Medical Policy

Policy Num:      02.001.033
Policy Name:    Transcranial Magnetic Stimulation as a treatment of Depression and Other Psychiatric/Neurologic Disorders
Policy ID:          [02.001.033]  [Ac / B / M+ / P+]  [2.01.50]

Last Review:      November 19, 2024
Next Review:      November 20, 2025
 

Related Policies BCBS: 

07.001.030 - Vagus Nerve Stimulation
08.003.001 - Treatment of Tinnitus

Related Policies TSSS: None

Transcranial Magnetic Stimulation as a Treatment of Depression and Other Psychiatric/Neurologic Disorders

Summary

Description

Transcranial magnetic stimulation (TMS) is a noninvasive method of delivering electrical stimulation to the brain. The technique involves the placement of a small coil over the scalp and the passing of a rapidly alternating current through the coil wire. The electrical current produces a magnetic field that passes unimpeded through the scalp and bone and stimulates neuronal function. Repetitive TMS is being evaluated for the treatment of treatment-resistant depression (TRD) and other psychiatric and neurologic disorders. A variety of TMS modalities have been developed, which differ on parameters including stimulation intensity, frequency, pattern, and site of the brain stimulation. In conventional TMS, high frequency stimulation is delivered over the left dorsolateral prefrontal cortex (DLPFC) or low frequency stimulation over the right DLPFC. In bilateral TMS, both procedures are performed in the same session. Deep TMS employs an H-coil helmet designed to encompass a broader surface area and stimulate deeper brain structures than conventional TMS. Theta burst stimulation is administered at lower intensities and shorter intervals than conventional TMS.

Summary of Evidence

For individuals who have treatment-resistant depression (TRD) who receive transcranial magnetic stimulation (TMS), the evidence includes a large number of sham-controlled randomized controlled trials (RCTs) and meta-analyses of these trials. Relevant outcomes are symptoms, functional outcomes, and quality of life. Meta-analyses found improved response rates and rates of remission for conventional TMS and theta burst stimulation compared with sham TMS. Additionally, a head-to-head trial showed noninferiority of theta burst stimulation to conventional TMS, with no difference in the incidence of adverse events. Meta-analyses have concluded that the effect of TMS on average depression scores is smaller than the effect of electroconvulsive therapy (ECT) on TRD and that the mean improvement in depression scores with TMS did not reach the minimal clinically important difference; however, clinically meaningful improvements were noted in a subgroup of studies using higher frequency pulses. One potential area of benefit for TMS is in accelerating or enhancing the response to antidepressant medications, and there is some evidence that TMS, when given in conjunction with the initiation of pharmacologic therapy, improves the response rate compared with pharmacologic therapy alone. The effect of TMS appears to be less robust when it is given in combination with a stable dose of antidepressant medication. Meta-analyses have also found that the efficacy of TMS decreases with longer follow-up, though some studies have reported a persistent response up to 6 months in some patients. There is limited evidence to compare the effects of these treatments on cognition, although the adverse events of TMS appear to be minimal. While meta-analyses have reported that the effect of TMS is smaller than the effect of ECT on TRD, because TMS does not require general anesthesia or induce seizures, some individuals may decline ECT so the balance of incremental benefits and harms associated with TMS may be reasonable compared with ECT. Based on the short-term benefit observed in RCTs and the lack of alternative treatments aside from ECT in patients with TRD, TMS may be considered a treatment option in patients with TRD who meet specific criteria. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have migraine headaches who receive TMS, the evidence includes a systematic review (n=8 trials) and a sham-controlled RCT of 201 patients conducted for submission to the Food and Drug Administration (FDA) for clearance in 2013. Relevant outcomes are symptoms, functional outcomes, and quality of life. The systematic review found that repetitive TMS (rTMS) reduced migraine pain intensity and frequency compared to sham; it was unclear whether patients were receiving background pharmacotherapy. The trial results were limited by the 46% dropout rate and the use of a post hoc analysis. No recent studies have been identified with these devices. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have obsessive compulsive disorder (OCD) who receive TMS, the evidence includes a number of small-to-moderate sized, sham-controlled, double-blind RCTs and meta-analyses of these studies. Relevant outcomes are symptoms, functional outcomes, and quality of life. A meta-analysis of 15 RCTs (N=483 patients, range 18 to 65 patients) conducted in 2016 found a benefit of TMS on patient-reported OCD symptom severity at time points ranging from 2 to 6 weeks, but there was substantial variability in the stimulation parameters, including the cortical region that was stimulated and the frequency of stimulation. A meta-analysis conducted in 2021 included 26 RCTs. The primary analysis found a significant effect of rTMS compared to sham on OCD symptoms, but the effect seemed to last only until 4 weeks after the last treatment. The RCT that was the basis of FDA clearance of deep TMS for treatment of OCD compared deep TMS to sham in 99 patients for 6 weeks, with an additional 4 weeks of follow-up as a secondary outcome. Using a modified intention-to-treat (ITT) analysis (n=94), there was a larger mean decrease from baseline (improvement) on the Yale-Brown Obsessive Compulsive Scale (YBOCS) score (the primary efficacy outcome) 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=.003), as measured by a 30% or greater increase in the YBOCS. The difference in the primary outcome measure between active and sham groups was not statistically significant in the ITT analysis. There was a benefit for TMS on clinician-reported measures of improvement, but no significant difference between groups on patient-reported disability and impairment. Additional trials with sufficient sample size and follow-up duration are needed to confirm these results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have psychiatric or neurological disorders other than depression, migraine, or OCD (eg, bipolar disorder, generalized anxiety disorder, panic disorder, posttraumatic stress disorder, schizophrenia, substance use disorder and craving, amyotrophic lateral sclerosis, chronic pain, epilepsy, fibromyalgia, Parkinson disease, stroke recovery) who receive TMS, the evidence includes numerous small RCTs and meta-analyses of these randomized trials. Relevant outcomes are symptoms, functional outcomes, and quality of life. The trials included in the meta-analyses are typically small and of low methodologic quality. In addition, stimulation parameters have not been established, and trial results are heterogeneous. There are no large, high-quality trials for any of these conditions demonstrating efficacy or the durability of any treatment effects. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable

Objective

The objective of this evidence review is to evaluate whether the use of repetitive transcranial magnetic stimulation of the brain improves the net health outcome for individuals with various psychiatric or neurologic conditions.

Policy STATEMENTS

Transcranial magnetic stimulation (TMS) of the brain using an FDA-cleared device and modality, which can include but is not limited to, conventional TMS, deep TMS, and theta burst stimulation (see Policy Guidelines) may be considered medically necessary as a treatment of major depressive disorder when all of the following conditions (1 to 3) have been met:

1. Confirmed diagnosis of severe major depressive disorder (single or recurrent) documented by standardized rating scales that reliably measure depressive symptoms; and

2. Any one of the following (a, b, c, or d):

   1. Individual has tried and had an inadequate response to 2 antidepressant agents from 2 different antidepressant classes (i.e., selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:

      1. 1. The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treating physician at the generally accepted doses; AND

         2. Individual was ≥80% adherent to the agent during the trial.

   2. Inability to tolerate a therapeutic dose of medications due to distinct side effects; or

   3. History of response to TMS in a previous depressive episode (at least 3 months since the prior episode); or

   4. Is a candidate for electroconvulsive therapy; further, electroconvulsive therapy would not be clinically superior to TMS (eg, in cases with psychosis, acute suicidal risk, catatonia or life-threatening inanition TMS should NOT be used);

and

3. Failure of a trial of a psychotherapy known to be effective in the treatment of major depressive disorder of an adequate frequency and duration, without significant improvement in depressive symptoms, as documented by standardized rating scales that reliably measure depressive symptoms.

TMS for major depressive disorder that does not meet the criteria listed above is considered investigational.

Continued treatment with TMS of the brain as maintenance therapy is considered investigational.

TMS of the brain is considered investigational as a treatment of all other psychiatric and neurologic disorders, including but not limited to bipolar disorder, schizophrenia, obsessive-compulsive disorder, or migraine headaches.

Policy Guidelines

Transcranial magnetic stimulation (TMS) should be performed using a U.S. Food and Drug Administration cleared device in appropriately selected individuals over age 18 years, by health care professionals who are adequately trained and experienced in the specific techniques used.

A variety of TMS modalities have been developed, which differ on parameters including stimulation intensity, frequency, pattern, and site of the brain stimulation.

In conventional TMS, high frequency stimulation is delivered over the left dorsolateral prefrontal cortex (DLPFC) or low frequency stimulation over the right DLPFC. In bilateral TMS, both procedures are performed in the same session.

Theta burst stimulation is administered at lower intensities and at shorter intervals than conventional TMS.

Deep TMS employs an H-coil helmet designed to encompass a broader surface area and stimulate deeper brain structures than conventional TMS.

A treatment course of conventional TMS usually does not exceed 5 days a week for 6 weeks (total of 30 sessions), however the treatment plan can be individualized depending on the type of device used, safety and side effect considerations and response to treatment.

Theta burst stimulation may be administered using an accelerated protocol. One example of an accelerated theta burst protocol is the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, consisting of 10 daily sessions over 5 consecutive days.

Contraindications to repetitive TMS include:

1. Seizure disorder or any history of seizure with increased risk of future seizure; or

2. Presence of acute or chronic psychotic symptoms or disorders (eg, schizophrenia, schizophreniform, or schizoaffective disorder) in the current depressive episode; or

3. Neurologic conditions that include epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, having a history of repetitive or severe head trauma, or with primary or secondary tumors in the central nervous system; or

4. Presence of an implanted magnetic-sensitive medical device located 30 centimeters or less from the TMS magnetic coil or other implanted metal items, including but not limited to a cochlear implant, implanted cardioverter defibrillator, pacemaker, vagus nerve stimulator, or metal aneurysm clips or coils, staples, or stents.

The following should be present for the administration of repetitive TMS:

1. An attendant trained in basic cardiac life support and the management of complications such as seizures, as well as the use of the equipment must be present at all times; and

2. Adequate resuscitation equipment including, eg, suction and oxygen; and

3. The facility must maintain awareness of response times of emergency services (either fire/ambulance or “code team”), which should be available within 5 minutes. These relationships are reviewed on at least a 1-year basis and include mock drills.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity. 

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS), introduced in 1985 as a new method of noninvasive stimulation of the brain, 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. Transcranial magnetic stimulation was initially used to investigate nerve conduction (eg, TMS over the motor cortex will produce a contralateral muscular-evoked potential). The motor threshold, which is the minimum intensity of stimulation required to induce a motor response, is empirically determined for each person by localizing the site on the scalp for optimal stimulation of a hand muscle, then gradually increasing the intensity of stimulation. Interest in the use of TMS as a treatment for depression was augmented by the development of a device that could deliver rapid, repetitive stimulation. Imaging studies had shown a decrease in the activity of the left dorsolateral prefrontal cortex in depressed patients, and early studies suggested that high-frequency (eg, 5 to 10 Hz) TMS of the left dorsolateral prefrontal cortex had antidepressant effects. In contrast to electroconvulsive therapy (ECT), TMS does not require general anesthesia and does not generally induce a convulsion. Repetitive TMS (rTMS) is also being tested as a treatment for a variety of other psychiatric and neurologic disorders.

Conventional TMS delivers repeated electromagnetic pulses to induce prolonged modulation of neural activity, typically applied over the dorsolateral prefrontal cortex. High-frequency rTMS (usually ≥10 Hz) induces an increase in neural activity whereas low-frequency TMS (usually ≤1 Hz) has the opposite effect. If both procedures are performed in the same session, the intervention is described as bilateral rTMS.

A variety of TMS modalities have been developed, which differ on parameters including stimulation intensity, frequency, pattern, and site of the brain stimulation. Deep TMS employs an H-coil helmet design to encompass a broader surface area and stimulate deeper brain structures than conventional TMS. Theta burst stimulation is administered at lower intensities and shorter intervals than conventional rTMS.

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:

• The device is only intended for patients experiencing the onset of pain associated with a migraine headache with aura.

• The device should not be used:

  • on headaches due to underlying pathology or trauma.

  • for medication overuse headaches.

• The device has not been demonstrated as safe and/or effective:

  • when treating cluster headache or a chronic migraine headache.

  • when treating during the aura phase.

  • in relieving the associated symptoms of a migraine (photophobia, phonophobia, and nausea).

  • in pregnant women, children under the age of 18, and adults over the age of 65.

Table 1 lists some devices that are FDA cleared for major depressive disorder (Product Code: OBP), migraine headache pain (Product Code: OKP), and obsessive-compulsive disorder (Product Code: QCI).

Table 1. Repetitive Transcranial Magnetic Stimulation Devices Cleared by the U.S. Food and Drug Administration for Major Depression, Migraine, or Obsessive-Compulsive Disorder

Rationale

This evidence review was created in November 2001 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 12, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Treatment-Resistant Depression

Clinical Context and Therapy Purpose

The purpose of repetitive transcranial magnetic stimulation (rTMS) is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with treatment-resistant depression (TRD).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with TRD.

Interventions

The therapy being considered is rTMS.

Comparators

The following therapies are currently being used to treat TRD: pharmacotherapy, psychological and behavioral therapy, and electroconvulsive therapy (ECT).

Outcomes

The general outcomes of interest are reductions in symptoms and improvements in quality of life and functional outcomes.

Table 2. Health Outcome Measures Relevant to Treatment-Resistant Depression, Major Depressive Disorder, Suicidal Ideation, and Suicidal Behavior

CGI-SR-I: Clinical Global Impression of Imminent Suicide Risk Scale, CGI-SS-r: Clinical Global Impression of Severity of Suicidality-Revised, CI: confidence interval; FDA: U.S. Food and Drug Administration; FoST: Frequency of Suicidal Thinking, HAM-D: Hamilton Rating Scale for Depression, MADRS: Montgomery-Asberg Depression Rating Scale, MDD: major depressive disorder; SIBAT: Suicide Ideation and Behavior Assessment Tool.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Evaluation of rTMS for TRD includes RCTs comparing rTMS with sham as well as evidence when used as a replacement for or adjunct to pharmacotherapy that has not improved depressive symptoms. In addition, evaluation of rTMS in TRD includes the use of rTMS as an alternative to ECT. However, some individuals may not elect ECT due to its requirement for general anesthesia and induction of seizures.

There has been a trend to use rTMS at increased levels of intensity, trains of pulses, total pulses per session, and the number of sessions.^5, Unless otherwise indicated, stimulation was set at 100% to 120% of motor threshold, clinical response was defined as an improvement of 50% or more on the Hamilton Rating Scale for Depression (HAM-D), and remission was considered to be a score of 7 or less on the HAM-D. Refer to the meta-analysis by Schutter (2009) for a summary of study characteristics and stimulation parameters used in trials conducted prior to 2008.^6,

Systematic Reviews

The Health Quality Ontario (2016) published a systematic review of left dorsolateral prefrontal cortex (DLPFC) rTMS for TRD.^7, 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 (Table 3). 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<.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=.011). Secondary analyses showed rTMS demonstrated statistically greater response rates among 20 studies (pooled relative risk [RR], 1.72) as well as statistically greater remission rates among 13 studies (pooled RR, 2.20). 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 RR for remission and response rates are shown in Table 3, which while favoring ECT were not statistically significant. Remission and relapse rates at the 6-month follow-up were reported in 2 studies (n=40 and n=46 subjects) comparing rTMS with 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.

Table 3. Statistical Comparisons for Depression Scores after Repetitive Transcranial Magnetic Stimulation

CI: confidence interval; ECT: electroconvulsive therapy; rTMS: repetitive transcranial magnetic stimulation; RR: relative risk; WMD: weighted mean difference.

Brunoni et al (2017) conducted a systematic review to compare different modalities of rTMS for TRD.^8, 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 (2021) focused on theta burst stimulation of TRD.^9, 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; I²=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; I²=0%). There was no difference between theta burst stimulation and rTMS in the incidence of adverse events.

Randomized Controlled Trials

The ASCERTAIN-TRD study was a 3-arm, open-label study published by Papakostas et al (2024).^10, In this study, patients with TRD (failed ≥2 antidepressants) were randomized to augmentation with either aripiprazole or rTMS or were switched to venlafaxine XR. The study was open-label and limited to 8 weeks duration. A total of 235 individuals completed the study. MADRS response rates were numerically improved with rTMS augmentation compared with either aripiprazole augmentation or switching to venlafaxine/duloxetine (52.2% vs 38.1% and 35.8%, respectively). MADRS remission rates were also better among rTMS-treated individuals (34.2% vs 25.3% and 24.9%, respectively). MADRS score changes were significantly improved with rTMS (-17.39; p=.015) compared with switch (-13.22); however, augmentation with aripiprazole (-14.9; p=.069) was not significantly better than switch.

Theta Burst Stimulation Compared to Conventional Transcranial Magnetic Stimulation

Blumberger et al (2018) published a multicenter, randomized, noninferiority trial, Conventional Versus Theta Burst Repetitive Transcranial Magnetic Stimulation in the Treatment of Major Depressive Disorder comparing 10-Hz rTMS with intermittent theta burst stimulation (iTBS).^11, Between 2013 and 2016, 414 patients with TRD were enrolled and randomized to 4 to 6 weeks of rTMS (n=205) or iTBS (n=209). Treatment resistance was defined as the failure to tolerate 2 or more antidepressant trials of inadequate dose and duration or no clinical response to an adequate dose of an antidepressant. Patients who failed more than 3 antidepressant trials of adequate dosage were excluded from the trials. Patients could alter their medications during this trial. Treatment with conventional rTMS (37 minutes) and iTBS (3 minutes) was delivered 5 times a week for 4 to 6 weeks. The primary outcome measure was the 17-item HAM-D, for which scores for patients treated with rTMS improved by 10.1 points and scores for patients treated with iTBS improved by 10.2 points (adjusted difference, 0.103; lower 95% CI, -1.16; p=.001). Treatment with iTBS resulted in a higher self-rated intensity of pain (mean score, 3.8) than treatment with rTMS (mean score, 3.4; p=.011). Headache was the most common treatment-related adverse event for both groups (rTMS , 64% [131/204]; iTBS , 65% [136/208]). Serious adverse events were noted in patients treated with rTMS (1 case of myocardial infarction) and iTBS (1 case each of agitation, worsening suicidal ideation, worsening depression); there was no significant difference in the number of adverse events in the 2 groups. The trial lacked a treatment group with a placebo.

Deep Transcranial Magnetic Stimulation

The RCT leading to 510(k) clearance of the Brainsway Deep TMS System in 2013 was conducted at 20 centers across the U.S. (n=13), Israel (n=4), Germany (n=2), and Canada (n=1).^12, The trial included 229 patients with major depressive disorder who had not received benefits from 1 to 4 antidepressant trials or were intolerant of at least 2 antidepressant treatments. Using a per-protocol analysis, which excluded 31 patients who did not receive adequate TMS treatment and 17 patients who did not meet the inclusion and exclusion criteria, the RCT showed a significant benefit for both response rate (38.4% vs. 21.4%) and remission rate (32.6% vs. 14.6%). A modified intention-to-treat analysis (ITT), which excluded the 17 patients not meeting selection criteria, showed a significant benefit in both response rate (37% vs. 22.8%) and remission rate (30.4% vs. 15.8%). At the end of the maintenance period (16-week follow-up), the response rate remained significantly improved for deep TMS. Remission rates were not reported. The ITT analysis found no significant benefit of treatment at 4 or 16 weeks.

Durability of Conventional Transcranial Magnetic Stimulation

Systematic Reviews

Kedzior et al (2015) examined the durability of the antidepressant effect of high-frequency rTMS on the left DLPFC in the absence of maintenance treatment.^13, Included were 16 double-blind, sham-controlled, randomized trials (N=495 patients). The range of follow-up was 1 to 16 weeks, but most studies only reported follow-up to 2 weeks. The overall effect size was small with a standardized mean difference (SMD; Cohen’s d) of -0.48, and the effect sizes were lower in RCTs with 8 to 16 weeks of follow-up (d=-0.42) than with 1 to 4 weeks of follow-up (d=-0.54). The effect size was larger when an antidepressant medication was initiated concurrently with rTMS (5 RCTs, d=-.56) than when patients were on a stable dose of medication (9 RCTs, d=-0.43) or were unmedicated (2 RCTs, d=-0.26).

Observational Studies

Dunner et al (2014) reported a 1-year follow-up with maintenance therapy from a large multicenter observational study (42 sites) of rTMS for patients with TRD.^14, A total of 257 patients agreed to participate in the follow-up study of 307 who were initially treated with rTMS. Of them, 205 completed the 12-month follow-up, and 120 patients had met the Inventory of Depressive Symptoms-Self Report response or remission criteria at the end of treatment. Ninety-three (36.2%) of the 257 patients who enrolled in the follow-up study received additional rTMS (mean, 16.2 sessions). Seventy-five (62.5%) of the 120 patients 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 a 1-year follow-up.

A variety of tapering schedules are being studied. For example, Richieri et al (2013) used propensity-adjusted analysis of observational data and found that patients who had rTMS tapered over 20 weeks (from 3 times per week to once a month) had a significantly reduced relapse rate than patients who had no additional treatment (37.8% vs. 81.8%).^15, Connolly et al (2012) reported that in the first 100 cases treated at their institution, the response rate was 50.6% and the remission rate was 24.7%.^16, At 6 months after the initial rTMS treatment, 26 (62%) of 42 patients who received tapered maintenance therapy (from 2 sessions per week for the first 3 weeks to monthly) maintained their response. In another study, Janicak et al (2010) evaluated patients who met criteria for a partial response during either a sham-controlled or an open-label phase of a prior study were tapered from rTMS and simultaneously started on maintenance antidepressant monotherapy.^17, During the 24-week follow-up, 10 of 99 patients relapsed, 38 had symptom worsening, and of these 32 (84%) had symptomatic benefit with adjunctive rTMS.

Section Summary: Treatment-Resistant Depression

There are a large number of sham-controlled randomized trials and meta-analyses of these RCTs evaluating the use of rTMS for depression. Meta-analyses found improved response rates and rates of remission for conventional rTMS and theta burst stimulation compared with sham TMS. Additionally, a head-to-head trial showed noninferiority of theta burst stimulation to conventional rTMS, with no difference in the incidence of adverse events. There is some evidence that rTMS, when given in conjunction with the initiation of pharmacologic therapy, improves the response rate compared with pharmacologic therapy alone, while the effect of rTMS is less robust when it is given in combination with a stable dose of antidepressant medication. There is limited evidence to compare the effects of these treatments on cognition, although the adverse events of rTMS appear to be minimal. While the most recent meta-analyses have found that the effect of rTMS is smaller than the effect of ECT on TRD, given that rTMS does not require general anesthesia or induce seizures and some individuals may not elect ECT, the balance of incremental benefits and harms associated with rTMS may be reasonable compared with ECT.

For individuals who have treatment-resistant depression (TRD) who receive transcranial magnetic stimulation (TMS), the evidence includes a large number of sham-controlled randomized controlled trials (RCTs) and meta-analyses of these trials. Relevant outcomes are symptoms, functional outcomes, and quality of life. Meta-analyses found improved response rates and rates of remission for conventional TMS and theta burst stimulation compared with sham TMS. Additionally, a head-to-head trial showed noninferiority of theta burst stimulation to conventional TMS, with no difference in the incidence of adverse events. Meta-analyses have concluded that the effect of TMS on average depression scores is smaller than the effect of electroconvulsive therapy (ECT) on TRD and that the mean improvement in depression scores with TMS did not reach the minimal clinically important difference; however, clinically meaningful improvements were noted in a subgroup of studies using higher frequency pulses. One potential area of benefit for TMS is in accelerating or enhancing the response to antidepressant medications, and there is some evidence that TMS, when given in conjunction with the initiation of pharmacologic therapy, improves the response rate compared with pharmacologic therapy alone. The effect of TMS appears to be less robust when it is given in combination with a stable dose of antidepressant medication. Meta-analyses have also found that the efficacy of TMS decreases with longer follow-up, though some studies have reported a persistent response up to 6 months in some patients. There is limited evidence to compare the effects of these treatments on cognition, although the adverse events of TMS appear to be minimal. While meta-analyses have reported that the effect of TMS is smaller than the effect of ECT on TRD, because TMS does not require general anesthesia or induce seizures, some individuals may decline ECT so the balance of incremental benefits and harms associated with TMS may be reasonable compared with ECT. Based on the short-term benefit observed in RCTs and the lack of alternative treatments aside from ECT in patients with TRD, TMS may be considered a treatment option in patients with TRD who meet specific criteria. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

With treatment-resistant depression

Population Reference No. 2

Migraine Headache

Clinical Context and Therapy Purpose

The purpose of rTMS is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with migraine headache pain.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with migraine headaches.

Interventions

The therapy being considered is rTMS.

Comparators

The following therapies are currently being used to treat migraine headache pain: pharmacotherapy (e.g., triptans, ibuprofen, combination analgesics).

Outcomes

The general outcomes of interest are reductions in symptoms and improvements in quality of life and functional outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Review

Saltychev et al (2022) conducted a systematic review and meta-analysis of 8 RCTs that compared rTMS to sham stimulation in patients with migraine.^18, 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 nonsignificant. Results for the frequency of migraine days per month and the intensity of migraine pain both favored rTMS; however, the authors stated that the difference in migraine pain intensity was clinically insignificant. The analysis is summarized in Tables 4 and 5.

Table 4. Systematic Review & Meta-Analysis Characteristics

Table 5. Systematic Review & Meta-Analysis Results

CI: confidence interval

Randomized Controlled Trial

A pivotal randomized, double-blind, multicenter, sham-controlled trial was performed with the Cerena TMS device to demonstrate the safety and effectiveness of a de novo application.^19, Enrolled in the trial were 201 patients with a history of an aura preceding more than 30% of headaches of moderate or severe severity for approximately 90% of migraine attacks. Following a month-long baseline phase to establish the frequency and severity of the migraine, patients were randomized to a treatment phase consisting of 3 treatments or 3 months, whichever occurred first. Patients were instructed to treat their migraine headache during the aura phase and to record their pain severity (0 to 3), severity of associated migraine symptoms (photophobia, phonophobia, nausea), presence of vomiting, and use of rescue medications at the time of treatment and at 1, 2, 24, and 48 hours after treatment. The primary endpoint was the proportion of patients who were pain-free 2 hours after treatment. Of the 201 patients enrolled, 164 recorded at least 1 treatment and 113 recorded at least 1 treatment when there was pain. Post hoc analysis of these 113 patients showed a benefit of the device for the primary endpoint (37.74% pain free after 2 hours for Cerena vs. 16.67% for sham ; p=.018) and for the proportion of subjects who were pain free after 24 hours (33.96% for Cerena vs. 10% for sham; p=.002). Active treatment was not inferior to sham for the proportion of subjects free of photophobia, suggesting that the device does not worsen photophobia. However, the device was not inferior to sham for the proportion of subjects free of nausea and phonophobia.

Section Summary: Migraine Headache

The available evidence on the use of TMS devices to treat migraine include a systematic review and a pivotal RCT. The systematic review found that rTMS reduced migraine pain and intensity compared to sham. The results of the pivotal trial were limited by the 46% dropout rate and post hoc analysis. According to the FDA labeling, the device has not been demonstrated as safe or effective when treating cluster headache, chronic migraine headache, or migraine headache during the aura phase. The device has not been demonstrated to be as effective in relieving the associated symptoms of migraine (photophobia, phonophobia, nausea).

For individuals who have migraine headaches who receive TMS, the evidence includes a systematic review (n=8 trials) and a sham-controlled RCT of 201 patients conducted for submission to the Food and Drug Administration (FDA) for clearance in 2013. Relevant outcomes are symptoms, functional outcomes, and quality of life. The systematic review found that repetitive TMS (rTMS) reduced migraine pain intensity and frequency compared to sham; it was unclear whether patients were receiving background pharmacotherapy. The trial results were limited by the 46% dropout rate and the use of a post hoc analysis. No recent studies have been identified with these devices. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

With migraine

Population Reference No. 3

Obsessive-Compulsive Disorder

Clinical Context and Therapy Purpose

The purpose of rTMS is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with obsessive-compulsive disorder (OCD).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with OCD.

OCD is characterized by the inability to suppress intrusive thoughts, impulses, images, and repetitive motor responses.

Interventions

The therapy being considered is rTMS.

The use of TMS for patients with OCD is based on the observation that OCD symptoms are associated with excessive activity in certain cortical areas. Transcranial magnetic stimulation is proposed as a treatment to modulate these brain areas.

Comparators

The following therapies are currently being used to treat OCD: pharmacotherapy, psychological, and behavioral therapy.

Outcomes

The general outcomes of interest are reductions in symptoms and improvements in quality of life and functional outcomes.

The Yale-Brown Obsessive Compulsive Scale (YBOCS) is a clinician-rated, 10-item scale commonly used to assess the severity of symptoms in OCD.^20, Each item is rated from 0 (no symptoms) to 4 (extreme symptoms) (total range, 0 to 40), with separate subtotals for the severity of obsessions and compulsions.

YBOCS scores of 0 to 13 correspond to 'mild symptoms' on the Clinical Global Impression of Severity (CGI-Severity=0 to 2), 14 to 25 with 'moderate symptoms' (CGI-Severity=3), 26 to 34 with 'moderate-severe symptoms' (CGI-Severity=4) and 35 to 40 with 'severe symptoms' (CGI-Severity=5 to 6).^21, An improvement of ≥35% on the YBOCS is most predictive of treatment response.^22,

Follow-up over months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review by Trevizol et al (2016) included 15 RCTs (N=483) that compared active with sham rTMS for OCD (Tables 6 and 7).^23, All studies were sham-controlled and double-blind. The sample sizes in the trials ranged from 18 to 65 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 researchers calculated the SMD for the primary outcome (YBOCS score). Response rates were not reported.

The pooled mean difference between groups on the YBOCS was 2.94 (95% CI, 1.26 to 4.62), translating to a small to moderate effect size for active stimulation of 0.45 (95% CI, 0.20 to 0.71). Individual adverse effects were not assessed due to a lack of reporting in the primary studies, but there was no difference between groups in the dropout rate. Intervention protocols were heterogeneous across the studies, but regression analysis did not identify any treatment protocol or other variables as predictors of TMS response.

More recently, Liang et al (2021) conducted a systematic review and meta-analysis of different TMS modalities for the treatment of OCD.^24, Three of the 5 protocols assessed were significantly more efficacious than sham TMS, and all treatment strategies were similar to sham TMS regarding tolerability (Table 7). Transcranial magnetic stimulation was not more effective than sham TMS, but there was direct evidence from only 1 RCT for this comparison (Carmi et al, 2019, discussed in the next section).^25, 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.

Perera et al (2021) conducted a systematic review and meta-analysis of rTMS in the treatment of OCD.^26, All RCTs in the analysis (n=26) had a low risk of bias. A random effects model was used to compare pre- and post-stimulation YBOCS scores, with effect sizes reported as Hedges' g. The analysis found that rTMS had a significant effect on YBOCS scores compared to sham (effect size, 0.64; 95% CI, 0.39 to 0.89; p<.0001). Raw mean difference in YBOCS score between treatments was 4.04 (95% CI, 2.54 to 5.54; p<.001). The effect size was still significant when 2 dominant trials were removed. Effect sizes with rTMS appeared to be significant until 4 weeks after treatment, and low- and high-frequency rTMS had similar efficacy to each other. The authors performed several subgroup analyses (cortical target, stimulation frequency, total pulses per session, total duration of treatment) but none of the effect sizes were significant between rTMS and sham.

Table 6. Systematic Review of Transcranial Magnetic Stimulation in Patients with Obsessive-Compulsive Disorder: Characteristics

OCD: obsessive-compulsive disorder; RCT: randomized controlled trial; SD: standard deviation.

Table 7 Systematic Review and Meta-Analysis: Results

CI: confidence interval; CrI: credible interval; NR: not reported; OR: odds ratio; rTMS: repetitive transcranial magnetic stimulation; SMD: standardized mean difference; YBOCS: Yale-Brown Obsessive-Compulsive Scale.

Randomized Controlled Trial

This section discusses in detail the sham-controlled RCT of deep TMS for OCD conducted by Carmi et al (2019).^25, 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.^27, Study characteristics and results are summarized in Tables 8 and 9, and limitations are shown in Tables 10 and 11. 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 6 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 (CGI-I), the Clinical Global Impression of Severity (CGI-S), and the Sheehan Disability Scale, a patient-reported measure of disability and impairment. Results at 10 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=.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=.0988). Results on the secondary outcomes were mixed. More patients in the active treatment group were considered improved based on the CGI-I and the CGI-S at 6 weeks, but there was no significant difference between groups on the Sheehan Disability Scale (Table 10).

Table 8. Summary of Key Randomized Controlled Trial Characteristics - Transcranial Magnetic Stimulation for Patients with Obsessive-Compulsive Disorder

CBT: cognitive behavioral therapy; OCD: obsessive-compulsive disorder; SRI: serotonin reuptake inhibitor; TMS: transcranial magnetic stimulation; YBOCS: Yale-Brown Obsessive-Compulsive Scale.

Table 9 Summary of Key Randomized Controlled Trial Results - Transcranial Magnetic Stimulation for Patients with Obsessive-Compulsive Disorder

CGI-I: Clinical Global Impression of Improvement; CGI-S: Clinical Global Impression of Severity; CI: confidence interval; NS: non-significant; TMS: transcranial magnetic stimulation; YBOCS: Yale-Brown Obsessive-Compulsive Scale.

Table 10. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 11. Study Design and Conduct Limitations

ITT: intention-to-treat.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Obsessive-Compulsive Disorder

The evidence on rTMS for OCD includes a number of small-to-moderate sized, sham-controlled, double-blind randomized trials and meta-analyses of these RCTs. A meta-analysis of 15 RCTs (N=483 patients, range 18 to 65 patients) conducted in 2016 found a benefit of rTMS on patient-reported OCD symptom severity at time points ranging from 2 to 6 weeks, but there was substantial variability in the stimulation parameters, including the cortical region that was stimulated and the frequency of stimulation. The largest meta-analysis conducted in 2021 included 26 RCTs. Differences in pre- and posttreatment YBOCS scores were significantly improved with rTMS compared to sham, but the evidence was only sufficient to conclude that the effects lasted until 4 weeks after the last treatment. In a network meta-analysis that included both direct and indirect evidence, the authors did not find that deep TMS was more effective than sham rTMS. The RCT that was the basis of FDA clearance of deep TMS for treatment of OCD compared deep rTMS to sham in 99 patients for 6 weeks, with an additional 4 weeks of follow-up as a secondary outcome. Using a modified ITT analysis (n=94), there was a larger mean decrease from baseline (improvement) on the YBOCS score (the primary efficacy outcome) 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=.003), as measured by a 30% or greater increase in the YBOCS. The difference in the primary outcome measure between active and sham groups was not statistically significant in the ITT analysis. There was a benefit for rTMS on clinician-reported measures of improvement, but no significant difference between groups on patient-reported disability and impairment. Additional trials with sufficient sample size and follow-up duration are needed to confirm these results.

For individuals who have obsessive compulsive disorder (OCD) who receive TMS, the evidence includes a number of small-to-moderate sized, sham-controlled, double-blind RCTs and meta-analyses of these studies. Relevant outcomes are symptoms, functional outcomes, and quality of life. A meta-analysis of 15 RCTs (N=483 patients, range 18 to 65 patients) conducted in 2016 found a benefit of TMS on patient-reported OCD symptom severity at time points ranging from 2 to 6 weeks, but there was substantial variability in the stimulation parameters, including the cortical region that was stimulated and the frequency of stimulation. A meta-analysis conducted in 2021 included 26 RCTs. The primary analysis found a significant effect of rTMS compared to sham on OCD symptoms, but the effect seemed to last only until 4 weeks after the last treatment. The RCT that was the basis of FDA clearance of deep TMS for treatment of OCD compared deep TMS to sham in 99 patients for 6 weeks, with an additional 4 weeks of follow-up as a secondary outcome. Using a modified intention-to-treat (ITT) analysis (n=94), there was a larger mean decrease from baseline (improvement) on the Yale-Brown Obsessive Compulsive Scale (YBOCS) score (the primary efficacy outcome) 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=.003), as measured by a 30% or greater increase in the YBOCS. The difference in the primary outcome measure between active and sham groups was not statistically significant in the ITT analysis. There was a benefit for TMS on clinician-reported measures of improvement, but no significant difference between groups on patient-reported disability and impairment. Additional trials with sufficient sample size and follow-up duration are needed to confirm these results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

With obsessive-compulsive disorder

Population Reference No. 4

Psychiatric or Neurologic Disorders Other Than Depression, Migraine, or Obsessive-Compulsive Disorder

Clinical Context and Therapy Purpose

The purpose of rTMS is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with psychiatric or neurologic disorders other than depression, migraine, or OCD.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with psychiatric or neurologic disorders other than depression, migraine, or OCD.

Interventions

The therapy being considered is rTMS.

Comparators

The following therapies are currently being used to treat psychiatric disorders other than depression or OCD: pharmacotherapy or psychological and behavioral therapy. The following therapies are currently being used to treat neurologic disorders other than migraine: pharmacotherapy and therapy as appropriate including either physical or occupational therapy.

Outcomes

The general outcomes of interest are reductions in symptoms and improvements in quality of life and functional outcomes.

Follow-up over months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Psychiatric Disorders Other Than Depression or Obsessive-Compulsive Disorder

Bipolar Disorder

Systematic Reviews

Konstantinou et al (2022) conducted a systematic review of 31 RCTs of rTMS for the treatment of bipolar disorder; meta-analysis was not performed.^28, Most included studies were in the setting of bipolar depression (n=24). Only 8 studies had a low risk of bias. Overall, rTMS seems safe and well-tolerated but efficacy results are mixed and there is no consensus about the optimal rTMS regimen. The authors noted limitations of the available literature including heterogeneity among studies, differences in sham treatments, and small sample sizes. They also stated that adequately powered sham-controlled studies are needed to verify the efficacy of rTMS in patients with bipolar disorder.

Tee et al (2020) conducted a systematic review and meta-analysis of sham-controlled RCTs of rTMS for the treatment of bipolar disorder.^29, Eight trials of rTMS in bipolar depression showed small but statistically significant improvements in depression scores compared to sham control (SMD, 0.302 ; p<.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.

Generalized Anxiety Disorder

Systematic Review

Cui et al (2019) 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.^30, Results of the analysis showed that rTMS improved anxiety symptoms as measured by the Hamilton Anxiety Scale (SMD, -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.

Panic Disorder

Systematic Review

A Cochrane review by Li et al (2014) identified 2 RCTs (N=40 patients) that compared low-frequency rTMS with sham rTMS over the right DLPFC.^31, The larger of the 2 studies was a randomized, double-blind, sham-controlled trial by Mantovani et al (2013) who assessed 21 patients with panic disorder and comorbid major depression.^32, The response was defined as a 40% or greater decrease on the Panic Disorder Severity Scale and a 50% or greater decrease in HAM-D scores. After 4 weeks of treatment, the response rate for panic was 50% with active rTMS and 8% with sham. The trial had a high-risk of attrition bias. The overall quality of evidence for the 2 trials was considered low, and the sample sizes were small, precluding certainty in the conclusions about the efficacy of rTMS for panic disorder.

Posttraumatic Stress Disorder

Systematic Review

Trevizol et al (2016) published a systematic review on the efficacy of low- and high-frequency rTMS for posttraumatic stress disorder.^33, Five sham-controlled randomized trials (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 1 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 posttraumatic stress disorder 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 across the trials was high.

Brown et al (2024) published a Cochrane systematic review of rTMS for posttraumatic stress disorder.^34, The search was conducted through January 2023, and the authors identified 13 RCTs (N=577). Notably, 5 studies were conducted in the US, primarily enrolling white, male veterans. The authors found that rTMS probably makes little to no difference on posttraumatic stress disorder severity immediately following treatment (SMD, -0.14; 95% CI, -0.54 to 0.27; 3 studies, 99 participants; moderate-certainty evidence); however, there was significant heterogeneity amongst the studies.

Schizophrenia

Systematic Reviews

He et al (2017) published a meta-analysis of the effects of 1-Hz (low frequency) and 10-Hz (high frequency) rTMS for auditory hallucinations and negative symptoms of schizophrenia, respectively.^35, For 1-Hz rTMS, 13 studies were included. Compared with sham, the rTMS group showed greater improvement in auditory hallucinations (SMD, -0.29; 95% CI, -0.57 to -0.01). However, significant heterogeneity across the studies was found (p=.06). In the 7 studies using 10-Hz rTMS, the overall effect size for improvement in negative symptoms was -0.41 (95% CI, -1.16 to -0.35); again, there was significant heterogeneity across studies (p<.001). The review was further limited by the small number of articles included and by the lack of original data for some studies.

A Cochrane review by Dougall et al (2015) selected 41 studies (N=1473 participants).^36, Based on very low-quality evidence, there was a significant benefit of low- and high-frequency temporoparietal TMS compared with sham for the global state (7 RCTs) and positive symptoms (5 RCTs). For prefrontal rTMS compared with sham, the evidence on global and cognitive state was of very low-quality and equivocal. Reviewers concluded that the evidence was insufficient to support or refute the use of TMS to treat symptoms of schizophrenia and, although some evidence suggested that temporoparietal TMS might improve certain symptoms (eg, auditory hallucinations, positive symptoms of schizophrenia), the results were not sufficiently robust to provide certainty.

Randomized Controlled Trials

Several additional small, single center RCTs of rTMS for the treatment of schizophrenia have been published since the systematic reviews described above (Tables 12 and 13).^37,38,39,40, These studies were limited by their small sample sizes, very high loss to follow-up, and inadequate duration of follow-up (Tables 14 and 15). Due to these limitations, these studies do not provide sufficient evidence to draw conclusions about the effectiveness of the technology in patients with schizophrenia.

Table 12. Summary of Key Randomized Controlled Trial Characteristics

DLPFC: dorsolateral prefrontal cortex; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ECT: electroconvulsive therapy; ICD-10: International Classification of Disease, 10th edition; rTMS: repetitive transcranial magnetic stimulation.

Table 13. Summary of Key Randomized Controlled Trial Results

PANSS: Positive and Negative Syndrome Scale; rTMS: repetitive transcranial magnetic stimulation. SANS: Scale for Assessing Negative Symptoms in Schizophrenia.

Table 14. Study Relevance Limitations

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 15. Study Design and Conduct Limitations

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Substance Use Disorder and Craving

Systematic Review

Jansen et al (2013) reported on results from a meta-analysis evaluating the effect of rTMS and transcranial direct current stimulation of the DLPFC on substance dependence (alcohol, nicotine, cocaine, marijuana) or food craving.^41, Seventeen double-blind, sham-controlled trials that used high-frequency stimulation were analyzed. Thirteen studies stimulated the left DLPFC and 7 studies stimulated the right DLPFC or both sides. Twelve of the studies gave only 1 or 2 sessions. The standardized effect size was 0.476 (95% CI, 0.316 to 0.636), indicating a medium effect size for active stimulation over sham for a reduction in craving. However, the studies were small (range, 9 to 48 patients) and there was significant heterogeneity in selected studies. No significant differences were found in the effectiveness of rTMS versus transcranial direct current stimulation, the different substances, or the side of stimulation, although this analysis might have been biased by the number of studies for each condition.

Chang et al (2022) conducted a meta-analysis of 7 double-blind RCTs (N=462) that used rTMS to treat methamphetamine use disorder.^42, All studies targeted the left DLPFC and the number of sessions ranged among studies from 5 to 20. Mean craving scores at baseline ranged from 22.63 to 57.68. A random effects model showed that clinical craving scores were significantly lower with rTMS than sham treatment (SMD, 0.983; 95% CI, 0.620 to 1.345; p≤.001; I²=67.814%). According to a subgroup analysis, intermittent theta burst stimulation had a greater effect than 10-Hz rTMS. The authors concluded that further trials with larger sample sizes are needed.

Neurologic Disorders Other Than Migraine

Amyotrophic Lateral Sclerosis or Motor Neuron Disease

Systematic Review

A Cochrane review by Fang et al (2013) identified 3 RCTs with a total of 50 participants with amyotrophic lateral sclerosis that compared rTMS with sham TMS.^43, All trials were considered of poor methodologic quality. Heterogeneity prevented pooling of results, and the high rate of attrition further increased the risk of bias. Reviewers concluded that evidence was insufficient to draw conclusions about the efficacy and safety of rTMS in the treatment of amyotrophic lateral sclerosis.

Chronic Pain

Systematic Reviews

A Cochrane review by O’Connell et al (2018) evaluating noninvasive brain stimulation techniques was first published in 2010 and was updated in 2014^44, and 2018.^45, The reviewers identified 42 RCTs (range, 4 to 70 participants) on TMS for chronic pain. Meta-analysis of 27 rTMS studies versus sham (N=655 participants) for pain intensity at short-term follow-up (0 to <1 week postintervention) 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 may have short-term effects on chronic pain and quality of life, 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 DLPFC, and cranial electrotherapy stimulation are effective for reducing pain intensity in chronic pain.

Jiang et al (2022) conducted a systematic review and meta-analysis of 38 RCTs that assessed the analgesic effect of rTMS in 1338 patients with neuropathic pain.^46, A single rTMS session was used in 13 studies and multiple sessions were used in the remaining 25 studies. The overall risk of bias in most studies was low or uncertain. According to a random effects analysis, rTMS was superior to sham therapy in reducing pain scores (effect size, -0.66; 95% CI, -0.87 to -0.46; p<.001; I²=78%). Beneficial effects of rTMS on pain were observed at 1 month (p<.001) and 2 months (p=.01). Low-frequency rTMS (≤1 Hz) did not effectively reduce pain compared to higher frequency stimulation. The analysis did not find an increased risk of adverse events with rTMS compared to sham therapy. The authors concluded that larger, well-designed trials are needed to determine the long-term effect of rTMS in this setting.

Epilepsy

Systematic Reviews

A Cochrane review by Chen et al (2016) included 7 RCTs on low-frequency rTMS for epilepsy, 5 of which were completed studies with published data.^47, The total number of participants was 230. All studies had active or placebo controls and 4 were double-blind. However, a meta-analysis could not be conducted due to heterogeneity in designs, interventions, and outcomes of the trials. 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 headaches, dizziness, and tinnitus. There were no significant changes in medication use.

A more recent meta-analysis conducted by Mishra and colleagues (2020) included 7 RCTs that compared rTMS with sham or placebo controls in patients with epilepsy.^48, 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=.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 standarized protocols and with adequate sample sizes and duration are still needed.

Fibromyalgia

Systematic Reviews

Su et al (2021) conducted a meta-analysis of 18 RCTs (N=643) with rTMS in patients with fibromyalgia.^49, Reduction in disease influence according to the Fibromyalgia Impact Questionnaire showed a significant effect of rTMS (SMD, -0.7; 95% CI, -1.173 to -0.228). The effect of rTMS on disease influence, pain, depression, and anxiety lasted for at least 2 weeks after the last session. Older patients were most likely to experience reduced Fibromyalgia Impact Questionnaire scores. The authors concluded that larger RCTs are needed to confirm these findings.

Saltychev and Laimi (2017) published a meta-analysis of rTMS for the treatment of patients with fibromyalgia.^50, The meta-analysis included 7 sham-controlled, double-blind trials with a low risk of bias. Trial sample sizes ranged from 18 to 54 patients. Five 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.

Parkinson Disease

Systematic Reviews

A meta-analysis by Chou et al (2015) included 20 sham-controlled randomized trials (N=470 patients) evaluating Parkinson disease.^51, Sample sizes ranged from 8 to 102 patients. The total effect size of low- and high-frequency rTMS on Unified Parkinson’s Disease Rating Scale part III score was 0.46, which is considered a small-to-medium effect size, and the mean change in the Unified Parkinson’s Disease Rating Scale part III score (-6.42) was considered a clinically important difference. The greatest effect on motor symptoms was from high-frequency rTMS over the primary motor cortex (SMD , 0.77 ; p<.001) and low-frequency rTMS over other frontal regions (SMD , 0.50 ; p=.008). High-frequency rTMS at other frontal regions and low-frequency rTMS over the primary motor cortex did not have a statistically significant benefit. The largest trial included in the systematic review was an exploratory, multicenter, double-blind trial reported by Shirota et al (2013) who randomized 106 patients to 8 weeks of 1-Hz rTMS, 10-Hz rTMS, or sham stimulation over the supplementary motor area.^52, At 9 weeks, all groups showed a similar amount of improvement.

Li et al (2022) conducted a meta-analysis of 32 sham-controlled RCTs of rTMS in patients with Parkinson disease and motor dysfunction (N=1048 patients).^53, Motor dysfunction was assessed using the United Parkinson's Disease Rating Scale part III score. Overall, rTMS had a significant effect on motor symptoms compared to sham (SMD, 0.64; 95% CI, 0.47 to 0.80; p<.0001; I²=64%). High-frequency rTMS to the primary motor cortex was the most effective intervention. Significant benefit of rTMS was also demonstrated for akinesia, rigidity, and tremor.

Stroke Recovery

Systematic Reviews

A number of RCTs and systematic reviews have evaluated rTMS for recovery from stroke. For example, a Cochrane review by Hao et al (2013) included 19 RCTs (N=588 participants) evaluating the effect of low- and high-frequency TMS for improving function after stroke.^54, The 2 largest trials (n=183 patients) showed that rTMS was not associated with a significant improvement in Barthel Index scores. Four trials (n=73) found no significant effect on motor function. Subgroup analyses for different stimulation frequencies or durations of illness also did not show a significant benefit of rTMS compared with sham rTMS or no treatment. Reviewers concluded that current evidence did not support the routine use of rTMS for the treatment of stroke.

A meta-analysis by Le et al (2014) assessed the effect of rTMS on the recovery of hand function and excitability of the motor cortex after stroke.^55, Eight RCTs (N=273 participants) were selected. The quality of the trials was rated moderate to high, although the size of the studies was small. There was variability in the time since stroke (5 days to 10 years), in the frequency of rTMS applied (1 to 25 Hz for 1 second to 25 min/d), and the stimulation sites (primary motor cortex or premotor cortex of the unaffected hemisphere). Meta-analysis found a positive effect on finger motor ability (4 studies; n=79 patients; SMD, 0.58) and hand function (3 studies; n=74 patients; SMD, -0.82), but no significant change in motor evoked potentials (n=43) or motor threshold (n=62).

A meta-analysis by Li et al (2015) included 4 RCTs on low-frequency rTMS over the right parstriangularis for patients (N=137) with aphasia after stroke.^56, All studies used double-blinding, but therapists were not blinded. Every trial used a different outcome measure, and sample sizes were small (range, 12 to 40 patients). Meta-analysis showed a medium effect size for naming (p=.004), a trend for a benefit on repetition (p=.08), and no significant benefit for comprehension (p=.18). Additional study in a larger number of patients would be needed to determine with greater certainty the effect of this treatment on aphasia after stroke.

Qiao et al (2022) performed a meta-analysis of RCTs that assessed the effect of rTMS in 433 patients with post-stroke dysphagia.^57, Twelve trials that used dysphagia severity rating scales (Dysphagia Grade and Penetration Aspiration Scale) were included. The specific controls used in each study were not specified. Study characteristics included duration of treatment of 1 to 10 days, stimulation frequency of 1 to 10 Hz, and duration of stimulation of 5 to 20 minutes. The analysis favored rTMS (SMD, -0.67; 95% CI, -0.88 to -0.45; p<.001; I²=42%). Subgroup analyses identified treatment duration >5 days and rTMS during the subacute phase after stroke as potential situations with greater clinical benefit, but there was no difference in efficacy according to stimulation frequency, location, or duration of each stimulation. The authors noted that publication bias was present and there may be limited clinical applicability of the dysphagia rating scales.

Zhang et al (2017) published a systematic review and meta-analysis evaluating the effects of rTMS on upper-limb motor function after stroke.^58, A search through October 2016 yielded 34 RCTs with a total of 904 participants (range, 6 to 108 participants). Pooled estimates found improvement with rTMS for both short-term (SMD, 0.43; p<.001) and long-term (SMD, 0.49; p<.001) manual dexterity. Of the 28 studies reporting on adverse events, 25 studies noted none. Mild adverse events, such as headache and increased anxiety, were reported in 3 studies. The review was limited by variation in TMS protocols across studies.

Graef et al (2016) reported a systematic review of rTMS combined with upper-limb training for improving function after stroke.^59, 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).

Section Summary: Psychiatric or Neurologic Disorders Other Than Depression, Migraine, or Obsessive-Compulsive Disorder

For individuals who have psychiatric disorders other than depression or OCD (eg, panic disorder, generalized anxiety disorder, posttraumatic stress disorder, schizophrenia, substance use disorder and craving) who receive rTMS, the evidence includes numerous small RCTs and meta-analyses of these studies. The trials included in the meta-analyses are typically small and of low methodologic quality. In addition, stimulation parameters have not been established, and trial results are heterogeneous. A number of sham-controlled randomized trials and meta-analyses of these have found a medium effect size of rTMS for the reduction of substance dependence or food craving. Most studies examined acute craving after 1 or 2 rTMS sessions, and there is limited evidence on the longer-term efficacy of this treatment approach. There are no large, high-quality trials for any of these conditions demonstrating efficacy or the durability of any treatment effects.

For individuals who have neurological disorders other than migraine (eg, amyotrophic lateral sclerosis, chronic pain, epilepsy, fibromyalgia, Parkinson disease, and stroke) who receive rTMS, the evidence includes numerous small RCTs and meta-analyses of these randomized trials. The trials included in the meta-analyses are typically small and of low methodologic quality. In addition, stimulation parameters have not been established, and trial results are heterogeneous. There are no large, high-quality trials for any of these conditions demonstrating efficacy or the durability of any treatment effects.

For individuals who have psychiatric or neurological disorders other than depression, migraine, or OCD (eg, bipolar disorder, generalized anxiety disorder, panic disorder, posttraumatic stress disorder, schizophrenia, substance use disorder and craving, amyotrophic lateral sclerosis, chronic pain, epilepsy, fibromyalgia, Parkinson disease, stroke recovery ) who receive TMS, the evidence includes numerous small RCTs and meta-analyses of these randomized trials. Relevant outcomes are symptoms, functional outcomes, and quality of life. The trials included in the meta-analyses are typically small and of low methodologic quality. In addition, stimulation parameters have not been established, and trial results are heterogeneous. There are no large, high-quality trials for any of these conditions demonstrating efficacy or the durability of any treatment effects. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

With psychiatric or neurologic disorders other than depression, migraine, or obsessive-compulsive disorder

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2014 Input

In response to requests, input was received from 1 physician specialty society and 3 academic medical centers while this policy was under review in 2014. Reviewers considered repetitive transcranial magnetic stimulation (rTMS) to be medically necessary for treatment-resistant depression. Input agreed with the proposed criteria for treatment of treatment-resistant depression with rTMS, as included in the policy statement.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Child and Adolescent Psychiatry

In 2013, the American Academy of Child and Adolescent Psychiatry published practice parameters on the assessment and treatment of children and adolescents with tic disorders.^60, The Academy did not recommend rTMS, citing the limited evidence on the safety, ethics, and long-term impact on development.

American Psychiatric Association

The American Psychiatric Association (2018) published consensus recommendations on rTMS for the treatment of depression.^61, 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.

The American Psychiatric Association’s (2007, reaffirmed in 2012) guidelines on the treatment of patients with obsessive-compulsive disorder have indicated that “findings of the 4 published trials of rTMS are inconsistent, perhaps because the studies differed in design, stimulation sites, duration, and stimulation parameters. The available results and the technique’s non-invasiveness and good tolerability should encourage future research, but the need for daily treatment may limit the use of TMS in practice.”

Veteran's Affairs/Department of Defense

The 2022 Veteran's Affairs/Department of Defense (VA/DoD) guideline for management of major depressive disorder recommends offering rTMS to patients who have experienced partial response or no response to an adequate trial of 2 or more pharmacologic treatments (strength of recommendation: weak).^62, Recommended options for the second treatment attempt after the initial therapy tried include switching to another antidepressant or adding augmentation therapy with a second-generation antipsychotic. The recommendation for rTMS was graded as weak due to limitations of the available literature including small study effects, high rates of discontinuation, lack of allocation concealment, and the practical limitations of the need for daily treatment and lack of widespread access to facilities that offer this therapy. The guideline also concluded that there is limited evidence to recommend for or against theta-burst stimulation for treatment of depression.

The 2023 VA/DoD guideline for management of bipolar disorder states "for individuals with bipolar disorder who have demonstrated partial or no response to pharmacologic treatment for depressive symptoms, we suggest offering repetitive transcranial magnetic stimulation [rTMS] as an adjunctive treatment."^63, However, the recommendation was rated as "weak" and the confidence in the evidence was very low. For the management of PTSD, the 2023 guideline found insufficient evidence for or against rTMS.^64,

National Institute for Health and Care Excellence

In 2015, the National Institute for Health and Care Excellence (NICE) provided revised guidance, stating that evidence on the short-term efficacy of rTMS for depression is adequate, although the clinical response is variable and some patients may not benefit.^65,

In 2014, the NICE provided guidance on the use of rTMS for treating and preventing migraine.^66, The guidance stated that evidence on the efficacy of TMS for the treatment of migraine was limited in quantity and for the prevention of migraine was limited in both quality and quantity. Evidence on its safety in the short- and medium-term was adequate, but there was uncertainty about the safety of long-term or frequent use of TMS.

In 2020, the NICE stated that rTMS has not demonstrated any major safety concerns for management of obsessive-compulsive disorder or auditory hallucinations, but evidence for both uses is lacking; therefore, NICE recommends that rTMS be used in patients with these conditions only in the context of research.^67,68,

International Neuromodulation Society/North American Neuromodulation Society

In 2020, an expert consensus panel from the International Neuromodulation Society-North American Neuromodulation Society performed a literature review and published recommendations for transcranial magnetic stimulation in the treatment of pain and headache.^69, For neuropathic pain, the panel recommended transcranial magnetic stimulation to the primary motor cortex (high level evidence) or the left dorsolateral prefrontal cortex (F3 location) (at least moderate level evidence). For postoperative pain, the panel recommended that transcranial magnetic stimulation to the F3 location be only selectively offered due to at least moderate certainty that the net benefit is small. For primary headache, the panel only based 2 recommendations on moderate certainty evidence: single transcranial magnetic stimulation for acute migraine and high-frequency rTMS to the primary motor cortex for migraine prevention. For posttraumatic brain injury, high level evidence supported a recommendation for high-frequency transcranial magnetic stimulation to the primary motor cortex or the F3 location.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing trials that might influence this review are listed in Table 16.

Table 16. Summary of Key Trials

NCT: national clinical trial.

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