). Ten randomized, controlled clinical trials (n=275 patients) were included in the meta-analysis. High-frequency rtms had an effect size of and low frequency effects were not significant. There were several limitations of this systematic review. First, the study outcomes were not uniformly reported. Second, there were considerable differences in the rtms protocol. Moreover, the analyzed studies also varied in patient selection criteria, demographics, and duration of follow-up and stages of PD. The authors concluded that the results of the systematic review showed that high-frequency rtms is a promising treatment of motor symptoms in PD. A large, randomized controlled trial with appropriate follow-up will be useful to further define its role in the treatment of PD. Future studies are also needed to clarify the optimal stimulation parameters, how the different stages of PD affect the response to rtms, and the effects of rtms on other aspects of the disease such as gait, cognition, and memory. In a Cochrane review, Meng et al. (2011) assessed the effectiveness and safety of rtms versus placebo in patients with tinnitus. Five trials that included 233 participants met inclusion criteria. The authors concluded that there is very limited support for the use of low-frequency rtms for the treatment of patients with tinnitus. According to the authors, more prospective, randomized, placebo-controlled, double-blind studies with large sample sizes are needed to confirm the effectiveness of rtms for tinnitus patients. In a meta-analysis, Leung et al. (2009) assessed the analgesic effect of rtms on various neuropathic pain states based on their neuroanatomical hierarchy. Raw data of 149 patients were extracted from 5 (1 parallel, 4 cross-over) RCTs. The authors found that visual analog scale (VAS) scores decreased more with rtms treatment versus sham treatment. Also, rtms delivered with a lower frequency and in more treatment sessions appeared to provide improved analgesic 10

11 results. According to the authors, rtms appears to be more effective in suppressing centrally than peripherally originated neuropathic pain states. In a Cochrane review, O'Connell et al. (2011) evaluated the efficacy of non-invasive brain stimulation techniques in chronic pain. Studies of rtms (368 participants) demonstrated significant heterogeneity. Pre-specified subgroup analyses suggest that low frequency stimulation is ineffective. A short-term effect on pain of active high-frequency stimulation of the motor cortex in single-dose studies was suggested. The authors stated that this equates to a 15% reduction in pain which does not clearly exceed the pre-established criteria for a minimally clinically important difference (>15%). Marlow et al., ( ) systematically reviewed the literature to evaluate the use of repetitive transcranial magnetic stimulation (rtms) or transcranial direct current stimulation (tdcs) for patients with fibromyalgia syndrome (FMS). The authors concluded that rtms/tdcs showed analogous pain reductions as well as considerably fewer side effects compared to U.S. Food and Drug Administration (FDA) approved FMS pharmaceuticals. The authors stated that further work into optimal stimulation parameters and standardized outcome measures is needed to clarify associated efficacy and effectiveness. Lipton et al. (2010) assessed the efficacy and safety of a new portable single-pulse transcranial magnetic stimulation (stms) device for acute treatment of migraine with aura in a randomized, double-blind, parallel-group, two-phase, sham-controlled. A total of 201 individuals were randomly allocated by computer to either sham stimulation (n=99) or stms (n=102). Participants were instructed to treat up to three attacks over 3 months while experiencing aura. Thirty-seven patients did not treat a migraine attack and were excluded from outcome analyses. 164 patients treated at least one attack with stms (n=82) or sham stimulation (n=82; modified intention-totreat analysis set). According to the investigators, early treatment of migraine with aura by stms resulted in increased freedom from pain at 2 hours compared with sham stimulation, and absence of pain was sustained 24 hours and 48 hours after treatment. The authors stated that TMS could be a promising acute treatment for some patients with migraine with aura. The study was funded by Neuralieve, manufacturer of the stms device. This conflict of interest limits the conclusions that can be drawn from this study. In a Cochrane review, Hao et al. (2013) assessed the efficacy and safety of rtms for improving function in people with stroke. The review included 19 trials involving a total of 588 participants. Two heterogenous trials with a total of 183 participants showed that rtms treatment was not associated with a significant increase in the Barthel Index score. Four trials with a total of 73 participants were not found to have a statistically significant effect on motor function. The authors concluded that current evidence does not support the routine use of rtms for the treatment of stroke. According to the authors, further trials with larger sample sizes are needed to determine a suitable rtms protocol and the long-term functional outcome. Hsu et al. (2011) preformed a meta-analysis to evaluate the antiepileptic efficacy of low frequency repetitive transcranial magnetic stimulation (rtms) in medically intractable epilepsy. Eleven articles were identified, with a total of 164 participants. The authors concluded that low frequency rtms has a favorable effect on seizure reduction, particularly evident in patients with neocortical epilepsy or cortical dysplasia. These findings require confirmation in larger studies. In a Cochrane review, Fang et al. (2013) evaluated the clinical efficacy and safety of rtms for treating amyotrophic lateral sclerosis (ALS). Three randomized, placebo-controlled trials with a total of 50 participants were included in the review. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. The authors concluded that there is currently insufficient evidence to draw conclusions about the efficacy and safety of rtms in the treatment of ALS. Freitas et al. (2009) conducted a meta-analysis that assessed the effects of high-frequency rtms to the left dorsolateral prefrontal cortex (DLPFC) to treat negative symptoms, and low-frequency 11

12 rtms to the left temporo-parietal cortex (TPC) to treat auditory hallucinations (AH) and overall positive symptoms in refractory schizophrenia. The authors found that effect sizes for all studies were significant and moderate for positive and negative symptoms. A sub-analysis of all shamcontrolled studies indicated that positive and negative symptoms showed a nonsignificant effect size. The assessment of auditory hallucinations showed a significant effect size for studies controlled by sham. According to the authors, these meta-analyses support the need for further controlled, larger trials to assess the clinical efficacy of rtms on negative and positive symptoms of schizophrenia, while suggesting the need for exploration for alternative stimulation protocols. Diabac-de Lange et al. (2010) assessed the efficacy of prefrontal rtms for treating negative symptoms of schizophrenia. Nine randomized controlled trials, involving 213 patients, were included in the meta-analysis. The overall mean weighted effect size for rtms versus sham was in the small-to-medium range and statistically significant. When including only the studies using a frequency of stimulation of 10 Hz, the mean effect size increased to When including only the studies requiring participants to be on a stable drug regimen before and during the study, the mean weighted effect size decreased to Studies with a longer duration of treatment (> or =3 weeks) had a larger mean effect size when compared to studies with a shorter treatment duration. The authors concluded that the results of this meta-analysis warrant further study of rtms as a potential treatment of negative symptoms of schizophrenia. In a systematic review, Guse et al. (2009) assessed high frequency rtms stimulation over the prefrontal cortex in patients with psychiatric/neurologic diseases and in healthy volunteers. The authors found that healthier patients have smaller cognitive improvements compared to patients with psychiatric/neurologic diseases. According to the authors, since the pathophysiological and neurobiological basis of cognitive improvement with rtms remains unclear, additional studies including genetics, experimental neurophysiology and functional brain imaging are necessary to explore stimulation-related functional changes in the brain. Based on a systematic review, Pallanti et al. (2009) concluded that TMS remains an investigational intervention that has not yet gained approval for the clinical treatment of any anxiety disorder. A 2011 BlueCross BlueShield TEC Assessment evaluated TMS as an adjunct treatment for schizophrenia. The assessment found that although meta-analyses would suggest that there is at least a short-term effect of TMS on auditory hallucinations, such effects were not observed in a review of the subset of studies that attempted to examine more long-term outcomes of TMS. None of these studies showed statistically significant effects of TMS on auditory hallucinations at the end of treatment, and only one found a difference at final follow-up. According to the assessment, most of the studies of TMS are very small trials, and outcomes are assessed using a variety of assessment instruments. The assessment concluded that the available evidence is insufficient to demonstrate that TMS is effective in the treatment of schizophrenia (BlueCross BlueShield TEC Assessment, Transcranial magnetic stimulation for the treatment of schizophrenia). Several randomized controlled trial and comparative studies with small patient populations suggest that TMS treatment may improve conditions such as the following: stroke (Khedr et al., 2010, n=48; Kim et al., 2010, n=18; Emara et al., 2010, n=60; Wang et al., 2012, n=24; Avenanti et al., 2012, n=30 alcohol dependence (Mishra, 2010, n=45) Alzheimer s disease (Ahmed et al., 2012, n=45; Rabey et al., 2013, n=15) aphasic stroke (Weiduschat et al. 2011, number not specified; Barwood et al. 2011, n=12) auditory hallucinations (Bagati et al., 2009, n=40;) auditory-verbal hallucinations (Vercammen et al., 2009, n=38) bipolar mania (Praharaj et al., 2009, n=41) bulimic eating disorders (Van den Eynde, 2010, n=38) cigarette consumption, dependence and craving (Amiaz et al., 2009, n=48) 12