|Subject:||Transcranial Magnetic Stimulation|
|Policy #:||BEH.00002||Current Effective Date:||02/11/2016|
|Status:||Revised||Last Review Date:||02/04/2016|
This document addresses the potential uses of transcranial magnetic stimulation (TMS), which include depression and other behavioral health conditions as well as a variety of other non-behavioral health indications such as migraine headache, spasticity associated with spinal cord injury, and tinnitus.
Note: Please see the following related document for additional information:
Transcranial magnetic stimulation (TMS) of the brain is considered medically necessary for use in an adult who meets the following criteria:
Note: TMS is associated with an increase in the risk of a seizure. As such, additional consideration should be given for individuals on medications which may lower the seizure threshold or with conditions rendering them more prone to seizure, such as alcoholism. For additional information concerning the use of TMS in individuals with concurrent medication use or a history of substance abuse, please refer to the Background/Overview section: Contraindications, Warnings and Precautions, and Use of TMS in Special Populations or Clinical Conditions.
Investigational and Not Medically Necessary:
TMS of the brain is considered investigational and not medically necessary for MDD when the above criteria are not met, including continued treatment as maintenance therapy.
TMS of the brain is considered investigational and not medically necessary for all other indications including, but not limited to, treatment of:
Transcranial magnetic stimulation (TMS) involves placement of a small coil over the scalp through which a rapidly alternating current, producing a magnetic field, is passed unimpeded through the cranium and scalp.
TMS for Treatment-Resistant Depression (TRD)
According to Gaynes and colleagues (2011), MDD is a common condition experienced by more than 13 million people over the course of a year. Treatment choices are wide ranging, including both pharmacologic and nonpharmacologic therapies. Each of the numerous antidepressant drugs available are categorized by class according to the neurotransmitter system with which it mostly interacts. If an antidepressant drug in one class does not relieve symptoms or causes intolerable side effects, an antidepressant drug in another class may be prescribed. The rate of remission, or complete symptom relief, has been reported to be approximately 33% for monotherapy with the first prescribed antidepressant drug and lessens with each successive antidepressant drug trial. Individuals with two or more prior treatment failures are considered to have TRD. These individuals represent a complex population with a disease that is difficult to manage. This data and the increasing prevalence of MDD and drug-resistant MDD suggest a need for alternative treatments for TRD.
Repetitive TMS (rTMS) has been studied as a nonpharmacologic treatment option for individuals with TRD. The peer-reviewed medical literature focusing on the use of rTMS for TRD (variably defined), includes a number of double-blind, randomized, sham-controlled, short-term trials. Trial results show statistically significant improvement with active treatment, suggesting a response rate 2 to 3 times that of sham controls. Approximately 15% to 25% of the active treatment population in these trials showed a clinical response to rTMS despite the existence of differences in study definitions for trial inclusion and prior treatment heterogeneity within each study.
O'Reardon and colleagues (2007) conducted an industry-sponsored study under an Investigational Device Exemption (IDE) to determine whether rTMS over the left dorsolateral prefrontal cortex (DLPFC) was effective and safe. The trial findings resulted in the FDA clearance of the NeuroStar® TMS Therapy System (Neuronetics, Malvern, PA), for the treatment of adults with MDD without psychosis who "have not adequately responded to appropriate pharmacological treatment intervention" (FDA, 2008). A total of 301 participants enrolled at 23 study sites with antidepressant medication-free major depression were randomly assigned to active (n=155) or sham (n=146) rTMS. Participants were required to have failed at least 1, but no more than 4 adequate antidepressant treatments in the current or most recent episode of depression. Treatment and rating personnel were blinded to participant assignments. rTMS occurred daily, 5 days a week for 6 weeks, followed by a tapering period of 3 additional weeks during which time antidepressant drug therapy was initiated. Participants achieving less than a 25% reduction on the Hamilton Depression Rating Scale-17 (HAMD-17) at 4 weeks could crossover to an open-label, acute treatment extension study. The primary outcome was the difference between active and sham rTMS using the last visit Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item HAMD and response and remission rates using the MADRS and HAMD. At the primary efficacy point of 4 weeks, the baseline to endpoint change on both the HAMD-17 and the HAMD-24 but not the MADRS showed a significant improvement for the active rTMS group. The result was sustained at 6 weeks. Significant response rates (> 50% improvement from baseline) were present at 4 and 6 weeks for the active treatment group using each of the 3 scales (HAMD-17, HAMD-24, and MADRS). A significant difference in remission rates did not occur at 4 weeks but was higher for the active group at 6 weeks for the MADRS and HAMD-24. A significant number of participants, 74 (47.7%) in the active group and 92 (63.0%) in the sham group, dropped out after 4 weeks to enter the open-label trial (Avery, 2008), thus, many of the 6-week observation values in the trial reflected 4-week values.
Avery and colleagues (2008) reported on the results of the open-label, crossover extension of participants from the O'Reardon trial (2007) who failed to receive benefit from at least 4 weeks of randomized treatment assignment, either active or sham rTMS, in the controlled trial. The first 6-week phase of the study was antidepressant-free followed by a 3-week rTMS taper phase with initiation of 1 of 15 different antidepressants. During the taper phase, rTMS was delivered 3 times in the first week, 2 times in the second week and 1 time in the third week. As noted above, 166 participants entered the study but only 158 were present for at least 1 post-baseline observation, 73 of whom had been in the active arm and 85 in the sham. The primary efficacy outcome was the change in total score on the MADRS from the start of the open-label phase to 6 weeks or study endpoint. Secondary outcome measures included the HAMD-17 and HAMD-24. Remission was defined as a score of < 10 on the MADRS, < 8 on the HAMD-17, or < 11 on the HAMD-24. Improvement was noted in both groups over the 6-week active and the 3-week taper periods. At the conclusion of the taper phase, in the sham-to-rTMS group, 44.7% of participants achieved response criteria on the MADRS, and 30.6% achieved remission. In the same group, 45.9% achieved response on the HAMD-24 and 36.5% achieved remission. Similar observations were noted in the extended rTMS group; at the end of the taper phase, 34.2% of participants achieved response criteria on the MADRS, and 17.8% achieved remission. In the same group, 31.5% achieved response on the HAMD-24 and 19.2% achieved remission.
George and colleagues (2010) published a prospective, multicenter, randomized, sham-controlled trial reporting results using daily DLPFC rTMS on 199 participants with a moderate level of antidepressant drug-free, unipolar MDD (that is, single episode or recurrent with < 5 years from onset). The study participants were required to be stable during a 2-week medication-free lead-in period and have a moderate level of treatment resistance defined as insufficient clinical benefit from 1 to 4 adequate medication trials or intolerant to 3 medication trials. The trial used the FDA-cleared NeuroStar TMS device. Magnetic resonance imaging was used to refine the location of the magnetic coil; relocation of the coil occurred in 33.2% of participants. Subjects received treatment for 3 to 6 weeks. Lack of improvement in the first 3 weeks (classified as treatment failures) led to discontinuation from Phase 1 of the clinical trial and crossover to open treatment in Phase 2 of the trial. Partial responders in the first 3 weeks continued with sham or rTMS. At the endpoint of the study, the response rate using an intention-to-treat (ITT) analysis for remitters (n=18) was 14.1% in the active rTMS group and 5.1% in the sham group (p=0.02). Most remitters had low antidepressant treatment resistance. Results were similar for response to treatment outcomes, 15.5% in the active rTMS group versus 5% in the sham group. Comparing participants receiving active rTMS to sham rTMS, active rTMS participants demonstrated significantly greater improvement in mean scores for the MADRS, Clinical Global Impression Improvement Scale (CGI-S), and the Inventory of Depressive Symptomatology-Symptoms Review/Self Rated (IDS-SR) but not the HAMD-24. A limitation of this trial was the failure to enroll the projected 240 participants as suggested by the initial power analysis, due in part to the delayed start of the trial as a result of extensive work in designing a sham system. It was also unclear how long participants required treatment. Those who met the 30% improvement criteria continued randomized treatment for an additional 3 weeks or until cessation of meaningful response to treatment; as such, no participant received treatment for a full 6 weeks. Despite more rigorous requirements for progression (30% improvement at 3 weeks compared to 25% improvement at 4 weeks), this study showed a significant improvement in remission at 3 to 5 weeks. The treatment was relatively well tolerated, with no difference in the adverse events between the sham and the active rTMS treatment arms. Adverse events included headache (active 29% versus sham 23%), discomfort at the stimulation site (active 17% versus sham 10%), insomnia (active 10% versus sham 7%) and worsening of depression or anxiety (active 6% versus sham 8%). No seizure activity was reported in any of the study participants. The investigators concluded that daily DLPFC rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval [CI], 1.21-13.24).
Levkovitz and colleagues (2015) evaluated the use of rTMS in a double-blind, randomized controlled, multicenter study evaluating the efficacy and safety of deep TMS (dTMS) in 212 individuals with MDD, who had either failed 1 to 4 antidepressant trials or were intolerant to at least 2 antidepressant treatments during the current episode. Participants were randomly assigned to monotherapy with active or sham dTMS using the Brainsway H-Coil Deep TMS (DTMS) System (Brainsway Ltd., Jerusalem, Israel). A total of 20 sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks of acute treatment, and then twice weekly for 12 weeks. Primary and secondary efficacy endpoints were a change in HAMD-21 score and response/remission rates at week 5, respectively. In the active treatment group, use of dTMS resulted in a 6.39 point improvement in HAMD-21 scores, while a 3.28 point improvement was observed in the sham group (p<0.008). In the ITT analysis, both response and remission rates were higher in the dTMS than in the sham group (response: 37.0% vs. 27.8%; p<0.031; remission: 30.4 vs. 15.8%; p<0.0158). The investigators reported these differences between active and sham treatment were stable during the 12-week maintenance phase. A total of 8 serious adverse events were reported in 7 participants; however, only 1 of the 8 adverse events was considered device-related and occurred in a participant (a seizure confounded by heavy alcohol use) who failed to comply with the study protocol. A limitation of this study was that 14.6% of the ITT analysis set were not treated at the stimulation intensity defined by the protocol and were excluded from the per protocol [PP] analysis. According to the investigators, this was "...presumably due to the flexibility of the operator in titrating stimulation intensity from 100% up to 120% of individual motor threshold in order to improve tolerability..." It was suggested that the lower intensity of dTMS to the deep prefrontal cortex areas could have produced a less than desirable clinical response in these participants.
TMS for Maintenance of Remission for TRD
While the antidepressant effects of rTMS for individuals with TRD have been demonstrated, a limited number of studies have examined the efficacy of rTMS for maintaining response or remission (that is, preventing relapse or recurrence) after treatment. The majority of the research focuses on the acute short-term efficacy of rTMS treatment, and there is considerable risk of relapse and variable rates reported post rTMS in these early published studies. For example, Dannon and colleagues (2002) reported a 20% 6-month relapse rate in a group of individuals with major depression treated with either ECT (n=20) or rTMS (n=21). In another small study of reintroduction of rTMS treatment for refractory MDD, the mean duration of rTMS benefit was reported as 5 months (Demirtas-Tatlidede, 2008).
Janicak and colleagues (2010) reported that rTMS can be an effective acute antidepressant treatment, but noted that few studies systematically examine the persistence of benefit. The investigators assessed the durability of antidepressant treatment after acute response to rTMS in individuals with MDD during a long-term observational study of responders in two trials using the NeuroStar TMS Therapy System. Participants that ultimately responded to active rTMS or sham in the original randomized controlled trial, or responded to active rTMS in the open label extension were followed for recurrence of depression and/or need for reintroduction of active rTMS over a 24-week treatment period. The participants who met criteria for partial response (that is, > 25% decrease from the baseline HAMD-17) (n=142) were tapered off rTMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. During this durability study, rTMS was readministered if participants met pre-specified criteria for symptom worsening (that is, a change of at least 1 point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure, defined as a recurrence of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depression or failure to achieve symptom improvement upon reintroduction of rTMS. A total of 10 of 99 (10%) participants relapsed, 38 (38.4%) participants had worsening symptoms, and 32 of the 38 participants (84%) achieved symptomatic benefit with adjunctive rTMS. Safety and tolerability were similar to acute rTMS monotherapy. It is difficult to draw conclusions from this data regarding the treatment effect of rTMS. All the study participants had initiated antidepressants, making it difficult to attribute the duration of response to rTMS alone. The control group only received sham rTMS. Although participants who initially responded to sham had higher relapse and rTMS re-treatment rates, the numbers are too small for statistically meaningful comparisons, and the groups may not be comparable. Additional data are needed to determine the durability of the treatment effect, particularly in maintenance phases.
Fitzgerald and colleagues (2013) reported on a large prospective, open-label trial of clustered maintenance rTMS that included 35 individuals with refractory depression. Participants with TRD received a second successful course of rTMS following relapse and were subsequently treated with monthly maintenance therapy consisting of 5 rTMS treatments over a 2.5-day period (Friday evening, Saturday and Sunday). Participants were treated with maintenance therapy of the same type that they had initially received (that is, 14 high frequency to the left DLPFC, 12 low frequency to the right DLPFC, and 9 bilateral rTMS). The primary outcome was the mean duration until clinical relapse, addition or change of antidepressant medication, or withdrawal from maintenance treatment to pursue other treatment options. A total of 25 of the 35 participants (71%) relapsed at a mean of 10.2 months (range, 2 to 48 months), which was substantially shorter than the interval (< 3 months) for relapse from the initial treatment. The other 10 participants either withdrew while still in remission or remained well and in maintenance treatment at the end of the study (n=6, mean 12.0 ± 9.7 months, range 1-24 months). In terms of prediction of time to relapse, there was no effect of any of the analyzed clinical or demographic variables on duration of time (in months) until relapse. Limitations of this study include the inability to compare the results to other rTMS follow-up or maintenance studies employing a more standardized approach, due to the unique form of the applied maintenance treatment and characteristics of the sample of participants. The overall relapse rate was fairly high when compared to the earlier study by Janicak (38% rTMS reinduction rate) (2010), although not greater than the results of a study by Cohen and colleagues (2009) that reported a 77% rate of relapse at 6 months. In addition, there was no form of placebo control in the trial and changes in medication treatment across the duration of maintenance therapy were not accurately documented.
Mantovani and colleagues (2012) examined the persistence of benefit of rTMS during a 3-month follow-up of individuals after acute treatment with rTMS for MDD. Participants were remitters from an acute double-blind sham-controlled trial of TMS (n=18), or from an open-label extension trial of those who did not respond to the acute trial (n=43). The primary outcome was relapse, defined as a HAMD-24 score of ≥ 20. Of the 61 remitters in the acute trial, 5 entered naturalistic follow-up and 50 entered the rTMS taper. A total of 32 participants completed rTMS taper and 1-, 2-, and 3-month follow-up. At the 3-month visit, 29 of 50 participants (58%) were classified as in remission (HAMD-24 score, ≤ 10), 2 of 50 participants (4%) as partial responders (30% ≤ HAMD-24 reduction, < 50% from baseline), and 1 of 50 participants (2%) met criteria for relapse. During the entire 3-month follow-up, 5 of the 37 participants relapsed (relapse rate, 13.5%; average time to relapse 7.2 ± 3.3 weeks), but 4 of them regained remission by the end of the study. Participants who relapsed had higher depression scores at 1 month. Limitations of this study include the small number of participants who completed the 3-month follow-up (one-third of the sample were lost to follow-up), and the nonrandomized study design.
Connolly and colleagues (2012) reported on a retrospective cohort study of 100 consecutive individuals treated with rTMS for depression in an outpatient treatment program. Out of the first 100 cases treated at the institution, 42 received maintenance rTMS. Most of the individuals had failed more than 1 adequate antidepressant trial and were treated with high-frequency rTMS over the DLPFC. Low-frequency rTMS to the right DLPFC was given in individuals with a family or personal history of seizures and in some who were also receiving high-frequency rTMS. The primary outcomes for the acute sample were the response and remission rates at treatment endpoint as measured by the CGI-S scale. At the endpoint of up to 30 adjunctive TMS sessions, the CGI-S response rate was 50.6% of the first 100 cases and the remission rate was 24.7%. Maintenance treatment (n=42 individuals) was tapered gradually from 2 sessions per week for the first 3 weeks to monthly. At 6 months after the initial rTMS treatment, 26 of the 42 individuals (62%) maintained their response. Overall, 40 individuals discontinued treatment for reasons including adverse events (n=3), logistical difficulties (n=10), or stopped treatment for lack of efficacy or were lost to follow-up (n=27). Additional limitations of this open-label study are inclusion of individuals with bipolar disorder in addition to those with MDD and reported differences in the treatment parameters and methods of targeting rTMS to the DLPFC. The absence of a control group and the sample of records reviewed from a single treatment center limit generalizing the results to other clinical rTMS treatment.
Dunner and colleagues (2014) report on the 1-year follow-up from a large multicenter, observational study (42 sites) of rTMS administered as maintenance therapy for individuals with TRD (unipolar, nonpsychotic MDD) who did not benefit from antidepressant medication. Of the 307 subjects successfully treated with an acute rTMS course, 257 subjects agreed to follow-up over 52 weeks. Assessments were obtained at 3, 6, 9, and 12 months. A total of 205 of 257 subjects completed the 12-month follow-up; 120 subjects met the IDS-SR response or remission criteria at the end of their acute rTMS treatment course. The proportion of subjects who achieved remission at the conclusion of acute treatment remained similar at conclusion of the long-term follow-up. After the first month when the majority of acute rTMS tapering was completed, 93 of the 257 subjects (36.2%) in the follow-up study received additional rTMS (mean, 16.2 sessions) for worsening of symptoms. A total of 75 of the 120 subjects (62.5%) who met response or remission criteria at the end of the initial treatment phase (including a 2-month taper phase) continued to meet response criteria throughout the 1-year period. The authors suggested that rTMS demonstrated a clinically meaningful durability of acute benefit over 12 months.
Kedzior and colleagues (2015) examined the durability of the antidepressant effect of rTMS in the absence of maintenance treatment. This meta-analysis included 16 double-blind, parallel-design, sham-controlled, randomized controlled trials with a total of 495 participants. The range of follow-up was 1 week to 16 weeks, but most studies only reported follow-up to 2 weeks. The overall antidepressant effect size was small with a standardized mean difference (SMD; Cohen's d) of -0.48 (95% CI: -0.70, -0.25; p<0.001), and the effect sizes were lower in randomized controlled trials with 8- to 16-week follow-up (d = -0.42) compared to shorter follow-up of 1 to 4 weeks (d = -0.54). The effect size was higher when antidepressant medication was initiated concurrently with rTMS during acute treatment phases (5 trials; d = -0.56) than when participants received a stable dose of medication (9 trials; d = -0.43) or were not medicated (2 trials; d = -0.26). The authors concluded that rTMS has only a small antidepressant effect during follow-up after short acute treatment (5-15 sessions) in the absence of active maintenance treatment. "This effect depends on illness severity, decreases over time, and appears to be enhanced by antidepressants."
Additional research is needed to determine the durability of remission produced by rTMS. This includes identification of which of the locations and treatment parameters are most effective to guide the number of sessions needed to elicit a clinically significant response, to determine whether the response is durable with or without antidepressant medications, and to provide some information about whether maintenance treatments are needed and which types of maintenance treatment are most effective.
Wall and colleagues (2013) performed a secondary post hoc analysis of neurocognitive outcomes in two prospective, multicenter pilot trials of adolescents treated with open-label rTMS for MDD. A total of 14 of 18 adolescents (mean age, 16.2 ± 1.1 years; 11 females, 7 males) who failed to adequately respond to at least 1 antidepressant agent completed all 30 rTMS treatments (5 days/week, 120% of motor threshold, 10 Hz, 3000 stimulations per session) applied to the LDPFC and neurocognitive testing at baseline and treatment completion. Depression was rated using the Children's Depression Rating Scale-Revised. Neurocognitive evaluation was performed at baseline and after completion of 30 rTMS treatments with the Children's Auditory Verbal Learning Test (CAVLT) and Delis-Kaplan Executive Function System Trail Making Test. Over the course of treatment, adolescents showed a substantial decrease in depression severity corresponding with a statistically significant improvement in memory and delayed verbal recall. Other learning and memory indices and executive function remained intact. Subjectively, neither participants nor their family members reported clinically meaningful changes in memory, cognitive functioning, or attention. As this is a small unblinded, nonrandomized study with preliminary findings, further controlled studies with larger sample sizes and rigorous designs are warranted to confirm these results.
Slotema and colleagues (2010) conducted a meta-analysis evaluating the efficacy of rTMS for various psychiatric disorders. Data were obtained from randomized, double-blind, sham-controlled trials of rTMS treatment for depression (34 studies, 1383 participants). Studies of rTMS versus ECT (six studies) for depression were meta-analyzed. The 2007 clinical trial by O'Reardon and colleagues is included in this meta-analysis. The analysis had very broad selection criteria for inclusion, allowing any type of rTMS treatment and any type of depression experienced by the study participants. Participants were free of antidepressant agents (that is, rTMS administered as monotherapy) in 7 studies, antidepressants were continued in 17 studies, and antidepressants were initiated along with rTMS in 5 studies. The mean weighted effect size of rTMS versus sham for depression was 0.55 (p<0.001). ECT therapy was superior to rTMS in the treatment of depression (mean weighted effect size of 0.54 (p<0.001). Subgroup analyses comparing rTMS as a monotherapy versus continuation or initiation of antidepressants showed that the mean weighted effect size for rTMS monotherapy (effect size 0.96, p<0.001), trended toward having a stronger treatment effect than for rTMS with continuation of antidepressants (effect size 0.51, p<0.001) or rTMS with initiation of antidepressants (effect size 0.37; p=0.03). This analysis, however, should not be interpreted to mean that rTMS monotherapy is possibly more effective than as used with antidepressants, but that the treatment difference between rTMS and the corresponding control group for each type of study is larger for rTMS monotherapy versus a no-treatment sham-only control group. According to the authors:
Although the efficacy of rTMS in the treatment of depression…may be considered proven, the duration of the effect is as yet unknown. Effect sizes were measured immediately after the cessation of rTMS treatment. There are indications that the effects of rTMS may last for several weeks to months. Further studies should assess symptom relief with longer follow-up periods to assess the cost-effectiveness of rTMS treatment, and to indicate its economic advantages and disadvantages. Although rTMS cannot replace ECT in depressive patients, there may be subgroups in which rTMS can replace antidepressant medication.
A work group of the American Psychiatric Association (APA) published the third edition of the Practice Guideline for the Treatment of Patients with Major Depressive Disorder (Gelenberg/APA, 2010). According to the work group:
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.
As an initial treatment modality, the APA guideline recommends:
Treatment in the acute phase should be aimed at inducing remission of the major depressive episode and achieving a full return to the patient's baseline level of functioning. Acute phase treatment may include pharmacotherapy, depression-focused psychotherapy, the combination of medications and psychotherapy, or other somatic therapies such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or light therapy. In comparisons of actual TMS versus sham TMS, most but not all recent meta-analyses have found relatively small to moderate benefits of TMS in terms of clinical response. Although the primary studies used in these meta-analyses are highly overlapping and the variability in TMS stimulus parameters and treatment paradigms complicates the interpretation of research findings, these meta-analyses also support the use of high-frequency TMS over the left dorsolateral prefrontal cortex. Lesser degrees of treatment resistance may be associated with a better acute response to TMS (Lisanby, 2009). In comparison with ECT, TMS has been found in randomized studies to be either less effective than ECT (Eranti, 2007) or comparable in efficacy to ECT (Grunhaus, 2003; Janicak, 2002; Rosa, 2006), but in the latter studies TMS was more effective and ECT was less effective than is typically seen in clinical trials.
For individuals who do not respond adequately to pharmacotherapy, the guideline states (Level II: Recommended with moderate clinical confidence): "TMS could also be an option, as it appears to be safe and well tolerated. In addition, it has shown small to moderate benefits in most but not all (Couturier, 2005; Herwig, 2007) clinical trials and recent meta-analyses."
When comparing rTMS to other somatic therapies such as ECT and VNS, the guideline states:
ECT is recommended as a treatment of choice for patients with severe major depressive disorder that is not responsive to psychotherapeutic and/or pharmacological interventions, particularly in those who have significant functional impairment or have not responded to numerous medication trials (Level I: Recommended with substantial clinical confidence) (Gelenberg/APA, 2010).
The Institute for Clinical Systems Improvement's (Mitchell, 2013) health care guideline titled Major Depression in Adults in Primary Care discusses rTMS as a treatment for MDD that fails to respond to at least one antidepressant trial during the current illness episode. The guideline states:
While many studies have been conducted, results are heterogeneous, likely due to small sample sizes and significant variability of anatomical localizations and stimulation intensities and parameters. Compared to early rTMS studies, more recent studies improve upon methodological limitations including active sham treatment mimicking the somatosenory experience of rTMS, masking rTMS administrators and patients to acoustic signals produced by stimulation, and competency certification for outcome evaluators.
The guideline summarizes:
At this time, a number of treatment and protocol variations for rTMS remain, and the optimum treatment protocol and patient characteristics may not yet be identified (Allan, 2011). Nonetheless, rTMS is a low-risk and appealing treatment for treatment-refractory depressed patients for whom it is practical and cost-effective.
The Agency for Healthcare Research and Quality (AHRQ) published a comparative effectiveness review of nonpharmacologic interventions for TRD in adults (Gaynes, 2011). Treatment modalities reviewed included ECT, rTMS, VNS and psychotherapy. The review focused on randomized controlled trials comparing one intervention with another for efficacy and effectiveness. The authors also evaluated trials using nonpharmacologic interventions versus placebo- or sham-controlled evidence or "treatment as usual" controls. The quality of individual studies was categorized as "good, fair, or poor," with only good or fair studies included in the analyses. The strength of the various bodies of evidence used principles in the AHRQ's method guide, grading strength of evidence as "high, moderate, low, or insufficient." The greatest volume of evidence found for TRD intervention was for ECT and rTMS; however, the direct comparative evidence about these treatments was limited. The available head-to-head literature concerning the efficacy of these interventions for TRD was limited to two trials (both rated as fair) in MDD-only populations. One trial compared ECT and rTMS, and the other compared ECT and ECT plus rTMS. They showed no differences between treatment options for depressive severity, response rates, and remission rates. Indirect evidence that was available to assess the potential benefits of nonpharmacologic interventions versus controls was also measured by calculating mean changes in depressive severity, relative risks of response, and relative risks of remission. rTMS was beneficial relative to controls receiving a sham procedure for all three outcomes and produced a greater decrease in depressive severity (high strength of evidence). Specifically, rTMS averaged a decrease in depressive severity measured by the HAMD of more than 5 points relative to sham control (a 3-point HAMD difference is considered clinically meaningful). Response rates were greater with rTMS than sham (also high strength of evidence); those receiving rTMS were more than three times as likely to achieve a depressive response as persons receiving a sham procedure. Finally, rTMS was also more likely to produce remission than the control procedure (moderate strength of evidence); persons receiving rTMS were more than six times as likely to achieve remission as those receiving the sham procedure. With respect to maintaining remission (or preventing relapse) for TRD, the authors found no direct comparisons involving ECT, rTMS, VNS, or cognitive behavioral therapy (CBT). Indirect evidence in three fair trials compared rTMS with a sham procedure and found no significant differences. However, too few participants were followed during the relapse prevention phases in two of the three studies, and participants in the third received a co-intervention providing insufficient evidence for a conclusion. In the final analysis, the report concludes that when used as an antidepressant therapy, rTMS appears to produce a clinical benefit without the systemic side effects typical with oral medications, has no adverse effects on cognition, and unlike ECT, does not induce amnesia or seizures. rTMS offers a well-tolerated, nonpharmacologic alternative that does not require attendant anesthesia services and can be administered in an outpatient setting for individuals with MDD who have failed to benefit from initial treatment of their depression. The report suggests that when effective, rTMS may prevent the need to utilize more complex pharmaceutical augmentation strategies (for example, atypical antipsychotic medication), ECT, and inpatient hospitalization at later stages of the illness.
In December 2011, the New England Comparative Effectiveness Public Advisory Council (CEPAC), an AHRQ funded, independent body composed of clinician and public representatives and led by a research team at the Institute for Clinical and Economic Review (ICER) at the Massachusetts General Hospital, reviewed the AHRQ comparative effective analysis on rTMS along with consideration of supplemental information. A majority of CEPAC members determined that for individuals with TRD, the evidence is adequate to demonstrate that rTMS provides a net health benefit equivalent or superior to usual care (that is, general supportive psychotherapy with or without continued use of antidepressant medication) and a net health benefit equivalent to ECT. In a subsequent coverage policy analysis of the CEPAC report, the ICER (2012) recommended the need to further identify: 1) the appropriate subpopulations of individuals with TRD to receive treatment with rTMS and ECT; 2) treatment duration and frequency for rTMS; 3) maintenance therapy requirements for rTMS; and 4) threshold for previously failed treatments required before considering rTMS (that is, ≥ 2 failed drug treatments during the most recent episode of depression, a higher threshold than that included in the FDA license).
In summary, the studies of rTMS in the peer-reviewed medical literature demonstrate a short-term benefit for individuals with treatment resistant MDD who received active versus sham rTMS. Treatment benefit has been defined by response or remission rates using depression rating scales. Most studies have short treatment periods, varying from 1 week to 6 weeks and few studies have included long-term outcomes. Durability of rTMS response at this time is unclear and the optimal approach to sustaining any benefit achieved is unknown. In addition, the use of rTMS as a maintenance therapy is not supported by a controlled clinical trial. A search of the ClinicalTrials.gov database has identified an industry-sponsored, randomized, open-label 12-month study (NCT01415154) evaluating the use of rTMS as maintenance therapy in individuals who have responded to a 6-week course of acute rTMS treatment for MDD. The study is posted as "completed" with the last update on November 11, 2015; however, to date, the study results are posted as unpublished on the ClinicalTrials.gov website and not identified in the peer-reviewed published medical literature.
Published evidence is limited and further investigation in large randomized controlled clinical trials is needed to assess the safety and durability of acute rTMS therapy followed by maintenance rTMS treatment for individuals with treatment resistant MDD. Despite questions that remain about stimulation parameters and the length of optimal treatment, rTMS is well-tolerated without significant adverse events and clinically significant results. rTMS is a safe and less invasive alternative treatment option for individuals with TRD.
rTMS as Treatment for Other Neuropsychiatric Disorders
The peer-reviewed published medical literature consists of randomized controlled trials, comparative and pilot studies, meta-analyses, and systematic reviews exploring the efficacy of TMS using various stimulus parameters, including low frequency (LF) and high frequency (HF) TMS, for the treatment of other neuropsychiatric disorders, including:
Methodological limitations in some of these studies include, but are not limited to, small sample size, heterogeneity of study participants, absence of a placebo control group, presence of concurrent pharmacotherapy, and lack of long-term outcomes. Additional controlled studies in larger populations are needed to evaluate optimal treatment parameters and determine the durability of rTMS therapy to improve symptom control in individuals with neuropsychiatric conditions.
The American Academy of Neurology (AAN) (Miyasaki, 2006) evidence-based practice parameter for the evaluation and treatment of depression, psychosis, and dementia has concluded there is insufficient evidence to support or refute the efficacy of rTMS or ECT in the treatment of depression associated with Parkinson disease.
The APA has practice guidelines that address the use of rTMS in individuals with auditory hallucinations in schizophrenia, eating disorders, and OCD. For individuals with hallucinations in schizophrenia, the practice guideline states:
Although it has been suggested that repetitive transcranial magnetic stimulation (rTMS) may share beneficial features of ECT and several studies with rTMS have shown promising results in decreasing auditory hallucinations, rTMS does not have an FDA indication for the treatment of psychosis, and additional research is needed before recommending its use in clinical practice (Lehman, 2004).
An APA Guideline Watch issued in August 2012 (Yager, 2012) updates the 2006 practice guideline for the treatment of individuals with eating disorders:
At the time of guideline publication, repetitive transcranial magnetic stimulation (rTMS) had been studied in case reports for the treatment of bulimia nervosa when co-occurring with major depressive disorder. In a small trial, Walpoth and colleagues (2008) randomly assigned 14 women with bulimia nervosa to receive 3 weeks of either active rTMS or sham rTMS, after a 1-week lead-in period in which all 14 women received sham treatment. All patients improved, and no advantage was seen for the active treatment over sham rTMS. Further study of this treatment approach is needed.
An APA Guideline Watch issued in March 2013 summarizes new evidence and developments since the 2007 publication (Koran, 2007) of the practice guideline for the treatment of individuals with OCD:
The guideline recommends that other somatic therapies should be considered only after first- and second-line treatments and well-supported augmentation strategies have been exhausted. New studies are available on repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), and other somatic treatments, but the overall strength of evidence for these treatments remains low… Controlled trials of rTMS have produced both negative and suggestively positive results; the studies differ in the brain region stimulated and in the nature of the stimulation (high versus low frequency).
In a Cochrane review, Dougall and colleagues (2015) evaluated 41 studies of 1473 participants and found there was insufficient evidence to support or refute the use of TMS to treat symptoms of schizophrenia. The authors concluded:
Although some evidence suggests that TMS, and in particular temporoparietal TMS, may improve certain symptoms (such as auditory hallucinations and positive symptoms of schizophrenia) compared to sham TMS, the results were not robust enough to be unequivocal across the assessment measures used. There was insufficient evidence to suggest any added benefit with TMS used as an adjunctive therapy to antipsychotic medication. The overall quality of evidence was graded as very low due to risk of bias, and this was accompanied by an imprecision in estimates due to the relatively small number of participants in the studies. Thus, consideration is required in improving the quality of trial processes, as well as the quality of reporting of ongoing and future TMS trials, so as to facilitate accurate future judgments in assessing risk of bias. Differences in TMS techniques in relation to stimulation intensity, stimulation length, brain areas stimulated and variations in the design of sham TMS all contributed to the heterogeneity of study findings and limited the interpretation and applicability of the results. In addition, the trials assessed their outcomes with a variety of scales, and usable data were limited.
TMS for the Treatment of Migraine Headaches and Tinnitus
Single-Pulse TMS (sTMS) for the Treatment of Migraine Headaches
On December 13, 2013, the Cerena sTMS device (eNeura Therapeutics LLC, Sunnyvale, CA) received 510(k) (K130556) clearance for marketing through the de novo process as a low- to moderate-risk medical device that is not substantially equivalent to an already legally marketed device. The Cerena sTMS device is indicated to relieve pain caused by migraine headaches that are preceded by an aura, described as a visual, sensory or motor disturbance immediately preceding the onset of a migraine attack.
The FDA clearance of the Cerena sTMS device was based on a single multicenter randomized, double-blind, parallel-group, two-phase, sham-controlled study of adults aged 18-70 years who met the International Classification Headache Disorders criteria for migraine headache with aura (Lipton, 2010). Phase I of the trial enrolled 267 adults who experienced visual aura preceding at least 30% of migraines followed by moderate or severe headache in more than 90% of those attacks. Participants in phase I were trained to use an electronic diary to verify prospectively the diagnosis of migraine with aura; 66 participants (25%) dropped out after phase I of the trial. In phase II, 201 individuals randomized to either sham stimulation (n=99) or sTMS (n=102) self-applied the device to the back of the head, pressing a button to administer 2 pulses, each approximately 0.9 Tesla and lasting < a millisecond, 30 seconds apart. Participants were instructed to treat up to 3 attacks over 3 months while experiencing aura. The primary outcome measure was pain-free response 2 hours after the first attack. A total of 37 participants did not treat a migraine attack and were excluded from the outcome analyses. A total of 164 participants treated for at least 1 attack of migraine with aura with sTMS (n=82) or with sham stimulation (n=82) reported that pain-free response rates 2 hours after stimulation were significantly higher with sTMS (39%, 32 of 82) than with sham stimulation (22%, 18 of 82; p=0.018). Sustained pain-free response rates with no recurrence and no rescue drug use significantly favored sTMS at 24 hours (29%, [24 of 82] vs. 16% [13 of 82]; p=0.0405) and 48 hours (27% [22 of 82] vs. 13% [11 of 82]; p=0.0327) after treatment. There were no significant differences in secondary outcomes (headache response at 2 hours, use of rescue drugs, Migraine Disability Assessment [MIDAS] score and consistency of pain relief response) between groups. The study did not demonstrate sTMS was effective in relieving the associated symptoms of migraine, including nausea, photophobia, and phonophobia. No device-related serious adverse events were reported. The authors suggested that early treatment with sTMS could be a promising acute treatment for some individuals with migraine with aura. Limitations of this study include the high dropout rate during phase I of the trial (25%, 66 of 267), the potential for unblinding of the device after administration of treatment, and variations in the time interval from the onset of aura to treatment and pain intensity at the time of treatment. Additional randomized controlled trials are needed to determine optimal treatment parameters, including the range of doses and timing of treatment, to confirm the safety and durability of sTMS for the treatment of pain associated with migraine headache with aura.
On May 21, 2014, the SpringTMS® (eNeura Therapeutics, LLC, Sunnyvale, CA) received 510(k) clearance (K140094) as substantially equivalent to the Cerena sTMS (predicate device), intended for use in the acute treatment of pain associated with migraine headache with aura. The portable, handheld device delivers 0.9 Tesla to the back of the head seeking to counter the "cortical inhibitory wave" that occurs at the early stages of a migraine headache. To date, no studies evaluating the SpringTMS device were found in the peer-reviewed published literature. A search of the ClinicalTrials.gov database has identified a multicenter, prospective, non-randomized, single arm, open label, post-market, observational study (ESPOUSE; NCT02357381) which is currently recruiting participants. The purpose of the study is to evaluate the SpringTMS system in the reduction of migraine headache symptoms. The estimated study completion date is March 2016.
In 2014, the California Technology Assessment Forum (CTAF) examined various treatment options for migraine headaches. In the document, Controversies in Migraine Management, the CTAF Panel voted that the evidence for the acute treatment of migraine with aura is inadequate "...to demonstrate that the net health benefits of transcranial magnetic stimulation (SpringTMS) are equivalent to or better than those of other standard acute treatment medications."
rTMS for the Treatment of Tinnitus
Therapeutic rTMS has been proposed as a treatment for chronic tinnitus that is associated with increased focal brain activity in the central auditory system. Two early, prospective, randomized, double-blind, crossover trials studied the use of low frequency rTMS in individuals with tinnitus. Participants in these studies experienced variable results, reported as a significant reduction in tinnitus when compared to placebo (Kleinjung, 2005) or as only an average improvement (35%) in visual analogue score (VAS) for active rTMS participants that was maintained for a short duration (1 week) following treatment (Rossi, 2007). Limitations of these studies include a small sample size, a high participant dropout rate (Rossi, 2007) and lack of long-term follow-up. A subsequent observational study by Kleinjung and colleagues (2007) delivered low-frequency rTMS in 10 sessions to individuals (n=45) with chronic tinnitus. A total of 40% of the participants were classified as responders (5 points or more on a tinnitus questionnaire) and 60% as nonresponders; improvement in symptoms was maintained for 90 days. Post hoc analysis found that a positive response was associated with absence of a hearing impairment and disease duration of less than 3 years. The authors concluded that tinnitus-related neuroplastic changes may be less pronounced in subjects with normal hearing and a short history of complaints, explaining why those individuals benefited more from rTMS treatment.
Kleinjung and colleagues (2008) studied an rTMS treatment strategy comparing participants (n=32) who received either low-frequency temporal rTMS or a combination of high-frequency prefrontal and low-frequency temporal rTMS for chronic tinnitus. Treatment effects were assessed with a standardized tinnitus questionnaire (TQ). The authors reported that during and immediately after stimulation, there was a significant reduction of the tinnitus score in both groups (p=0.016), however, no significant difference between the 2 stimulation protocols (p=0.828) was observed. An evaluation after 3 months suggested a "tendency toward tinnitus improvement" with a significant difference (p=0.08) between the 2 treatment conditions, including a more pronounced effect for the combined protocol (p=0.029). Limitations of this pilot study include the lack of a placebo/control group and a short duration of the post-treatment observation period.
Piccirillo and colleagues (2011) examined the effectiveness and safety of low-frequency rTMS in a double-blind, randomized, crossover clinical trial of 14 adults with subjective, unilateral or bilateral, nonpulsatile tinnitus of 6 months duration or longer and a score of 38 or greater on the Tinnitus Handicap Inventory (THI). Low-frequency (1-Hz) 110% motor threshold rTMS or sham treatment was administered to the left temporoparietal junction for 2 weeks. The primary outcome measure was the difference in the change of the THI score between active and sham rTMS. The results indicated that active treatment was associated with a median (95% CI) reduction in THI score of 5 (0-14) points compared to sham treatment which was associated with a median reduction in THI score of 6 (-2 to 12) points. The difference in THI scores between the change associated with active and sham rTMS ranged from a 34-point reduction in THI score after active treatment to a 22-point increase after sham treatment, with a median difference change of only 1 point (-6 to 4 points). The investigators concluded that active rTMS was no more effective than sham treatment, citing possible explanations for the negative findings as the "short duration of treatment, failure of rTMS stimulation over the temporoparietal area to affect the auditory cortex buried within the Sylvian fissure, or more widespread cortical network changes associated with severe bothersome tinnitus not amenable to localized rTMS effects."
A Cochrane review (Meng, 2011) included 233 participants from five sham-controlled trials (including studies by Anders, 2010; Khedr, 2008; and Marcondes, 2010) with parallel groups that examined rTMS for the treatment of tinnitus. Each study described the use of a different rTMS device that delivered different frequencies ranging from 1 Hz to 25 Hz. All of the studies were relatively small but were considered to have a low risk of bias. Four trials reported tinnitus severity and disability using the THI; only one study demonstrated a statistically significant improvement in THI scores. Pooled results of two studies that used a self-rating scale showed a statistically significant reduction in tinnitus loudness (risk ratio, 4.17, 95% CI; 1.30 to 13.40). However, the validity of these pooled results were limited since one trial had a risk of selection bias and the confidence interval of the two small trials (n=37; n=54) was wide. This analysis suggests there is limited evidence to support the use of low-frequency rTMS for tinnitus and that larger placebo-controlled double-blind studies are needed to confirm its effectiveness for this indication.
Piccirillo and colleagues (2013) examined the effectiveness and safety of low-frequency rTMS to the left temporoparietal junction in a double-blind, randomized controlled crossover trial of a cohort of 14 adults with unilateral or bilateral, nonpulsatile subjective tinnitus of 6 months duration or greater and a score of 34 or greater on the THI. After 4 weeks of treatment, the investigators concluded that active rTMS was safer but no more effective than sham rTMS for individuals with chronic bothersome tinnitus; however, limitations in the study design may have influenced interpretation of these results.
Additional systematic reviews of the literature have been published investigating rTMS as a treatment for chronic tinnitus (Peng, 2013; Theodoroff, 2013). The authors concluded that although optimism for the use of rTMS as an effective treatment for tinnitus remains high among many researchers and clinicians, clinical issues remain unresolved concerning optimal treatment patterns, including: 1) coil placement; 2) stimulation intensity, frequency and duration; and, 3) use of rTMS in combination with other treatment modalities. Further study is required as the long-term effects of rTMS treatment for tinnitus are unclear.
In 2013, the AHRQ published a comparative effectiveness review of the existing scientific evidence regarding the evaluation and treatment of tinnitus (Pichora-Fuller, 2013). Five studies (including Anders, 2010 and Marcondes, 2010) evaluated rTMS as a medical intervention for tinnitus, consisting of small sample sizes (n≤60 subjects) and use of rTMS that appeared to stimulate the cortex most commonly associated with auditory function. Two of these studies investigated low frequency (1 Hz) rTMS relative to sham stimulation and measured the outcome using the THI. In both studies, the groups receiving placebo stimulation did not experience statistically significant changes in THI scores over the course of follow-up. Two other studies investigated higher frequency (5 Hz) rTMS relative to sham stimulation and measured the outcome using the THI. One study (low risk of bias) showed significant differences on THI scores at 1-week post treatment (p<0.01); however, there was no significant difference at 1-month post treatment. The second study (high risk of bias) showed no significant differences between the treatment and sham groups at 2-, 4-, and 12 weeks post treatment. The report concluded the underlying mechanism of the effect of rTMS to provide tinnitus relief is not yet understood, the risk of bias in the studies was generally fair, and the evidence in the studies was insufficient to determine the ability of rTMS to improve quality of life when compared with sham treatment for idiopathic tinnitus.
Hoekstra and colleagues (2013) performed a randomized controlled trial of bilateral low-frequency rTMS of the auditory cortex in 50 individuals with chronic tinnitus. At 1-week, 1-, 3- and 6 months after treatment, no significant differences between rTMS and placebo were observed in changes in the TQ or THI scores relative to pretreatment scores. The investigators concluded that bilateral low-frequency rTMS was not effective in treating chronic tinnitus.
Folmer and colleagues (2015) reported results of a randomized, participants and clinician or observer-blinded, placebo-controlled clinical trial of rTMS (NCT01104207) in individuals with chronic tinnitus. The primary objective was to determine if rTMS could reduce the perception or severity of tinnitus and result in a statistically significantly greater percentage of individuals who responded to active rTMS compared with placebo rTMS. Follow-up assessments were conducted at 1, 2, 4, 13, and 26 weeks after the last treatment session. A total of 70 individuals met the inclusion criteria; no participants withdrew because of adverse effects of rTMS. Active or placebo rTMS was administered at a rate of 1Hz rTMS daily on 10 consecutive workdays. Based on Tinnitus Functional Index (TFI) measurements, 18 of 32 participants (56%) in the active rTMS group and 7 of 32 participants (22%) in the placebo rTMS group responded to rTMS treatment. The difference in the percentage of responders to treatment in each group was statistically significant (p< 0.005). Responders experienced sustained improvements in tinnitus severity during the 26-week follow-up period. Larger scale studies with refinement in treatment protocols are needed to determine the durability of rTMS in individuals with chronic tinnitus.
The American Academy of Audiology's (AAA) Audiologic Guidelines for the Diagnosis & Management of Tinnitus Patients (AAA, 2000), states:
Prior to recommending or beginning any treatment for tinnitus, it is essential that a differential diagnosis be attempted. There are many factors that can cause and affect tinnitus and its perception that will influence the management plan and outcome of any treatment. The evaluation and treatment of patients with tinnitus is most likely to succeed when a multidisciplinary approach is employed. That at this time there is no cure for most cases of tinnitus…a number of treatment approaches that can be performed by audiologists have been described with various degrees of reported success.
In summary, despite the suggested benefit of rTMS reported in some of the peer-reviewed literature, sufficient evidence is lacking from larger scale randomized controlled trials that compare rTMS with placebo therapies and demonstrate a durable outcome benefit for the treatment of tinnitus.
TMS for Other Non-Behavioral Health Indications
The peer-reviewed published medical literature consists of case series, cohort studies, prospective and retrospective single and double-blind randomized controlled trials, and several Cochrane reviews, systematic reviews, and meta-analyses that explore the efficacy of TMS for other non-behavioral, neurodegenerative, and neurophysiologic conditions, including treatment of symptoms associated with the following conditions:
In some of these studies and meta-analyses, no significant differences or limited treatment effect pre- and post- rTMS treatment were reported in those that included a placebo control group. Other studies reported a limited treatment benefit or lack of a sustained benefit following active rTMS treatment. Methodological limitations in other studies include absence of a placebo control group, limited sample size, heterogeneity of study participants, presence of concurrent pharmacotherapy, differences in rTMS treatment protocols (such as, stimulus parameters), and variances in, or lack of, parameters assessing long-term outcomes, including inconsistencies in the duration of follow-up and the number of post-treatment assessments.
Two small, randomized, double blind placebo-controlled trials investigated the safety and efficacy of rTMS and intermittent theta-burst stimulation (iTBS) (a novel type of rTMS) in the treatment of motor symptoms in Parkinson's disease. Benninger and colleagues (2011) treated 26 individuals with mild to moderate Parkinson's disease with iTBS of the motor and dorsolateral prefrontal cortices in 8 sessions over 2 weeks (13 iTBS sessions and 13 sham stimulation sessions). Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neuropsychological, and neurophysiologic measures. The investigators reported that iTBS improves mood and was safe, but failed to improve gait, upper extremity bradykinesia, UPDRS, or other motor symptoms. The second trial conducted by Arias and colleagues (2010) evaluated the effect of low-frequency rTMS on motor signs in 18 individuals randomly assigned to receive either active (n=9) or sham (n=9) rTMS for 10 days. The effect of the stimulation was evaluated through several gait variables, hand dexterity, and the total and motor sections of the UPDRS. Total and motor section of the UPDRS and the turn time during gait were the only measures affected by the stimulation, with treatment effect appearing during either 'ON' or 'OFF' evaluation; however, this effect was equally displayed in both active and sham treatment groups. The remaining measures were not influenced by the treatment. The investigators concluded:
The protocol of stimulation used, different from most protocols that apply larger amount of stimuli, but very similar to some previously reported to have excellent results, has no therapeutic value and should be abandoned. This contrasts with the positive reported effects using higher frequency and focal coils. Our work also reinforces the need for sham stimulation when evaluating the therapeutic effect of rTMS.
In summary, the durability of rTMS and its role in improving health outcomes in the treatment of non-behavioral health indications is unknown. Further randomized controlled trials comparing rTMS to placebo therapy are needed to determine the net health benefit of rTMS as treatment for any of these conditions.
Functional Description of TMS
TMS was first introduced in 1985 as a method of noninvasive, nonconvulsive neurostimulation of the brain. The technique involves placement of a small coil over the scalp; a rapidly alternating current is passed through the coil wire, producing a magnetic field that passes unimpeded through the cranium and scalp. rTMS was initially used to investigate nerve conduction, when rTMS over the motor cortex of the brain was noted to produce a muscle-evoked response on the opposite side. Devices for transcranial stimulation have also received FDA clearance for diagnostic uses.
Interest in the use of rTMS as a treatment for depression was prompted by the development of a device that could deliver rapid, repetitive stimulation. Early studies suggested that rTMS of the left DLPFC was associated with antidepressant properties. In October 2008, the FDA granted clearance of an rTMS device using 10 Hz stimulation of the left DLPFC as a treatment for major depression in individuals who were unresponsive to 1 antidepressant medication. Conventional rTMS protocols typically target the left DLPFC. The discharge frequency of stimulation (that is, the number of times the magnetic field is generated and the current induced on brain tissue) is usually at a frequency of 10 Hz; this high-frequency (HF) stimulation increases cortical excitability. Other protocols have targeted the right DLPFC using low-frequency (LF) stimulation at 1 Hz; this protocol decreases cortical excitability. In contrast to ECT, rTMS does not require anesthesia, and does not induce a convulsion. Devices delivering LF- and HF-rTMS have been studied as of treatment of neuropsychiatric disorders and medical conditions. In addition to the potential for altering interhemispheric imbalance, it has been proposed that HF rTMS may facilitate neuroplasticity.
TMS for Depression and Other Neuropsychiatric Disorders
The National Institute of Mental Health (NIMH, 2014) estimates there were 9.8 million adults aged 18 or older (4.2%) in the United States (U.S.) in 2014 with a serious mental illness. Serious mental illness includes the occurrence of mood disorders, including major depressive disorder, dysthymic disorder, and bipolar disorder. Other conditions such as anxiety disorders, including generalized anxiety disorder, OCD, panic disorder, phobias, and PTSD affect approximately 40 million U.S. adults ages 18 and older, or about 18% in this age group in a given year. Individuals who suffer from depression may experience functional impairment, increased risk of suicide, higher health care expenses and losses in productivity. Complaints of sleep disturbance, fatigue and pain are the most common presentations of depression. Treatment in the acute phase of a major depressive episode may include pharmacotherapy, depression-focused psychotherapy (that is, "talk therapy"), and the combination of medications and psychotherapy, or other somatic therapies such as ECT, recommended as the treatment of choice for individuals with severe major depression not responsive to psychotherapeutic and/or pharmacological interventions.
The NeuroStar TMS Therapy System (Neuronetics, Malvern, PA) received clearance for marketing as a Class II rTMS device in December, 2008. NeuroStar TMS Therapy is indicated for the treatment of adults with "major depressive disorder who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the episode" (FDA, 2008). To date, 3 additional rTMS therapy systems have received FDA 510(k) clearance (Product Code: OBP) as substantially equivalent to the predicate rTMS device (Neurostar TMS Therapy System). These rTMS therapy systems include:
According to the FDA 510(k) summaries, these systems are "...indicated for the treatment of major depressive disorder in adult patients who have failed to achieve satisfactory improvement from prior antidepressant medication in the current episode" (FDA, 2015).
rTMS may be performed on an outpatient procedure but must be repeated several times per week over the course of 4 weeks to 6 weeks to achieve maximum response. rTMS may be used alone or as an adjunct to antidepressant medication. An acute treatment course of rTMS may consist of 30 treatments for 30 minute to 60 minute sessions, usually delivered daily for 5 days a week with treatment taper of 3 weeks duration. Each session consists of rTMS to the left DLPFC area at around 120% of the individual's observed motor threshold (stimulation intensity). Device treatment parameters and specifications for the NeuroStar TMS Therapy System, MagVita TMS Therapy System, and Rapid2 Therapy System are as follows: (10Hz, 4-second train duration, 26 second inter-train interval, administered at 3000 pulses per session using a biphasic figure 8 coil; and, for the Brainsway H-Coil Deep TMS device treatment, parameters and device specifications are: 18 Hz, 2-second train duration, 20 second inter-train interval, administered at 1980 pulses per session.
Contraindications, Warnings and Precautions, and Use of TMS in Special Populations or Clinical Conditions
The FDA's substantially equivalent designation given to the Brainsway H-Coil Deep TMS System, MagVita TMS Therapy System, and Rapid2 Therapy System states that the devices are similar to the NeuroStar TMS Therapy System "...regarding use and basic technological characteristics." Minor difference in the system components and software do not affect the treatment procedure or outcome. Any differences in coil or treatment stimulation parameters do not raise new questions of safety and effectiveness.
The prescribing information for the predicate device, the NeuroStar TMS Therapy System, is discussed in detail and considered relevant to the other TMS systems. TMS is contraindicated for use in some individuals. These individuals should not be treated with the system or will need to take special precautions before treatment, including those having conductive, ferromagnetic, or other magnetic-sensitive metals in the head or within 30 centimeters (cm) of the treatment coil. Examples include cochlear implants, ocular implants, implanted electrodes and stimulators such as deep brain stimulation devices, pacemakers, ICDs, or VNS devices, and aneurysm clips or coils, stents, and bullet fragments. Failure to follow this restriction could result in serious injury or death. TMS is also contraindicated for use in an individual with a wearable cardioverter defibrillator (WCD), even if the device is removed, due to the potentially unstable cardiac condition of such a person. Caution should be used in individuals with other implanted devices or metallic objects that are not controlled by physiologic signals including sutures and implanted insulin pumps located in areas outside the 30 cm distance from the coil during rTMS therapy, otherwise serious injury could result.
Clinical warnings and precautions to consider before proceeding with TMS treatment include being alert for signs of an imminent seizure. Individuals at potential increased risk of seizure include, but are not limited to, those who have concurrent medication use such as tricyclic antidepressants, neuroleptic medications, or other drugs that are known to lower the seizure threshold. An updated international workshop consensus guideline (Rossi, 2009) evaluated the risks and safety of use of conventional TMS protocols in clinical practice and research. When considering selection of candidates for rTMS, the guideline states "a special risk is occult substance abuse or dependence (alcohol, caffeine, drugs) conditions associated with altered seizure risk." Intake of one or a combination of certain drugs (for example, alcohol, amitriptyline, amphetamines, cocaine, and theophylline) "forms a strong potential hazard for application of rTMS due to their significant seizure threshold lowering potential..." In addition, withdrawal from certain drugs (for example, alcohol, barbiturates, benzodiazepines, chloral hydrate, and meprobamate) "forms a strong relative hazard for application of rTMS due to resulting significant seizure threshold lowering potential…" rTMS should be performed, if required, with caution in instances when withdrawal of these medications is clinically or scientifically indicated.
The safety and effectiveness of NeuroStar TMS Therapy has not been established in the following special populations or clinical conditions through a controlled clinical trial (NeuroStar TMS User Manual):
According to the NeuroStar TMS User Manual, additional warnings and precautions associated with operation of the system include practitioner judgment to determine whether or not treatment should continue for an individual who may be at increased risk of thermal injury (impaired ability to sense heat/pain) due to:
Safe operation of the NeuroStar TMS System is based on treatment parameters to reduce the potential risk of seizure. These treatment parameters observe the 1998 National Institute of Neurological Disorders and Stroke (NINDS) Workshop report guidelines and are outlined in the NeuroStar TMS System User Manual available on the FDA Advisory Committee web site. Treatment outside of these guidelines is not recommended. Additional warnings and precautions associated with the operation of the NeuroStar TMS System are also included in the User Manual (FDA, 2007).
The major adverse effects of rTMS therapy are headache and pain or discomfort at the site of application of the device. In a study reported by Janicak and colleagues (2008), aggregate safety data were obtained from a comprehensive clinical development program examining the use of rTMS in the treatment of MDD. There were 3 separate clinical protocols, including 325 individuals from 23 clinical sites in the United States, Australia, and Canada. The authors reported that rTMS was associated with a low incidence of adverse events that were mild to moderate in intensity and demonstrated a largely predictable time course of resolution.
TMS for Neurological Disorders and Conditions
Neurological (nervous system) disorders or events are conditions of the brain, spinal cord, and nerves that make up the nervous system. The nervous system controls both motor and cognitive functions of the body (that is, conscious mental activities including thinking, understanding, learning, and remembering abilities). Neurological disorders can result from any of the following: congenital or genetic conditions, environmental factors, infections, or physical injuries. These disorders can affect a person's memory, concentration, speech, and/or physical capabilities, such as breathing, learning, moving, speaking, or swallowing. There are over 600 reported neurological conditions and disorders, including but not limited to, Alzheimer's disease, ALS, chronic and neuropathic pain, epilepsy, migraine headache, multiple sclerosis, Parkinson's disease, spinal cord injury, stroke, and tinnitus. Treatment or symptomatic relief is different for each condition. The use of TMS (rTMS and sTMS) has been proposed as a treatment for neurological disorders and symptoms associated with these conditions.
Adequate trial of an antidepressant drug: The therapeutic dose range of a drug for a duration of at least 6 weeks at the maximum dose for the specific antidepressant as approved by the FDA, or, documentation exists that higher doses were not tolerated when the dose is less than the FDA-approved maximum.
Augmentation therapy: A drug regimen consisting of 1 or more drugs, which are not antidepressant drugs, added to increase the efficacy of an antidepressant drug in an adult with MDD. An example would be to add pindolol to fluoxetine.
Depression: A state of depressed mood characterized by feelings of sadness, despair and discouragement.
Depression Rating Scales: Standardized rating scales to reliably assess the range of symptoms that are most frequently observed in adults with major depression. The following rating scales comprehensively survey the type and magnitude of symptom burden present, and are therefore considered to be measures of illness severity:
Dysthymia: A type of depression involving long-term, chronic symptoms that does not disable a person but inhibits their ability to function at a high level or to feel well.
Hyperacusis: Abnormally acute hearing due to heightened irritability of the sensory neural mechanism.
Major depression: A combination of symptoms (for example, overwhelming sadness, anxiety, or "empty" feelings, hopelessness and pessimism, trouble making decisions, remembering, and concentrating) that are disabling and makes daily functioning extremely difficult if not impossible.
Major depressive disorder (MDD): Diagnostic criteria representing a major depressive episode in adults according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (APA, 2013):
Objective tinnitus: Internal sounds that may be audible to an observer with a stethoscope or other auscultation device placed over the head and neck structures near the individual's ear.
Schizophrenia: A disorder or group of disorders characterized by disturbances in form and content of thought, mood, sense of self, and relationship to the external world.
Subjective tinnitus: The false perception of noise that is heard only by an individual in the absence of acoustic stimulation of the cochlea.
Tinnitus: A perception of sound in the head when no outside sound is present; typically referred to as "ringing in the ears" or "head noise," but other forms of sound have been described such as hissing, roaring, pulsing, whooshing, chirping, whistling and clicking.
Transcranial magnetic stimulation (TMS): Involves placement of a small coil over the scalp through which a rapidly alternating current, producing a magnetic field, is passed unimpeded through the cranium and scalp; magnetic pulses are delivered one at a time in single-pulse TMS (sTMS) or as a train of pulses in repetitive TMS (rTMS).
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
|90867||Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management|
|90868||Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent delivery and management, per session|
|90869||Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent motor threshold re-determination with delivery and management|
|F32.2||Major depressive disorder, single episode, severe, without psychotic features|
|F33.2||Major depressive disorder, recurrent, severe, without psychotic features|
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
Brainsway Deep TMS System
Intermittent Theta-burst Stimulation (iTBS)
MagVita TMS Therapy
NeuroStar TMS Therapy System
Rapid2 Therapy System
Repetitive Transcranial Magnetic Stimulation (rTMS)
Single-Pulse Transcranial Magnetic Stimulation (sTMS)
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Revised||02/04/2016||Medical Policy & Technology Assessment Committee (MPTAC) review. Added conditions to the investigational and not medically necessary statement for other uses of TMS. Updated Rationale, Background, Definitions, References, Websites for Additional Information, and Index sections.|
|Revised||01/29/2016||Behavioral Health Subcommittee review. Clarified medically necessary criterion #2, 3rd bullet and added a Note for use of TMS for a recurrent episode of severe MDD if there was a history of response to TMS in a previous depressive episode as evidenced by a greater than 50% response improvement in a standard rating scale measurement. Clarified medically necessary criterion #4 for frequency of a course of TMS for acute MDD. Clarified investigational and not medically necessary statement for MDD when criteria are not met, adding "...continued treatment as maintenance therapy." Added conditions to the investigational and not medically necessary statement for other uses of TMS. Updated Rationale, Background, Definitions, References, Websites for Additional Information, and Index sections. Removed ICD-9 codes from Coding section.|
|Reviewed||01/30/2015||Behavioral Health Subcommittee review. Updated Description, Rationale, Background, and References.|
|Revised||02/07/2014||Behavioral Health Subcommittee review. Revised Subject of document. Merged contents of MED.00108 Transcranial Magnetic Stimulation for Non-Behavioral Health Indications into document. Clarified medically necessary statement for TMS for MDD (criteria #2, 1st bullet), added a Note, and revised investigational and not medically necessary statement. Added an investigational and not medically necessary statement for TMS for all other indications. Updated and reformatted Rationale section, including the FDA clearance of the Cerena sTMS device. Updated Background, Definitions, Coding, References, Websites for Additional Information, and Index sections.|
|Revised||02/08/2013||Behavioral Health Subcommittee review. Clarified medically necessary criteria (4). Added bullet that individuals with specified neurological disorders do not meet the medically necessary criteria for rTMS (e.g. cerebrovascular disease, dementia). Updated Rationale, Background, References, and Websites for Additional Information.|
|Revised||08/03/2012||Behavioral Health Subcommittee review. Added medically necessary indications for the treatment of major depressive disorder (MDD) when criteria are met. Revised investigational and not medically necessary statement. Updated the Description, Rationale, Background, Definitions, Coding, References and Index.|
|01/01/2012||Updated Coding section with 01/01/2012 CPT changes.|
|Reviewed||08/12/2011||Behavioral Health Subcommittee review. Updated Rationale and References. Updated Coding section; removed CPT 0160T, 0161T deleted 12/31/2010.|
|Revised||11/18/2010||MPTAC review. Revised the Subject of document to: Transcranial Magnetic Stimulation for Depression and Other Neuropsychiatric Disorders. Revised investigational and not medically necessary statement, adding …for all "behavioral health" indications to the Position Statement. Rationale updated to address rTMS for an individual with antidepressant medication treatment failure, including discussion of recently updated practice guidelines. Updated Description and References. Added section: Websites for Additional Information. Updated Coding section to include 01/01/2011 CPT changes.|
|Reviewed||02/25/2010||MPTAC review. Updated Rationale, Background, and References.|
|Reviewed||02/26/2009||MPTAC review. Rationale, Background, Index, and References updated to address the FDA 510(k) determination for the NeuroStar TMS Therapy device for treatment of major depressive disorder.|
|Reviewed||05/15/2008||MPTAC review. Title changed to: Transcranial Magnetic Stimulation as a Treatment of Depression and Other Neuropsychiatric Disorders. Updated Rationale and References.|
|02/21/2008||The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.|
|Reviewed||05/17/2007||MPTAC review. Rationale, Definitions, and References updated.|
|Reviewed||06/08/2006||MPTAC review. References and Coding updated.|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
Last Review Date
|BEH.00002||Transcranial Magnetic Stimulation as a Treatment of Depression and Other Psychiatric Disorders|
|WellPoint Health Networks, Inc.|
|6.01.03||Transcranial Magnetic Stimulation as a Treatment of Depression and Other Neuropsychiatric Disorders|