| Coverage Policy Manual | |
| Policy #: | 2003055 |
| Category: | Medicine |
| Initiated: | July 2003 |
| Last Review: | October 2023 |
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| Transcranial Magnetic Stimulation as a Treatment of Depression and Other Psychiatric Disorders | |
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| Description: |
Transcranial Magnetic Stimulation (TMS) was developed in 1985 and was initially a research tool used to non-invasively probe neurologic function in the cortex. The procedure consists of placing an electromagnetic coil on the scalp. A powerful AC current is passed through the coil. This results in a rapidly fluctuating intense magnetic field, which changes ionic flow in neural tissue located below the coil. The frequency of the fluctuation can also be manipulated. “Fast” TMS is delivered at frequencies of 3 to 20 Hz. By contrast, “slow” TMS is defined as a frequency of less than 1 Hz.
In late 2008, the Food and Drug Administration (FDA) approved the NeoPulse device, now known as NeuroStar® TMS, marketed by Neuronetics. Since that time, other machines have also been approved for safety. The original FDA device approval indication is for treatment of depression in adult patients who have failed one 6-week course of an antidepressant. This approval was done under a 501K submission, demonstrating safety, but not substantial equivalence in efficacy. According to FDA documents, both the BrainsWay Deep TMS systems and the NeuroStar TMS Therapy System are currently indicated for the treatment of Major Depressive Disorder in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current depressive episode. Since then, the FDA has approved a deep TMS (dTMS) unit for treatment of Obsessive-Compulsive Disorder. At this time there are multiple device approvals made by the FDA for TMs devices.
TMS has been explored in migraine, spinal cord injury, tinnitus, mania, anxiety, movement disorders, pain, OCD, auditory hallucinations in schizophrenia and multiple other disorders.
The side effects of TMS are local discomfort at the site of the magnetic field, muscle twitching and headaches. If the frequency is too great, seizures may develop. Magnetic Seizure Therapy (MST), which is using TMS to stimulate the induction of seizures, has been tried as an alternative to the electrical induction of seizures in electroconvulsive therapy (ECT). MST is currently in research and considered experimental/investigational.
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. nTMS is considered experimental and investigational.
Regulatory Status
Devices for transcranial stimulation have been cleared for marketing by the U.S. Food and Drug Administration (FDA) for diagnostic uses (FDA Product Code: GWF). A number of devices subsequently received FDA clearance for the treatment of major depressive disorder in adults who have failed to achieve satisfactory improvement from prior antidepressant medication in the current episode. Some of these devices use deep TMS or theta burst protocols. For example, the Brainsway Deep TMS system was FDA cleared for treatment resistant depression in 2013 based on substantial equivalence to the Neurostar TMS Therapy System, and the Horizon (Magstim) and MagVita (Tonica Elektronik) have FDA clearance for their theta burst protocols.
Indications were expanded to include treating pain associated with certain migraine headaches in 2013, and obsessive-compulsive disorder in 2018.
In 2014, eNeura Therapeutics received 510(k) marketing clearance for the SpringTMS® for the treatment of migraine headaches. The device differs from the predicate Cerena™ TMS device with the addition of an LCD screen, a use authorization feature, a lithium battery pack, and a smaller size. The stimulation parameters are unchanged. The sTMS Mini (eNeura Therapeutics) received marketing clearance by the FDA in 2016. FDA product code: OKP.
In August 2018, the Deep TMS System (Brainsway) was granted a de novo 510(k) classification by the FDA as an adjunct for the treatment of adult patients with obsessive-compulsive disorder. The new classification applies to this device and substantially equivalent devices of this generic type.
The NeoPulse, now known as NeuroStar® TMS, was granted a de novo 510(k) classification by the FDA in 2008. The de novo 510(k) review process allows novel products with moderate or low-risk profiles and without predicates, which would ordinarily require premarket approval as a class III device, to be down-classified in an expedited manner and brought to market with a special control as a class II device.
In 2014, the Cerena™ TMS device (eNeura Therapeutics) was granted a de novo 510(k) classification by the FDA for the acute treatment of pain associated with migraine headache with aura. Warnings, precautions, and contraindications include the following:
Repetitive TMS Devices Cleared by FDA for Major Depression, Migraine, or Obsessive-Compulsive Disorder
There are CPT category I codes for this procedure:
90867: Therapeutic repetitive transcranial magnetic stimulation treatment; planning
90868: delivery and management, per session.
90869: subsequent motor threshold re-determination with delivery and management
Code 90867 is reported once per course of treatment, and codes 90868 and 90869 cannot be reported for the same session.
Prior to 2011, there were specific CPT category III codes for this procedure:
0160T: Therapeutic repetitive transcranial magnetic stimulation treatment planning
(Pre-treatment determination of optimal magnetic field strength via titration, treatment location determination and stimulation parameter and protocol programming in the therapeutic use of high power, focal magnetic pulses for the direct, non-invasive modulation of cortical neurons)
0161T: Therapeutic repetitive transcranial magnetic stimulation treatment delivery and management, per session
(Treatment session using high power, focal magnetic pulses for the direct, non-invasive modulation of cortical neurons. Clinical evaluation, safety monitoring and treatment parameter review in the therapeutic use of high power, focal magnetic pulses for the direct, non-invasive modulation of cortical neurons.)
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Policy/ Coverage: |
Effective January 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Transcranial Magnetic Stimulation (nTMS) meets member benefit certificate primary coverage criteria there be scientific evidence of effectiveness in improving health outcomes when ALL of the following criteria are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Transcranial Magnetic Stimulation (nTMS) not meeting the criteria listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria,Transcranial Magnetic Stimulation (nTMS) not meeting the criteria listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 2023 through December 2023
Transcranial Magnetic Stimulation (nTMS) meets primary coverage criteria when ALL of the following criteria are met:
1. Requests for TMS
2. Treatment and Authorization Codes
3. Initial TMS Treatment Certification Guideline
4. Retreatment Requests for TMS:
5. Exclusions
Effective January 2022 through December 2022
Transcranial Magnetic Stimulation (nTMS) meets primary coverage criteria when all of the following criteria are met:
1. Requests for TMS
2. Treatment and Authorization Codes
3. Initial TMS Treatment Certification Guideline
Must meet criteria (1) and (2):
4. Retreatment Requests for TMS:
Must meet both (1) and (2):
5. Exclusions
Lucet Behavioral Health Services and Solutions considers the following to be exceptions to authorizing benefits. However, the member’s health plan policy contract will control if a service is eligible to be covered for benefit payments.
Effective February 2021 through December 2021
Transcranial Magnetic Stimulation (nTMS) meets primary coverage criteria when all of the following criteria are met:
1. Requests for TMS
2. Treatment and Authorization Codes
3. Initial TMS Treatment Certification Guideline
Must meet criteria (1) and (2):
4. Retreatment Requests for TMS:
Must meet both (1) and (2):
5. Exclusions
Lucet Behavioral Health Services and Solutions considers the following to be exceptions to authorizing benefits. However, the member’s health plan policy contract will control if a service is eligible to be covered for benefit payments.
Due to the length of the policy, criteria for dates of service prior to February 2021, is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
This policy was created in 2001 and updated periodically with searches of the MEDLINE database. At the time this policy was created, the U.S. Food and Drug Administration (FDA) had not cleared transcranial magnetic stimulation (TMS) as a therapeutic device for any neuropsychiatric disorder, including depression. In October 2008, the NeuroStar® TMS received U.S. Food and Drug Administration (FDA) marketing clearance as a de novo device for therapy of patients with treatment-resistant depression (TRD) who have failed one 6-week course of antidepressant medication.
Following is a summary of the key literature to date, focusing on randomized controlled trials (RCTs). The evidence review is divided by indication and by key differences in treatment protocols, specifically high-frequency left dorsolateral prefrontal cortex stimulation (DLPFC), low-frequency (1–2 Hz) stimulation of the right dorsolateral prefrontal cortex, or combined high-frequency and low-frequency stimulation.
Depression
Studies published prior to 2008 are included if the study design was a randomized sham-controlled double-blind trial that enrolled at least 40 subjects; refer to the 2008 meta-analysis by Schutter for a summary of study characteristics and stimulation parameters used in these trials (Schutter, 2009). Note that over the last decade, there has been a trend to increase the intensity, trains of pulses, total pulses per session, and number of sessions (Gross, 2007). Unless otherwise indicated in the trials described below, stimulation was set at 100% to 120% of motor threshold, clinical response was defined as an improvement of 50% or more on the Hamilton Depression Rating Scale (HAM-D), and remission was considered to be a score of 7 or less on the HAM-D.
High Frequency rTMS of the Left Dorsolateral Prefrontal Cortex for Treatment-Resistant Depression
Lam and colleagues conducted a meta-analysis of 24 randomized controlled trials (RCTs) comparing active versus sham repetitive TMS (rTMS) in patients with TRD, although there were varying definitions of TRD (Lam, 2008). This analysis calculated a number needed to treat of 6, with a clinical response in 25% of active rTMS and 9% of sham rTMS patients. Remission was reported for 17% of active rTMS and 6% of sham rTMS patients.
The largest study (23 study sites) included in the meta-analysis was a double-blind multicenter trial with 325 TRD patients randomly assigned to daily sessions of high-frequency active or sham rTMS (Monday to Friday for 6 weeks) of the left dorsolateral prefrontal cortex (DLPFC) (O’Reardon, 2007). Treatment-resistant depression was defined as failure of at least 1 adequate course of antidepressant treatment. Patients had failed an average of 1.6 treatments in the current episode, with approximately half of the study population failing to benefit from at least 2 treatments. Loss to follow-up was similar in the 2 groups, with 301 (92.6%) patients completing at least 1 post-baseline assessment and an additional 8% of patients from both groups dropping out before the 4-week assessment. Intent-to-treat (ITT) analysis showed a trend favoring the active rTMS group in the primary outcome measure (2 points on the Montgomery-Asberg Depression Rating Scale (MADRS); p=0.057) and a modest (2-point) but significant improvement over sham treatment on the HAM-D. The authors reported that after 6 weeks of treatment, subjects in the active rTMS group were more likely to have achieved remission than the sham controls (14% vs. 5%, respectively), although this finding is limited by loss to follow-up.
In 2010, George et al. reported a randomized sham-controlled trial that involved 199 patients treated with left-prefrontal rTMS (George, 2010). This was a multi-centered study involving patients with a moderate level of treatment resistance. The response rate using an ITT analysis was 14% for rTMS and 5% for sham (p=0.02). In this study, the site for stimulation was determined through pre-treatment magnetic resonance imaging (MRI). Results from Phase 2 (open treatment of non-responders) and Phase 3 (maintenance and follow-up) will be reported in the future.
Another randomized sham-controlled double-blind trial was conducted in 68 patients who had failed at least 2 courses of antidepressants (Avery, 2006). Three patients in each group did not complete the 15 treatment sessions or were excluded due to a change in medication during treatment, resulting in 91% follow-up. Independent raters found a clinical response in 31% (11 of 35) of the active rTMS patients and 6% (2 of 33) of the sham group. The average change in HAM-D was 7.8 for the active group and 3.7 for the control group. The Beck Depression Inventory (BDI) decreased by 11.3 points in the active rTMS group and 4.8 points in controls. Remission was observed in 7 patients (20%) in the active rTMS group and 1 patient (3%) in the control group. Regarding effectiveness of blinding; 15% of subjects in each group guessed that they were receiving active TMS after the first session. After the 15th session, 58% of the rTMS group and 43% of the sham group guessed that they had received active TMS; responders were more likely than non-responders (85% vs. 42%, respectively) to think that they had received the active treatment. The 11 responders were treated with antidepressant medication and followed up for 6 months. Of these, 1 was lost to follow-up, 5 (45%) relapsed, and 5 (45%) did not relapse.
Rossini and colleagues randomly assigned 54 patients who had failed at least 2 adequate courses of antidepressants to sham control or active rTMS at 80% or 100% of motor threshold (MT) for 10 sessions over a 2-week period (Rossini, 2005). Double-blind evaluation found an intensity-dependent response with 6% (1 of 16) of the sham, 28% (5 of 18) of the 80% MT, and 61% (11 of 18) of the 100% MT groups showing improvement of 50% or more over a 5-week evaluation. All of the patients reported that they were unaware of the differences between sham and active stimulation.
In a 2008 report, Mogg et al. randomly assigned 59 patients with major depression who had failed at least 1 course of pharmacotherapy for the index depressive episode (Mogg, 2008). In this study population, 78% of the patients had failed 2 treatment courses and 53% had failed 3. The sham coil, which was provided by Magstim, was visually identical to the real coil and made the same clicking sound but did not deliver a magnetic field to scalp or cortex. Blinded assessments were performed 2 days after the fifth and final (tenth) sessions (97% follow-up), with additional assessments at 6 weeks (90% follow-up) and 4 months (83% follow-up). The mean group difference was estimated to be 0.3 points in HAM-D scores for the overall analysis. Interpretation of this finding is limited, since 7 sham patients (23%) were given a course of real rTMS after the 6-week assessment and analyzed as part of the sham group in the ITT analysis. The study was powered to detect a difference of 3.5 points in the HAM-D between the active and sham groups, and the 2.9-point group difference observed at the end of treatment was not significant. A higher percentage of patients in the active rTMS group achieved remission criteria of 8 points or less on the HAM-D (25% vs.10% control, respectively), and there was a trend for more patients to achieve clinical response in the active rTMS group (32% vs.10%, respectively, p=0.06). All of the 12 patients who met the criterion for clinical response (9 active and 3 sham) thought that they had received real rTMS, with more patients in the active group (70%) than the sham group (38%) guessing that they had received the real treatment. Interpretation of this finding is also limited, since the reason the subjects guessed that they had active treatment was not reported, and the subjects were not asked to guess before they began to show a clinical response.
A small double-blind randomized trial from 2009 suggests that specific targeting of Brodmann areas 9 and 46 may enhance the anti-depressant response compared with the standard targeting procedure, i.e., measuring 5 cm anterior from the motor cortex (Fitzgerald, 2009). Fifty-one patients who had failed at least two 6-week courses of antidepressant medication (average 5.7 failed courses) were randomly assigned to a standard localization procedure or to structural magnetic resonance imaging (MRI)-aided localization for 3 weeks (with 1-week extension if >25% reduction on the MADRS). Six patients in the targeted group and 10 in the standard group withdrew due to lack of response. A single patient in the targeted group and 5 in the standard group withdrew for other reasons, resulting in 17 patients in the targeted group and 12 in the standard group continuing for the full 4 weeks of treatment. To adjust for the imbalance in discontinuation rates, a mixed model statistical analysis was used. There was a significant difference between the groups in the overall mixed model analysis, and planned comparisons showed significant improvement in MADRS scores for the targeted group at 4 weeks. Response criteria were met by 42% of the targeted group and 18% of the standard group. Remission criteria were met by 30% of the targeted group and 11% of the standard group. Although encouraging, additional trials with a larger number of subjects are needed to evaluate this procedure.
Several studies have compared the outcomes of rTMS with those from electroconvulsive therapy. In one study, 40 patients with nonpsychotic major depression were treated over the course of 1 month (20 total sessions) and evaluated with the HAM-D, in which a response was defined as a 50% decrease with a final score of less than or equal to 10 (Grunhaus, 2003). There was no difference in response rate between the 2 groups; 12 of 20 responded in the electroconvulsive therapy group compared to 11 of 20 in the magnetic stimulation group. A United Kingdom National Institute for Health Research health technology assessment compared efficacy and cost effectiveness of rTMS and electroconvulsive therapy (McLoughlin, 2007). Forty-six patients who had been referred for electroconvulsive therapy were randomly assigned to either electroconvulsive therapy (average of 6.3 sessions) or a 15-day course (5 treatments per week) of rTMS of the left DLPFC. Electroconvulsive therapy resulted in a 14-point improvement in the HAM-D and a 59% remission rate. Repetitive TMS was less effective than electroconvulsive therapy (5-point improvement in HAM-D and a 17% remission rate). Another study reported no significant difference between electroconvulsive therapy and rTMS in 42 patients with TRD; however, response rates for both groups were low. (14) The number of remissions (score of 7 or less on the HAM-D) totaled 3 (20%) for electroconvulsive therapy and 2 (10%) for rTMS.
Low Frequency rTMS of the Right Dorsolateral Prefrontal Cortex or Bilateral Stimulation for Treatment-Resistant Depression
Fitzgerald et al. randomly assigned 60 patients who had failed a minimum of at least two 6-week courses of antidepressant medications into 1 of 3 groups; high frequency left rTMS, low frequency right rTMS, or sham stimulation over 10 sessions (Fitzgerald, 2003). All patients who entered the study completed the double-blind randomized phase, which showed no difference between the 2 active treatments (left: 13.5% reduction; right: 15% reduction) and greater improvements in the MADRS scores compared to the sham group (0.76% reduction). Only 1 patient achieved 50% improvement during the initial 2 weeks. Then, only the subjects who showed at least 20% improvement at the end of the 10 sessions (15 active and 2 sham) continued treatment. Patients who did not respond by at least 20% were switched to a different active treatment. From week 2 to week 4, there was greater improvement in the low frequency right rTMS group compared with the high frequency left rTMS group (39% vs. 14% improvement in MADRS, respectively). Seven patients (18% of 40) showed a clinical response of greater than 50% by the end of the 4 weeks.
In a subsequent study, Fitzgerald and colleagues randomly assigned 50 patients with TRD to sequential bilateral active or sham rTMS (Fitgerald, 2006). After 2 weeks of treatment, 3 subjects had dropped out of the sham treatment group, and there was a slight but non-significant improvement favoring the active group for the MADRS (26.2 vs. 30.9, respectively) and the BDI (18.3 vs. 21.6, respectively). At this time point, 60% of subjects receiving active rTMS and 50% of subjects receiving sham treatment guessed that they were in the active group. The clinical response was reported by subjects as the major reason for their guess, with 11 of 13 responders (9 active and 2 sham) guessing that they were in the active group. As in the earlier study, only the subjects who showed at least 20% improvement at the end of each week continued treatment. Treatment on week 3 was continued for 15 subjects in the active group and 7 subjects in the sham group. By week 6, 11 subjects in the active rTMS remained in the study, with no control subjects remaining. Final ratings for the 11 subjects who continued to respond through week 6 were 8.9 on the MADRS and 9.2 on the BDI.
Another multicenter double-blind trial randomly assigned 130 patients with TRD to 5 sessions per week of either 1- or 2-Hz rTMS over the right dorsolateral prefrontal cortex (Fitgerald, 2006). Sixty-eight patients (52%) completed 4 weeks of treatment; there was an approximate 30% improvement in depression scales, with no differences between the 1- or 2-Hz groups. Due to the potential for placebo effects for this type of intervention, the absence of a sham control group limits interpretation.
A small randomized, sham-controlled trial was published in 2010 that involved either right or left rTMS in 48 patients with TRD (Triggs, 2010). Overall reductions in the HAM-D-24 from baseline to 3 months were not significantly different between rTMS and sham treatment groups. In this small study, right cranial stimulation was significantly more effective than left cranial stimulation (sham or rTMS).
rTMS as an Adjunctive Treatment for Moderate to Severe Depression
Schutter conducted a meta-analysis of 30 double-blind randomized sham-controlled trials (1,164 patients) of high-frequency rTMS over the left dorsolateral prefrontal cortex in patients with major depression. (3) The pooled weighted mean effect size for treatment was calculated with Hedges g, a standardized mean difference that adjusts for sampling variance, to be 0.39 (95% confidence interval [CI]: 0.25–0.54), which is considered moderate. For 27% of the population, rTMS was used as a primary/adjunctive treatment; 3 trials were included that used rTMS as a primary/adjunctive treatment for depression and enrolled more than 40 subjects (Koerselman, 2004; Rumi, 2005; Herwig, 2007). Repetitive TMS has also been examined in patients with clinical evidence of cerebrovascular disease and late-life depression (Jorge, 2008).
A 2012 study examined the efficacy of ultra-high-frequency (30 Hz) rTMS over the left prefrontal cortex in moderate to severely depressed patients who were taking medication (ullrich, 2012). Sham treatment consisted of low frequency stimulation to the left prefrontal cortex. No benefit of rTMS for depressive symptoms was found when lithium was added as a covariate. Ultra-high-frequency rTMS was found to improve performance on the trail-making test, which covaried with improvement of psychomotor retardation.
Additional research on whether adjunctive rTMS can improve response to pharmacologic treatment as a first-line therapy is needed.
Maintenance Therapy
Fitzgerald et al. reported a prospective open-label trial of clustered maintenance rTMS for patients with refractory depression (Fitgerald, 2012). All patients had received a second successful course of rTMS following relapse and were then treated with monthly maintenance therapy consisting of 5 rTMS treatments over a 2.5-day period (Friday evening, Saturday and Sunday). Patients were treated with maintenance therapy of the same type that they had initially received (14 high frequency to the left dorsolateral prefrontal cortex, 12 low frequency to the right dorsolateral prefrontal cortex, and 9 bilateral). 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. Of 35 patients, 25 (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.
Janicak and colleagues reported on assessment of relapse during a multisite, open-label study (Janicak, 2010). In this study, patients who met criteria for partial response during either a sham–controlled or open-label phase of a prior study were tapered from rTMS and simultaneously started on maintenance antidepressant monotherapy. They were then followed for 24 weeks. Ten of 99 patients relapsed. Thirty-eight patients had symptom worsening, and 32 of these (84%) had symptomatic benefit with adjunctive rTMS.
A retrospective study that included maintenance rTMS was reported by Connolly et al. in 2012 (Connolly, 2012). Out of the first 100 cases treated at their institution, 42 received maintenance rTMS. Most of the patients had failed more than 1 adequate antidepressant trial and were treated with high-frequency rTMS over the dorsolateral prefrontal cortex. Low-frequency rTMS to the right dorsolateral prefrontal cortex was given in patients with a family or personal history of seizures and in some patients who were also receiving high-frequency rTMS. The response rate was 50.6% of the first 100 cases and the remission rate was 24.7%. Maintenance treatment (42 patients) 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 patients (62%) maintained their response.
Additional data are needed related to durability of effect and to maintenance phases.
Alzheimer’s Disease
Ahmed et al. randomized 45 patients with probable Alzheimer’s disease to 5 sessions of bi-lateral high-frequency rTMS, bi-lateral low-frequency rTMS, or sham TMS over the dorsolateral prefrontal cortex (Ahmed, 2012). Thirty-two patients had mild to moderate dementia and 13 had severe dementia. There were no significant differences between groups at baseline. Measures of cortical excitability immediately after the last treatment session showed that treatment with high-frequency rTMS reduced the duration of transcallosal inhibition. At 3 months after treatment, the high-frequency rTMS group improved significantly more than the other 2 groups in standard rating scales, and subgroup analysis showed that this was due primarily to improvements in patients with mild/moderate dementia. Patients in the subgroup of mild to moderate dementia who were treated with high-frequency rTMS improved from 18.4 to 22.6 on the Mini Mental State Examination (MMSE), from 20.1 to 24.7 on the Instrumental Daily Living Activity (IADL) scale and from 5.9 to 2.6 on the Geriatric Depression Scale (GDS).
Rabey et al. reported an industry-sponsored randomized double-blind trial of rTMS with cognitive training (NeuroAD system) in15 patients with probable mild to moderate Alzheimer’s disease (Rabey, 2012). Patients received 5 sessions per week for 6 weeks over 6 different brain areas, followed by biweekly sessions for 3 months. Specific cognitive tasks were designed for the 6 targeted brain regions. These included syntax and grammar for Broca’s area, comprehension and categorization for Wernicke’s area, action naming, object naming and spatial memory tasks for the right and left dorsolateral prefrontal cortex, and spatial attention tasks for the right and left somatosensory association cortex. After 6 weeks of treatment, there was an improvement in the average Alzheimer Disease Assessment Scale, cognitive subsection (ADAS-cog) score of 3.76 points in the rTMS group compared to 0.47 in the placebo group. After 4.5 months of treatment, the ADAS-cog score in the rTMS group had improved by 3.52 points compared to a worsening of 0.38 in the placebo group. The Clinical Global Impression of Change improved significantly by an average of 3.57 after 6 weeks and 3.67 after 4.5 months compared to 4.25 and 4.29, respectively, in the placebo group.
Attention-Deficit/Hyperactivity Disorder
In 2012, Weaver et al. reported a randomized sham-controlled crossover study of rTMS in 9 adolescents/young adults with attention-deficit/ hyperactivity disorder (ADHD) (Weaver, 2012). rTMS was administered in 10 sessions over 2 weeks, with 1 week of no TMS between the active and sham phases. The clinical global impression and ADHD-IV scales improved in both conditions over the course of the study, with no significant differences between the active and sham phases.
Bulimia Nervosa
In 2008, Walpoth et al. reported no evidence of efficacy of rTMS in a small trial (n=14) of patients with bulimia nervosa (Walpoth, 2008).
Dysphagia
rTMS for the treatment of dysphagia following stroke has been examined in small randomized controlled trials. One study randomized 26 patients to rTMS or sham over the affected esophageal motor area of the cortex (Khedr, 2009). Ten minutes of rTMS over 5 days reduced both dysphagia on the Dysphagic Outcome and Severity scale and disability measured by the Barthel Index. There was a trend for improved hand grip strength in the rTMS group. Blinded assessment showed that the effects were maintained at 1 month and 2 month follow-up. Another study randomized 30 patients with dysphagia following stroke or traumatic brain injury to high-frequency rTMS, low-frequency rTMS, or sham stimulation (Kim, 2011). Active or sham rTMS was administered bilaterally over the anterolateral scalp over a period of 2 weeks. Swallowing scale scores improved in both the low-frequency and sham groups. Improvement in videofluoroscopic evaluation was greater in the low-frequency rTMS group than the other 2 groups. Blinding of evaluators was not described. Study in a larger number of subjects is needed to determine the efficacy of this treatment with greater certainty.
Epilepsy
In 2012, Sun et al. reported a randomized double-blind controlled trial of low-frequency rTMS to the epileptogenic zone for refractory partial epilepsy (Sun, 2012). Sixty patients were randomized into 2 groups; one group received 2 weeks of rTMS at 90% of resting motor threshold and the other group received rTMS at 20% of resting motor threshold. Outcomes were measured for 8 weeks after the end of treatment. With intent-to-treat analysis, high-intensity rTMS resulted in a significant decrease in seizures when compared to baseline (from 8.9 per week at baseline to 1.8 per week at follow-up) and when compared to low-intensity rTMS (from 8.6 at baseline to 8.4 per week at follow-up). High-intensity rTMS also decreased interictal discharges (from 75.1 to 33.6 per hour) and improved ratings on the Symptom Checklist-90. These initial results are promising, but require substantiation in additional trials.
Fibromyalgia
A 2012 systematic review included 4 studies on transcranial direct current stimulation and 5 on rTMS for treatment of fibromyalgia pain (Marlow, 2012). Three of the 5 trials were considered to be high quality. Four of the 5 were double-blind randomized controlled trials; the fifth included study was a case series of 4 patients who were blinded to treatment. Quantitative meta-analysis was not conducted due to variability in brain site, stimulation frequency/intensity, total number of sessions, and follow-up intervals, but 4 of the 5 studies on rTMS reported significant decreases in pain. Greater durability of pain reduction was observed with stimulation of the primary motor cortex compared to the dorsolateral prefrontal cortex.
One of the studies included in the systematic review was a small 2011 trial that was conducted in the U.S. by Short et al. (Short, 2011) Twenty patients with fibromyalgia, defined by the American College of Rheumatology criteria, were randomized to 10 sessions of left prefrontal rTMS or sham TMS along with their standard medications. At 2 weeks after treatment, there was a significant change from baseline in average visual analog scale (VAS) for pain in the rTMS group (from 5.60 to 4.41) but not in the sham-treated group (from 5.34 to 5.37). There was also a significant improvement in depression symptoms in the active group compared to baseline (from 21.8 to 14.10) but not in the sham group (from 17.6 to 16.4). There were no statistically significant differences between the groups in this small trial.
Additional study is needed to determine effective treatment parameters in a larger number of subjects and to evaluate durability of the effect.
Obsessive Compulsive Disorder
Two small (n=18 and 30) randomized sham-controlled trials found no evidence of efficacy for treatment of obsessive compulsive disorder (OCD), although another small sham-controlled trial (n=21) reported promising results with bilateral stimulation of the supplementary motor area (Sachdev, 2007; Mantovani, 2010; Mansur, 2011).
Panic Disorder
In 2013, Mantovani et al. reported a randomized double-blind sham-controlled trial of low-frequency rTMS to the right dorsolateral prefrontal cortex in 21 patients with panic disorder with comorbid major depression (Mantovani, 2013). Response was defined as a 40% or greater decrease on the panic disorder severity scale (PDSS) and a 50% or greater decrease on the HAM-D. After 4 weeks of treatment, the response rate for panic was 50% with active rTMS and 8% with sham. There was no significant difference in the response rate for depressive symptoms (25% active rTMS vs. 8% for sham). After an additional 4 weeks of open-label treatment, the response rate was 67% for panic and 50% for depressive symptoms. Five of 12 responders returned for 6-month follow-up and showed sustained improvement.
Parkinson Disease
A systematic review from 2009 included 10 randomized controlled trials with a total of 275 patients with Parkinson disease (Elahi, 2009). Seven of the studies were double-blind, one was not blinded and 2 of the studies did not specify whether the raters were blinded. In studies that used high-frequency rTMS there was a significant improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) with a moderate effect size of -0.58. For low-frequency rTMS, the results were heterogeneous and did not significantly reduce the UPDRS. The analyzed studies varied in outcomes reported, rTMS protocol, patient selection criteria, demographics, stages of Parkinson disease and duration of follow-up, which ranged from immediate to 16 weeks after treatment
In 2012, Benninger et al. reported a randomized double-blind sham-controlled trial of brief (6 sec) very-high-frequency (50 Hz) rTMS over the motor cortex in 26 patients with mild to moderate Parkinson disease (Benninger, 2012). Eight sessions of 50 Hz rTMS did not improve gait, bradykinesia, or global and motor scores on the UPDRS compared to the sham-treated group. Activities of daily living were significantly improved a day after the intervention, but the effect was no longer evident at 1 month after treatment. Functional status and self-reported well-being were not affected by the treatment. No adverse effects of the very-high-frequency stimulation were identified.
Another study from 2012 randomized 20 patients with Parkinson disease to 12 brief sessions (6 min) of high-frequency (5-Hz) rTMS or sham rTMS over the leg area of the motor cortex followed by treadmill training (Yang, 2013). Blinded evaluation showed a significant effect of rTMS combined with treadmill training on neurophysiological measures, and change in fast walking speed and the timed up and go task. Mean treadmill speed improved to a similar extent in the active and sham rTMS groups.
Additional study with a larger number of subjects and longer follow-up is needed to determine if rTMS improves motor symptoms in patients with Parkinson disease.
Postpartum Depression
Myczkowski et al. conducted a double-blind sham-controlled study of 14 patients with postpartum depression randomized to 20 sessions of active or sham rTMS over the left dorsolateral prefrontal cortex (Myczkowski, 2012). A positive response to treatment was defined as a reduction of at least 30% in the HAM-D and Edinburgh Postnatal Depression Scale (EPDS). At 2 weeks after the end of treatment, the active rTMS group showed significant improvements in the HAM-D, Global Assessment Scale, Clinical Global Impression and Social Adjustment Scale. The difference in the EPDS (reduction of 39.4% vs. 6.2% for sham) did not reach statistical significance in this small study, and there were marginal cognitive and social improvements. In addition, results were presented as mean values, rather than by the proportion of patients who showed clinically meaningful improvement.
Posttraumatic Stress Disorder
The efficacy of rTMS for posttraumatic stress disorder (PTSD) has been examined in several small randomized controlled trials.
A 2004 study randomized 24 patients with PTSD to 10 sessions of low-frequency (1 Hz), high-frequency (10 Hz) or sham rTMS over the right dorsolateral prefrontal cortex (Cohen, 2004). Blinded assessment 2 weeks after the intervention found that high-frequency rTMS improved the self-reported PTSD checklist (PCL) by 29.3%, the clinician evaluation on the Treatment Outcome PTSD scale by 39.0%, the HAM-D by 25.9%, and the Hamilton Anxiety Rating Scale by 44.1%. Scores for the sham and low-frequency group were not significantly improved.
In 2012, Watts et al reported a double-blind trial with 20 patients randomized to low -frequency rTMS or sham over the right dorsolateral prefrontal cortex (Watts, 2012). Blinded evaluation at the end of treatment showed clinically significant improvements in the Clinician Administered PTSD Scale (CAPS) and the PCL compared with sham. Depressive and anxiety symptoms also improved in the rTMS group. Six of the 10 rTMS patients showed a degradation of symptoms between the immediate post-treatment assessment and the 2-month post-treatment follow-up.
In another double-blind trial, 30 patients with PTSD were randomized to deep, high-frequency rTMS after brief exposure to a script of the traumatic event, rTMS after a script of a non-traumatic event, or sham stimulation after a brief script of the traumatic event (Isserles, 2012). Patients received 3 treatment sessions per week for 4 weeks, and response was defined as a 50% or greater improvement in CAPS score. Intent-to-treat analysis showed a significant improvement in the total CAPS score in the exposure + stimulation group (24.3) compared to rTMS alone (7.9) or traumatic exposure with sham rTMS (9.1). The greatest improvement was in the intrusive component of the CAPS scale. Heart rate responses to the traumatic script were also reduced over the 4 weeks of treatment. The proportion of patients who showed a response to treatment was not reported and the durability of the response was not assessed.
Conclusions. Several small randomized controlled trials have reported improvement of PTSD with rTMS over the right dorsolateral cortex. Results of high-frequency versus low-frequency stimulation are conflicting, and durability of the response has not been assessed. Additional study is needed.
Schizophrenia
One of the largest areas of TMS research outside of depressive disorders is the treatment of auditory hallucinations in schizophrenia resistant to pharmacotherapy. In 2011, a technology assessment reviewed five meta-analyses along with randomized controlled trials (RCTs) in which measurements were carried out beyond the treatment period (TEC, 2011). A meta-analysis of the effect of TMS on positive symptoms of schizophrenia (hallucinations, delusions, and disorganized speech and behavior) did not find a significant effect of TMS (Freitas, 2009). Four meta-analyses that looked specifically at auditory hallucinations showed a significant effect of TMS (Freitas, 2009; Tranulis, 2008; Aleman, 2007; Slotema, 2010). It was noted that outcomes were evaluated at the end of treatment, and the durability of the effect is unknown.
A 2012 meta-analysis included 17 randomized double-blind sham-controlled trials (n=337) of the effect of rTMS on auditory hallucinations (Slotema, 2012). When measured at the end of treatment, the mean effect size of rTMS directed at the left temporoparietal area was 0.40 (moderate), and the effect size of rTMS directed at all brain regions was 0.33 (small). For the 5 trials that examined outcomes of rTMS one month after treatment, the effect was no longer significant.
Blumberger et al. examined the efficacy of priming stimulation (6 Hz) prior to low-frequency stimulation (1 Hz) of Heschl’s gyrus within the left temporoparietal cortex (Blumberger, 2012). Fifty-four patients with medication-resistant auditory hallucinations were randomized to receive 20 sessions of left-sided stimulation, priming, or sham rTMS. Response rates on the Psychotic Symptoms Rating Scale did not differ between the 3 treatment groups.
A small (n=18) double-blind randomized sham-controlled trial from 2012 found no significant effect of deep rTMS with an H1 coil on auditory hallucinations (Rosenberg, 2012).
Conclusions: The evidence on rTMS for the treatment of auditory hallucinations in schizophrenia consists of a number of small randomized controlled trials. Evidence to date shows small to moderate effects on hallucinations when measured at the end of treatment, but evidence suggests that the effect is not durable.
Stroke
Hsu et al. reported a meta-analysis of the effect of rTMS on upper limb motor function in patients with stroke in 2012 (Hsu, 2012). Eighteen randomized controlled trials with a total of 392 patients were included in the meta-analysis. Most of the studies were double blind (n=11) or single blind (n=3). Eight studies applied low frequency (1 Hz) rTMS over the unaffected hemisphere, 5 applied high frequency (5 Hz) rTMS over the affected hemisphere, and 2 used both low- and high-frequency stimulation. Outcomes included kinematic motion analyses (5 trials), hand grip (2 trials), and the Wolf Motor Function Test (2 trials). Meta-analysis of results showed a moderate effect size (0.55) for rTMS on motor outcome, with a greater effect size of rTMS in patients with subcortical stroke (mean effect size, 0.73) compared to non-specified lesion sites (mean effect size, 0.45), and for studies applying low-frequency rTMS (mean effect size, 0.69) compared to high-frequency rTMS (effect size, 0.41). Effect size of 0.5 or greater was considered to be clinically meaningful.
In 2012, Seniow et al. reported a randomized double-blind sham-controlled pilot study of low-frequency rTMS (1 Hz at 90% of resting motor threshold for 30 min) to the contralesional motor cortex combined with physiotherapy in patients with moderate upper extremity hemiparesis following stroke (Seniow, 2012). Power analysis indicated that a sample size of 129 patients would be required to detect changes in functional motor ability, but only 40 patients met eligibility criteria over the 4 years of the study. Blinded analysis showed no significant difference in hand function or level of neurological deficit between active or sham rTMS when measured either immediately after the 3-week intervention or at 3-month follow-up.
Conclusions. Evidence consists of a number of randomized controlled trials and a meta-analysis of the effect of rTMS on recovery from stroke. Results are conflicting, and efficacy may depend on the location of the stroke and frequency of the rTMS. Additional study is needed to determine whether rTMS facilitates standard physiotherapy in patients with stroke.
Summary
Transcranial magnetic stimulation (TMS) involves placement of a small coil over the scalp; passing a rapidly alternating current through the coil wire, which produces a magnetic field that passes unimpeded through the scalp and bone, resulting in electrical stimulation of the cortex. Evidence on repetitive transcranial magnetic stimulation ( rTMS) for depression and other psychiatric/neurologic disorders is insufficient to permit conclusions regarding the effect of this technology on health outcomes. The literature on rTMS for treatment-resistant depression is the most developed and includes a number of double-blind randomized sham-controlled short-term trials. Results of these trials show mean improvements of uncertain clinical significance across groups as a whole. The percentage of subjects who show a clinically significant response is reported at approximately 2 to 3 times that of sham controls, with approximately 15% to 25% of patients meeting the definition of clinical response (Connolly, 2012).
The treatment protocols are time intensive, and the patients who are most likely to benefit from treatment are not currently known. Importantly, a number of open issues need to be addressed before this procedure is widely implemented. The available studies do not establish that rTMS is as good as available alternatives, as the vast majority of the trials do not compare rTMS to alternative active treatments. Alternative treatments include a variety of different medication regimens and psychological talk therapy, both of which have demonstrated efficacy. In addition, further research is needed to determine which of the locations and treatment parameters examined to date 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 anti-depressant medications, and to provide some information about whether maintenance treatments are needed, and which types of maintenance treatment are most effective.
For other psychiatric/neurologic conditions, the evidence is insufficient to determine whether rTMS leads to improved outcomes. The available clinical trials are small and report mixed results for a variety of conditions other than depression. There are no large, high-quality trials for any of these other conditions.
Practice Guidelines and Position Statements
The Canadian Network for Mood and Anxiety Treatments (CANMAT) updated their clinical guidelines on neurostimulation therapies for the management of major depressive disorder in adults (Kennedy, 2009). The evidence reviewed supported electroconvulsive therapy (ECT) as a first-line treatment under specific circumstances; when used in patients who have failed to respond to one or more adequate antidepressant medication trials, ECT response rates have been estimated to be 50–60%. The guidelines considered rTMS to be a safe and well-tolerated treatment, with no evidence of cognitive impairment. Based on the 2008 meta-analysis by Lam et al., (Lam, 2008) response (25%) and remission (17%) rates were found to be greater than sham but lower than for other interventions for TRD, leading to a recommendation for rTMS as a second-line treatment. The guidelines indicated that there is a major gap in the evidence base regarding maintenance rTMS, as only one open-label case series was identified.
The Movement Disorder Society published an evidence-based review of treatments for the non-motor symptoms of Parkinson’s disease in 2011 (Seppi, 2011). The review found insufficient evidence to make adequate conclusions on the efficacy rTMS for the treatment of depression in Parkinson’s disease.
2014 Update
A literature search conducted through February 2014 did not reveal any new information that would prompt a change in the coverage statement.
2015 Update
This policy was reviewed with a literature search using the MEDLINE database through February 2015. There was no new RCTs or other publications identified that would prompt a change in the coverage statement.
2015 Update- Addendum
The available literature on the use of rTMS for the treatment of depression was reviewed again through August 2015 focusing on the use of rTMS in the treatment of depression. The coverage statement has been changed as a result of the review. The following is a summary of the key identified literature.
A 2013 systematic review by Berlim et al identified 7 RCTs with a total of 294 patients that directly compared rTMS and ECT treatment for patients with depression (Berlim, 2013). After an average of 15.2 sessions of high-frequency rTMS over the left DLFPC, 33.6% of patients were classified as remitters. This compared to 52% of patients who were classified as remitters following an average of 8.2 ECT sessions. The pooled odds ratio was 0.46, indicating a significant difference in outcome favoring ECT. There was no significant difference in dropout rates for the 2 treatments.
In 2014, Dunner et al reported 1 year follow-up with maintenance therapy from a large multicenter observational study (42 sites) of rTMS for patients with TRD (Dunner, 2014). A total of 257 patients agreed to participate in the follow-up study out of 307 who were initially treated with rTMS. Of these, 205 completed the 12-month follow-up, and 120 patients had met the Inventory of Depressive Symptoms-Self Report (IDS-SR) response or remission criteria at the end of treatment. Ninety-three of the 257 patients (36.2%) who enrolled in the follow-up study received additional rTMS (mean of 16.2 sessions). Seventy-five of the 120 patients (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 through follow-up.
A group of European experts was commissioned to establish evidence-based guidelines on the therapeutic use of rTMS. The guidelines included evidence published up until March 2014 (Lefaucheur, 2014). For most indications there was an absence of sufficient evidence and the committee could provide no recommendation. Indications which had a recommendation of a definite effect were neuropathic pain and depression. Indications which had a recommendation for a possible or probable effect included CRPS, Parkinson disease, motor stroke, hemispatial neglect, epilepsy, tinnitus, anxiety disorders, auditory hallucinations, negative symptom of schizophrenia, addiction and craving.
In summary, the literature on repetitive TMS (rTMS) for treatment-resistant depression (TRD) includes numerous double-blind, randomized sham-controlled short-term trials. Results of these trials show mean improvements of uncertain clinical significance across groups as a whole. The percentage of subjects who show a clinically significant response is reported at approximately 2 to 3 times that of sham controls, with approximately 15% to 25% of patients meeting the definition of clinical response. Based on the short-term benefit observed in randomized controlled trials, clinical input, and the lack of alternative treatments aside from electroconvulsive therapy (ECT) in patients with treatment resistant depression, rTMS meets primary coverage criteria in patients with TRD who meet specific criteria.
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement. A summary of the key identified literature is included below.
In 2016, the Health Quality Ontario published a systematic review of left DLPFC rTMS for TRD (Health Quality Ontario, 2016). Reviewers included 23 RCTs (n=1156 patients) that compared rTMS with sham and 6 RCTs (n=266 patients) that compared rTMS with ECT. In 16 studies, patients received rTMS in addition to antidepressant medication. Seven studies used intensities of less than 100% motor threshold and the definition of remission in the included studies varied (from ≤7 to ≤10 on the HAM-D). Meta-analysis showed a statistically significant improvement in depression scores compared with sham, with a weighted mean difference (WMD) of 2.31. However, this was smaller than the prespecified clinically important difference of 3.5 points on the HAM-D, and the effect size was small (0.33; 95% confidence interval [CI], 0.17 to 0.5; p<0.001). Subgroup analysis showed a larger and clinically significant treatment effect in the rTMS studies using 20 Hz with shorter train duration compared with other rTMS techniques (WMD=4.96; 95% CI, 1.15 to 8.76; p=0.011). Secondary analyses showed rTMS demonstrated a statistically greater rate of response among 20 studies (pooled relative risk, 1.72; 95% CI, 1.13 to 2.62; p=0.11) as well as statistically greater rate of remission among 13 studies (pooled relative risk, 2.20; 95% CI, 1.44 to 3.38, p<0.001). For the 6 trials that compared rTMS with ECT, the WMD of 5.97 was both statistically and clinically significant in favor of ECT. The relative risk for remission and response rates are
shown in, which while favoring ECT were not statistically significant. Remission and relapse rates at the 6-month follow-up were reported in 2 studies including 40 and 46 subjects, comparing rTMS and ECT. While 1 study reported a slightly higher remission rate for ECT (27.3%) than for rTMS (16.7%), the other study did not find a significant difference between ECT and rTMS for mean depression scores at 3 or 6 months, but did note relapses were less frequent for ECT. Statistical comparisons were either not significant or not available, limiting the interpretation of these findings.
Epilepsy
A 2016 Cochrane review by Chen et al included 7 RCTs on rTMS for epilepsy, 5 of which were completed studies with published data (Chen, 2016). The total number of participants was 230. All studies had active or placebo controls, and four were double-blinded. However, a meta-analysis could not be conducted due to differences in the design, interventions, and outcomes of the studies. Therefore, a qualitative synthesis was performed. For the outcome of seizure rate, 2 studies showed a significant reduction and 5 studies did not. Of the 4 studies evaluating the mean number of epileptic discharges, 3 studies showed a statistically significant reduction in discharges. Adverse events were uncommon and mild, involving headache, dizziness, and tinnitus. There were no significant changes in medication use.
Fibromyalgia
In 2017, Saltychev and Laimi published a meta-analysis of rTMS for the treatment of patients with Fibromyalgia (Saltychev, 2017). The meta-analysis included 7 sham-controlled double-blinded controlled trials with low risk of bias. The sample sizes of the trials ranged from 18 to 54. Five of the studies provided high-frequency stimulation to the left primary motor cortex, and the others were to the right or left DLPFC. The number of sessions ranged from 10 to 24, and follow-up ranged from immediately after treatment to 3 months posttreatment. In the pooled analysis, pain severity decreased after the last simulation by 1.2 points (95% CI, -1.7 to -0.8 points) on a 10-point numeric rating scale, while pain severity measured at 1 week to 1 month after the last simulation decreased by 0.7 points (95% CI, -1.0 to -0.3 points). Both were statistically significant but not considered clinically significant, based on a minimal clinically important difference of 1.5 points.
Obsessive-Compulsive Disorder
A 2016 systematic review by Trevizol et al included 15 RCTs (total N=483 patients) that compared active with sham rTMS for OCD (Trevizol, 2016). All studies were sham-controlled and double-blinded. Sample sizes in the trials were small-to-moderate, ranging from 18 to 65 patients (mean sample size, 16.1 patients). Seven studies used low-frequency stimulation and 8 studies used high-frequency stimulation. The cortical regions varied among the studies, targeting the supplementary motor area, orbitofrontal cortex, or left, right, or bilateral DLPFC. The effect size for active stimulation was modest at 0.45 (95% CI, 0.2 to 0.71). The SMD was 2.94 (95% CI, 1.26 to 4.62). Regression did not identify any significant factors. There was no evidence of publication bias from funnel plots.
Posttraumatic Stress Disorder
In 2016, Trevizol et al published a systematic review on the efficacy of rTMS for posttraumatic stress disorder (PTSD) (Trevizol, 2016). Five sham-controlled randomized trials (total N=118 patients) were included. Most trials used stimulation of the right DLPFC, though some delivered rTMS to the left DLPFC or bilaterally. Three trials used high-frequency stimulation while one used low-frequency stimulation and another compared high- with low-frequency stimulation; the percent motor threshold ranged from 80% to 120%. Some trials provided rTMS in combination with a scripted narrative of the traumatic event, and different PTSD scales were used. In a meta-analysis, active rTMS was found to be superior to sham (SMD=0.74; 95% CI, 0.06 to 1.42), although heterogeneity of the trials was high.
Stroke
In 2016, Graef et al reported a systematic review of rTMS combined with upper-limb training for improving function after stroke (Graef, 2016). Included were 11 sham-controlled randomized trials with 199 patients that evaluated upper-limb motor and functional status and spasticity; 8 RCTs with sufficient data were included in the meta-analysis. These studies were considered to have a low-to-moderate risk of bias. In the overall analysis, there was no benefit of rTMS on upper-limb function or spasticity (SMD=0.03; 95% CI, -0.25 to 0.32).
2018 Update
A literature search was conducted through September 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
TREATMENT-RESISTANT DEPRESSION
Repetitive TMS for TRD
Systematic ReviewsThe Health Quality Ontario published a systematic review of left DLPFC rTMS for TRD (HQO, 2016). Reviewers included 23 RCTs (n=1156 patients) that compared rTMS with sham and 6 RCTs (n=266 patients) that compared rTMS with ECT. In 16 studies, patients received rTMS in addition to antidepressant medication. Seven studies used intensities of less than 100% motor threshold and the definition of remission in the included studies varied (from ≤7 to ≤10 on the HAM-D). Meta-analysis showed a statistically significant improvement in depression scores compared with sham, with a weighted mean difference (WMD) of 2.31. However, this was smaller than the prespecified clinically important difference of 3.5 points on the HAM-D, and the effect size was small (0.33; 95% confidence interval [CI], 0.17 to 0.5; p<0.001). Subgroup analysis showed a larger and clinically significant treatment effect in the rTMS studies using 20 Hz with shorter train duration compared with other rTMS techniques (WMD=4.96; 95% CI, 1.15 to 8.76; p=0.011). Secondary analyses showed rTMS demonstrated a statistically greater rate of response among 20 studies (pooled relative risk, 1.72; 95% CI, 1.13 to 2.62; p=0.11) as well as statistically greater rate of remission among 13 studies (pooled relative risk, 2.20; 95% CI, 1.44 to 3.38, p<0.001). For the 6 trials that compared rTMS with ECT, the WMD of 5.97 was both statistically and clinically significant in favor of ECT. Remission and relapse rates at the 6-month follow-up were reported in 2 studies including 40 and 46 subjects, comparing rTMS and ECT. While 1 study reported a slightly higher remission rate for ECT (27.3%) than for rTMS (16.7%), the other study did not find a significant difference between ECT and rTMS for mean depression scores at 3 or 6 months, but did note relapses were less frequent for ECT. Statistical comparisons were either not significant or not available, limiting the interpretation of these findings.
PSYCHIATRIC AND NEUROLOGIC DISORDERS OTHER THAN DEPRESSION
Epilepsy
A 2016 Cochrane review by Chen et al included 7 RCTs on rTMS for epilepsy, 5 of which were completed studies with published data (Chen, 2016). The total number of participants was 230. All studies had active or placebo controls, and four were double-blinded. However, a meta-analysis could not be conducted due to differences in the design, interventions, and outcomes of the studies. Therefore, a qualitative synthesis was performed. For the outcome of seizure rate, 2 studies showed a significant reduction and 5 studies did not. Of the 4 studies evaluating the mean number of epileptic discharges, 3 studies showed a statistically significant reduction in discharges. Adverse events were uncommon and mild, involving headache, dizziness, and tinnitus. There were no significant changes in medication use.
Fibromyalgia
Saltychev and Laimi published a meta-analysis of rTMS for the treatment of patients with fibromyalgia (Saltychev, 2017). The meta-analysis included 7 sham-controlled double-blinded controlled trials with low risk of bias. The sample sizes of the trials ranged from 18 to 54. Five of the studies provided high-frequency stimulation to the left primary motor cortex, and the others were to the right or left DLPFC. The number of sessions ranged from 10 to 24, and follow-up ranged from immediately after treatment to 3 months post-treatment. In the pooled analysis, pain severity decreased after the last simulation by 1.2 points (95% CI, -1.7 to -0.8 points) on a 10-point numeric rating scale, while pain severity measured at 1 week to 1 month after the last simulation decreased by 0.7 points (95% CI, -1.0 to -0.3 points). Both were statistically significant but not considered clinically significant, based on a minimal clinically important difference of 1.5 points.
Obsessive-Compulsive Disorder
A systematic review by Trevizol et al included 15 RCTs (total N=483 patients) that compared active with sham rTMS for OCD (Trevizol, 2016). All studies were sham-controlled and double-blinded. Sample sizes in the trials were small-to-moderate, ranging from 18 to 65 patients (mean sample size, 16.1 patients). Seven studies used low-frequency stimulation and 8 studies used high-frequency stimulation. The cortical regions varied among the studies, targeting the supplementary motor area, orbitofrontal cortex, or left, right, or bilateral DLPFC. The effect size for active stimulation was modest at 0.45 (95% CI, 0.2 to 0.71). The SMD was 2.94 (95% CI, 1.26 to 4.62). Regression did not identify any significant factors. There was no evidence of publication bias from funnel plots.
Posttraumatic Stress Disorder
Trevizol et al published a systematic review on the efficacy of rTMS for posttraumatic stress disorder (PTSD) (Trevizol, 2016). Five sham-controlled randomized trials (total N=118 patients) were included. Most trials used stimulation of the right DLPFC, though some delivered rTMS to the left DLPFC or bilaterally. Three trials used high-frequency stimulation while one used low-frequency stimulation and another compared high- with low-frequency stimulation; the percent motor threshold ranged from 80% to 120%. Some trials provided rTMS in combination with a scripted narrative of the traumatic event, and different PTSD scales were used. In a meta-analysis, active rTMS was found to be superior to sham (SMD=0.74; 95% CI, 0.06 to 1.42), although heterogeneity of the trials was high.
2019 Update
A literature search was conducted through September 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A more recent RCT was not included in the systematic review conducted by Trevizol et al (Carmi, 2019). The trial was submitted to the FDA as part of the de novo classification request, to establish a reasonable assurance of safety and effectiveness of the device (USFDA, 2018). A total of 99 patients were randomized to active treatment or sham. The primary outcome was the difference between groups in the mean change from baseline to six weeks on the YBOCS. Secondary outcomes included the response rate (defined as a 30% or greater improvement from baseline on the YBOCS), the Clinical Global Impression of Improvement, the CGI-S and the Sheehan Disability Scale, a patient-reported measure of disability and impairment. Results at ten weeks were also reported as secondary outcomes.
The primary efficacy analysis used a modified ITT analysis (n=94), excluding 5 patients who were found to not meet eligibility criteria following randomization. There was a greater decrease from baseline in the active treatment group (-6.0 points) than the sham group (-2.8 points), translating to a moderate effect size of 0.69. At 6 weeks, the response rate was 38.1% in the active treatment group compared to 11.1% in the sham group (P=0.003). The FDA review provides data from the ITT analysis of the mean change in the YBOCS score (n=99). In the ITT data set, the YBOCS score decreased by -6.0 points (95% CI, -3.8 to -8.2) in the active group and by -4.1 points (95% CI, -1.9 to -6.2) in the sham group. Although the decreases were both statistically significant from baseline, the difference of 1.9 points between the treatment arms was not statistically significant (P=0.0988). Results on the secondary outcomes were mixed. More patients in the active treatment group were considered improved based on the Clinical Global Impression of Improvement and the CGI-S at six weeks, but there was no significant difference between groups on the Sheehan Disability Scale.
Tee et al conducted a systematic review and meta-analysis of sham-controlled RCTs of rTMS for the treatment of bipolar disorder (Tee, 2020). Eight trials of rTMS in bipolar depression showed small but statistically significant improvements in depression scores compared to sham control (standardized mean difference = 0.302, P < 0.05). However, most studies had a high risk of bias which could have exaggerated the treatment effects. The effect of rTMS was inconclusive in bipolar mania due to the high heterogeneity and limited number of controlled trials.
Cui et al included 21 studies (N=1481 patients) in a meta-analysis of rTMS plus drug therapy compared to drug therapy alone for the treatment of generalized anxiety disorder (Cui, 2019). Results of the analysis showed that rTMS improved anxiety symptoms as measured by the Hamilton Anxiety Scale, (standardized mean difference = −0.68, 95% CI −0.89 to −0.46). The conclusions that could be drawn from the body of evidence were limited by significant heterogeneity across studies, and the authors concluded that additional high-quality studies are needed to confirm the results
Several additional small, single center RCTs of rTMS for the treatment of schizophrenia have been published (Guan, 2020; Zhuo, 2019; Kumar, 2020). These studies were limited by their small sample sizes, very high loss to follow-up, and inadequate duration of follow-up. Due to these limitations, these studies do not provide sufficient evidence to draw conclusions about the effectiveness of the technology in patients with schizophrenia.
A Cochrane review by O’Connell et al evaluating noninvasive brain stimulation techniques was first published in 2010 and was updated in 2014 and 2018 (O’Connell, 2014; O’Connell, 2018). The reviewers identified 42 RCTs (range 4 to 70 participants) on TMS for chronic pain. Meta-analysis of rTMS studies vs sham for pain intensity at short-term follow-up (0 to < 1 week postintervention), (27 studies, involving 655 participants), demonstrated a small effect with heterogeneity (SMD -0.22, 95%CI -0.29 to -0.16, low-quality evidence). This equates to a 7% (95% CI 5% to 9%) reduction in pain, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale, which did not meet the minimum clinically important difference threshold of 15% or greater. There is very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and QOL but multiple sources of bias exist that may have influenced the observed effects. We did not find evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex and cranial electrotherapy stimulation are effective for reducing pain intensity in chronic pain.
A more recent meta-analysis conducted by Mishra and colleagues included 7 RCTs that compared rTMS with sham or placebo controls in patients with epilepsy (Mishra, 2020). Two of the included studies showed statistically significant reductions in the seizure rate from baseline, 3 trials failed to show any statistically significant difference in seizure frequency, and 2 had unclear results due to inadequate power. In a meta-regression, when adjusted for other potential variables such as the type of coil used, stimulation frequency, and the total duration of the active intervention, seizure frequency worsened by 2.00 ± 0.98 (p=0.042) for each week of lengthening of the posttreatment follow-up period. These results suggested that rTMS exerted only a short-term effect. The reviewers concluded that although the procedure may be a therapeutic alternative for patients with drug-resistant epilepsy, further RCTs using standardized protocols and with adequate sample sizes and duration are still needed.
The American Psychiatric Association published consensus recommendations on repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression (McClintock, 2017). The guidelines state, "Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy." The recommendations include information on the following variables: clinical environment, operator requirements, documentation, coils, cortical targets, coil positioning methods, determination of motor threshold, number of treatment sessions for acute treatment, and allowable psychotropic medications during TMS treatment.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Brunoni et al conducted a systematic review to compare different modalities of rTMS for TRD (Brunoni, 2017). Bilateral, high frequency rTMS, low-frequency rTMS, and theta burst stimulation were statistically significantly more effective than sham with respect to response (odds ratio [OR], 3.39; 95% CI, 1.91 to 6.02]; OR, 3.28 [95% CI, 2.33 to 4.61]; OR, 2.48 [95% CI, 1.22 to 5.05]; OR, 2.57 [95% CI, 1.17 to 5.62], respectively). In network meta-analysis, deep TMS was not more effective than sham TMS for response (OR 1.49 ; 95% CI 0.50 to 4.47) or remission (OR 2.45; 95% CI 0.74 to 8.07), but this result was based on only 1 RCT. A systematic review conducted by Voigt et al focused on theta burst stimulation of TRD (Voigt, 2021). The reviewers included 8 RCTs comparing theta burst stimulation to sham treatment and 1 comparing theta burst stimulation to conventional rTMS. As measured by the HAM-D, theta burst stimulation was superior to sham on response (RR 2.4; 95% CI: 1.27 to 4.55; p=.007; I 2 = 40%). There was no statistically significant difference between theta burst stimulation and conventional rTMS (RR 1.02; 95% CI: 0.85 to 1.23; p=.80; I 2 = 0%). There was no difference between theta burst stimulation and rTMS in the incidence of adverse events
More recently, Liang et al conducted a systematic review and meta-analysis of different TMS modalities for the treatment of OCD (Liang, 2021). Three of the 5 protocols assessed were significantly more efficacious than sham TMS, and all treatment strategies were similar to sham TMS regarding tolerability. Transcranial magnetic stimulation was not more effective than sham TMS, but there was direct evidence from only 1 RCT for this comparison (Carmi, 2019). The overall quality of the evidence was rated very low for efficacy and low for tolerability, and the reviewers concluded that high quality RCTs with low selection and performance bias are needed to further verify the efficacy of specific rTMS strategies for OCD treatment.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Saltychev et al conducted a systematic review and meta-analysis of 8 RCTs that compared rTMS to sham stimulation inpatients with migraine (Saltychev, 2022). All RCTs used high frequency rTMS to the left dorsolateral prefrontal cortex and all studies except 1 included patients with chronic migraine. All studies except 1 had a low risk of bias and the risk of publication bias was non
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Blumberger D, Vila-Rodriguez F, Thorpe K, Feffer, K, et al.(2018) Effectiveness of theta burst versus highfrequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet, Volume 391, ISSUE 10131, P1683-1692, April 28, 2018. DOI:https://doi.org/10.1016/S0140-6736(18)30295-2. Carmi L, Alyagon U, Barnea-Ygael N, et al.(2018) Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patients. Brain Stimulation. 2018 Jan - Feb;11(1):158-165. DOI: 10.1016/j.brs.2017.09.004. PMID: 28927961. Carmi L, Tendler A, Bystritsky A, Hollander E, et al.(2019) Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial. American Journal of Psychiatry Online 2019. 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