This policy has been updated periodically with searches of the MEDLINE database. The most recent literature update was performed through August 18, 2023.
TREATMENT-RESISTANT DEPRESSION
Studies published prior to 2008 are included if the study design was a randomized sham-controlled double-blind trial that enrolled at least 40 subjects; refer to the 2008 meta-analysis by Schutter for a summary of study characteristics and stimulation parameters used in these trials. Note that over the last decade, there has been a trend to increase the intensity, trains of pulses, total pulses per session, and number of sessions (Gross, 2007).
Systematic Reviews
In 2016, the Health Quality Ontario published a meta-analysis of left DLPFC rTMS for TRD. 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 when compared with sham with a weighted mean difference (WMD) of
2.31. However, this was smaller than the prespecified clinically important difference of 3.5 points on the HAM-D, and the effect size was small (0.33; 95% confidence interval [CI], 0.17 to 0.5; p<0.001). While one study reported slightly higher remission rate for ECT (27.3%) compared with rTMS (16.7%), the other study did not find significant difference between ECT and rTMS for mean depression scores at three or six 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.
Brunoni et al (2017) conducted a systematic review to compare different modalities of rTMS for TRD. 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. 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.
The Agency for Healthcare Research and Quality published a comparative effectiveness review on nonpharmacologic interventions for treatment-resistant depression (TRD) in adults in 2011.Reviewers concluded that comparative clinical research on nonpharmacologic interventions in a TRD population is early in its infancy, and many clinical questions about efficacy and effectiveness remain unanswered.
Berlim et al reported a 2013 meta-analysis on the effect of rTMS for accelerating and enhancing the clinical response to antidepressants. Data were obtained from 6 double-blind RCTs with a total of 392 patients. Another 2013 systematic review by Berlim et al identified 7 RCTs with a total of 294 patients that directly compared rTMS and ECT treatment for patients with depression. There was no significant difference in dropout rates for the 2 treatments.
Randomized Controlled Trials
The largest study (23 study sites) included in the meta-analysis was a double-blind multicenter trial with 325 TRD patients randomly assigned to daily sessions of high-frequency active or sham rTMS (Monday to Friday for 6 weeks) of the left dorsolateral prefrontal cortex (DLPFC) (O’Reardon, 2007). Treatment-resistant depression was defined as failure of at least 1 adequate course of antidepressant treatment. Patients had failed an average of 1.6 treatments in the current episode, with approximately half of the study population failing to benefit from at least 2 treatments. Loss to follow-up was similar in the 2 groups, with 301 (92.6%) patients completing at least 1 post-baseline assessment and an additional 8% of patients from both groups dropping out before the 4-week assessment. Intent-to-treat (ITT) analysis showed a trend favoring the active rTMS group in the primary outcome measure (2 points on the Montgomery-Asberg Depression Rating Scale (MADRS); p=0.057) and a modest (2-point) but significant improvement over sham treatment on the HAM-D. The authors reported that after 6 weeks of treatment, subjects in the active rTMS group were more likely to have achieved remission than the sham controls (14% vs. 5%, respectively), although this finding is limited by loss to follow-up.
More recently, Blumberger et al (2018) published a multicenter, randomized noninferiority trial (THREE-D) comparing 10-Hz rTMS with intermittent theta burst stimulation (iTBS). Between 2013 and 2016, 414 patients with treatment-resistant major depressive disorder were enrolled and randomized to 4 to 6 weeks of rTMS (n=205) or iTBS (n=209). Treatment resistance was defined as 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 medication during this trial. Treatment with 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=0.001). 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=0.011). 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 placebo.
The RCT leading to 510(k) clearance of the Brainsway deep TMS system was conducted at 20 centers in the U.S. (n=13), Israel (n=4), Germany (n=2), and Canada (n=1) (FDA, 2013). The study included 229 patients with major depressive disorder who had not received benefit from 1 to 4 antidepressant trials or were intolerant to at least 2 antidepressant treatments. Per protocol analysis, which excluded 31 patients who did not receive adequate TMS treatment and 17 patients who did not meet the inclusion/exclusion criteria, showed a significant benefit for both response rate (38.4% vs 21.4%) and remission rate (32.6% vs 14.6%). Modified ITT analysis, which excluded the 17 patients who did not meet the inclusion/exclusion 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 by deep TMS. Remission rates were not reported. ITT analysis found no significant benefit of treatment at 4 or 16 weeks.
Durability of rTMS and Maintenance Therapy
Systematic Reviews
A 2015 meta-analysis by Kedzior et al examined the durability of the antidepressant effect of high-frequency rTMS of the left DLPFC in the absence of maintenance treatment.12 Included were 16 double-blind, sham-controlled RCTs with a total of 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 -.48, and the effect sizes were lower in RCTs with 8- to 16-week follow-up (d = -.42) than with 1- to 4-week follow-up (d = -0.54). The effect size was higher when antidepressant medication was initiated concurrently with rTMS (5 RCTs, d = -.56) than when patients were on a stable dose of medication (9 RCTs, d = -.43) or were unmedicated (2 RCTs, d = -.26).
In 2014, Dunner et al reported 1-year follow-up with maintenance therapy from a large multicenter observational study (42 sites) of rTMS for patients with TRD. A total of 257 patients agreed to participate in the follow-up study of 307 who were initially treated with rTMS. Of these, 205 completed the 12-month follow-up, and 120 patients had met the Inventory of Depressive Symptoms-Self Report response or remission criteria at the end of treatment. Ninety-three of the 257 patients (36.2%) who enrolled in the follow-up study received additional rTMS (mean, 16.2 sessions). Seventy-five of the 120 patients (62.5%) who met response or remission criteria at the end of the initial treatment phase (including a 2 month taper phase) continued to meet response criteria through follow-up.
A variety of maintenance schedules are being studied (Richieri et al, 2013; Connolly et al, 2012; Janicak, 2010).
AMYOTROPHIC LATERAL SCLEROSIS OR MOTOR NEURON DISEASE
A Cochrane review by Fang (2013) identified 3 RCTs with a total of 50 participants with amyotrophic lateral sclerosis (ALS) that compared rTMS with sham TMS. All of the trials were considered to be of poor methodologic quality. Heterogeneity prevented pooling of results, and the high rate of attrition further increased the risk of bias. The review concluded that evidence is currently insufficient to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS.
CHRONIC PAIN
Jiang et al conducted a systematic review and meta-analysis of 38 RCTs that assessed the analgesic effect of rTMS in 1338patients with neuropathic pain (Jiang, 2022). 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.
Su et al conducted a meta-analysis of 18 RCTs (N=643) with rTMS in patients with fibromyalgia (Su, 2021). 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.
A Cochrane review by O’Connell et al evaluating noninvasive brain stimulation techniques was first published in 2010 and was updated in 2014 and 2018. (O’Connell et al, 2014; O’Connell et al, 2018). The reviewers identified 42 RCTs (range 4 to 70 participants) on TMS for chronic pain. There was low to very low quality evidence that low frequency rTMS or rTMS to the DLPFC is ineffective.
EPILEPSY
A 2016 Cochrane review by Chen et al included seven RCTs on rTMS for epilepsy, five of which were completed studies with published data. The total number of participants was 230. All studies had active or placebo controls, and four were double-blinded. However, a meta-analysis could not be conducted due to differences in the design, interventions, and outcomes of the studies. Therefore, a qualitative synthesis was performed. For the outcome of seizure rate, two studies showed a significant reduction and five studies did not. Of the four studies evaluating the mean number of epileptic discharges, three showed a statistically significant reduction in discharges. Adverse effects were uncommon and mild, involving headache, dizziness, and tinnitus. There were no significant changes in medication use.
In 2012, Sun et al reported a randomized double-blind controlled trial of low-frequency rTMS to the epileptogenic zone for refractory partial epilepsy. Sixty patients were randomized into 2 groups; one group received 2 weeks of rTMS at 90% of resting motor threshold and the other group received rTMS at 20% of resting motor threshold. The initial results are promising, but require substantiation in additional trials.
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. Two of the included studies showed statistically significant reductions in the seizure rate from baseline, 3 trials failed to show any statistically significant difference in seizure frequency, and 2 had unclear results due to inadequate power. In a meta-regression, when adjusted for other potential variables such as the type of coil used, stimulation frequency, and the total duration of the active intervention, seizure frequency worsened by 2.00 ± 0.98 (p=0.042) for each week of lengthening of the posttreatment follow-up period. These results suggested that rTMS exerted only a short-term effect. The reviewers concluded that although the procedure may be a therapeutic alternative for patients with drug-resistant epilepsy, further RCTs using standarized protocols and with adequate sample sizes and duration are still needed.
FIBROMYALGIA
In 2017, Saltychev and Laimi published a meta-analysis of rTMS for the treatment of patients with fibromyalgia. The meta-analysis included seven sham-controlled double-blinded RCTs with low risk of bias. The sample size of the trials ranged from 18 to 54. Five of the studies provided high-frequency stimulation to the left primary motor cortex, the remaining two were to the right DLPFC or left DLPFC. The number of sessions ranged from 10 to 24, and follow-up ranged from immediately after treatment to 3 months after treatment. In the pooled analysis, pain severity decreased after the last simulation by 1.2 points (95% CI, -1.7 to -0.8) 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 to be clinically significant, with a minimal clinically important difference of 1.5 points.
A 2012 systematic review included 4 studies on transcranial direct current stimulation and 5 on rTMS for treatment of fibromyalgia pain. Three of the 5 trials were considered to be high quality. Four of the 5 were double-blind randomized controlled trials; the fifth included study was a case series of 4 patients who were blinded to treatment. Quantitative meta-analysis was not conducted due to variability in brain site, stimulation frequency/intensity, total number of sessions, and follow-up intervals, but 4 of the 5 studies on rTMS reported significant decreases in pain. Greater durability of pain reduction was observed with stimulation of the primary motor cortex compared to the dorsolateral prefrontal cortex.
One of the studies included in the systematic review was a small 2011 trial that was conducted in the U.S. by Short et al Twenty patients with fibromyalgia, defined by the American College of Rheumatology criteria, were randomized to 10 sessions of left prefrontal rTMS or sham TMS along with their standard medications. At 2 weeks after treatment, there was a significant change from baseline in average visual analog scale (VAS) for pain in the rTMS group (from 5.60 to 4.41) but not in the sham-treated group (from 5.34 to 5.37). There was also a significant improvement in depression symptoms in the active group compared to baseline (from 21.8 to 14.10) but not in the sham group (from 17.6 to 16.4). There were no statistically significant differences between the groups in this small trial.
Additional study is needed to determine effective treatment parameters in a larger number of subjects and to evaluate durability of the effect.
MIGRAINE HEADACHE
Saltychev et al conducted a systematic review and meta-analysis of 8 RCTs that compared rTMS to sham stimulation inpatients with migraine (Saltychev, 2022). All RCTs used high frequency rTMS to the left dorsolateral prefrontal cortex and all studies except 1 included patients with chronic migraine. All studies except 1 had a low risk of bias and the risk of publication bias was 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.
A pivotal randomized, double-blind, multicenter, sham-controlled trial was performed with the Cerena™ TMS device to demonstrate safety and effectiveness for the de novo application (FDA, 2013). According to the FDA labeling, the device has not been demonstrated as safe or effective when treating cluster headache, chronic migraine headache, or when treating migraine headache during the aura phase. The device has not been demonstrated as effective in relieving the associated symptoms of migraine (photophobia, phonophobia, nausea) (FDA,2013).
OBSESSIVE COMPULSIVE DISORDER
Perera et al conducted a systematic review and meta-analysis of rTMS in the treatment of OCD (Perera, 2021). 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 4weeks 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.
Two small (n=18 and 30) randomized sham-controlled trials found no evidence of efficacy for treatment of obsessive compulsive disorder (OCD), although another small sham-controlled trial (n=21) reported promising results with bilateral stimulation of the supplementary motor area (Sachdev, 2007; Mantovani, 2010; Mansur, 2011).
A 2013 meta-analysis by Berlim et al included 10 small RCTs totaling 282 patients with obsessive-compulsive disorder (OCD).23 Response rates of rTMS augmentation therapy were 35% for active and 13% for sham rTMS. The pooled odds ratio was 3.39, and the number needed to treat was 5. There was no evidence of publication bias. Exploratory subgroup analysis suggested that the two most promising stimulation parameters were low-frequency rTMS and non-DLPFC regions (ie, orbitofrontal cortex or supplementary motor area). Further study focusing on these stimulation parameters is needed.
A 2016 meta-analysis by Trevizol et al included 15 RCTs (total N=483 patients) that compared active vs sham rTMS for OCD.24 All studies were sham-controlled and double-blinded. Sample sizes in the trials were small-to-moderate, ranging from 18 to 65 patients (mean sample size, 16.1 patients). Seven studies used low-frequency stimulation and eight used high-frequency stimulation. The cortical regions varied among the studies, targeting the supplementary motor area, orbitofrontal cortex, or left, right, or bilateral DLPFC. The effect size for active stimulation was modest at 0.45 (95% CI, 0.2 to 0.71). The SMD was 2.94 (95% CI, 1.26 to 4.62). Regression did not identify any significant factors. There was no evidence of publication bias from funnel plots.
More recently, Liang et al (2021) conducted a systematic review and meta-analysis of different TMS modalities for the treatment of OCD. Three of the 5 protocols assessed were significantly more efficacious than sham TMS, and all treatment strategies were similar to sham TMS regarding tolerability. Transcranial magnetic stimulation was not more effective than sham TMS, but there was direct evidence from only 1 RCT for this comparison (Carmi et al, 2019, discussed in the next section). 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.
Trial
A more recent RCT was not included in the SR conducted by Trevizol et al (2019) (Carmi et al, 2019). The trial was submitted to FDA as part of the de novo classification request, to establish a reasonable assurance of safety and effectiveness of the device (U.S. Food and Drug Administration, 2018). A total of 99 patients were randomized to active treatment or sham. The primary outcome was the difference between groups in the mean change from baseline to 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 intention to treat 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 (-2.8points), translating to a moderate effect size of 0.69. At 6 weeks, the response rate was 38.1% in the active treatment group compared to 11.1% in the sham group (P=0.003). The FDA review provides data from the ITT analysis of the mean change in YBOCS score (N=99). In the ITT data set, the YBOCS score decreased by -6.0 points (95% CI, -3.8 to -8.2) in the active group and by -4.1 points (95% CI, -1.9 to -6.2) in the sham group. Although the decreases were both statistically significant from baseline, the difference of 1.9 points between the treatment arms was not statistically significant (P=0.0988). Results on the secondary outcomes were mixed. More patients in the active treatment group were considered improved based on the Clinical Global Impression of Improvement (CGI-I) and the Clinical Global Impression of Severity (CGI-S) at 6 weeks, but there was no significant difference between groups on the Sheehan Disability Scale.
PSYCHIATRIC DISORDERS OTHER THAN DEPRESSION OR OBSESSIVE-COMPULSIVE DISORDER
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. Eight trials of rTMS in bipolar depression showed small but statistically significant improvements in depression scores compared to sham control (standardized mean difference = 0.302, P < 0.05). However, most studies had a high risk of bias which could have exaggerated the treatment effects. The effect of rTMS was inconclusive in bipolar mania due to the high heterogeneity and limited number of controlled trials.
Konstantinou et al conducted a systematic review of 31 RCTs of rTMS for the treatment of bipolar disorder; meta-analysis was not performed (Konstantinou, 2022). 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.
Generalized Anxiety Disorder
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. Results of the analysis showed that rTMS improved anxiety symptoms as measured by the Hamilton Anxiety Scale, (standardized mean difference = -0.68, 95% CI -0.89 to -0.46). The conclusions that could be drawn from the body of evidence were limited by significant heterogeneity across studies, and the authors concluded that additional high-quality studies are needed to confirm the results.
Panic Disorder
A 2014 Cochrane review by Li et al identified 2 RCTs with a total of 40 patients that compared low frequency rTMS with sham rTMS over the right DLPFC. The larger of the 2 studies was a randomized double-blind sham-controlled trial of low-frequency rTMS to the right dorsolateral prefrontal cortex in 21 patients with panic disorder with comorbid major depression (Mantovani et al, 2013). Response was defined as a 40% or greater decrease on the panic disorder severity scale (PDSS) and a 50% or greater decrease on the HAM-D. After 4 weeks of treatment, the response rate for panic was 50% with active rTMS and 8% with sham. The study had a high risk of attrition bias. The overall quality of evidence for the 2 studies was considered to be low, and the sample sizes were small, precluding any conclusions about the efficacy of rTMS for panic disorder.
Posttraumatic Stress Disorder
In 2016, Trevizol et al published a meta-analysis on the efficacy of rTMS for posttraumatic stress disorder
(PTSD). Five sham-controlled RCTs (total N=118 patients) were included in the review. Most studies used stimulation of the right DLPFC, though some delivered rTMS to the left DLPFC or bilaterally. Three studies used high-frequency stimulation while one used low-frequency stimulation and one compared high- with low-frequency stimulation; the percent motor threshold ranged from 80% to 120%. Some trials provided rTMS in combination with a script of the traumatic event, and different PTSD scales were used. In a meta-analysis, active rTMS was found to be superior to sham (SMD=0.74; 95% CI, 0.06 to 1.42), although heterogeneity of the trials was high.
Schizophrenia
Zhu et al conducted a study in China at 7 sites between 2017-2018 (Zhu, 2021). Participants included Inpatients between the ages of 18 to50 years with a diagnosis of schizophrenia per ICD-10 criteria who were right-handed and clinically stable for the past 3 months (N=32). Intermittent theta burst stimulation over the cerebellum (3 pulses at 50 Hz repeated at a rate of 5 Hx for a total of600 pulses) was
administered 5 times a week (Monday to Friday) for 2 weeks. At 2, 6, 12, and 24 weeks after the end of treatment, PANSS negative symptom scores were significantly lower in the rTMS group compared to the sham group (p<.05). The effect of treatment on positive symptoms and PANSS total scores was not significant.
One of the largest areas of TMS research outside of depressive disorders is the treatment of auditory hallucinations in schizophrenia resistant to pharmacotherapy. In 2011, TEC published an Assessment of TMS as an adjunct treatment for schizophrenia (BCBSA, 2011). Five meta-analyses were reviewed, along with randomized controlled trials (RCTs) in which measurements were carried out beyond the treatment period. A meta-analysis of the effect of TMS on positive symptoms of schizophrenia (hallucinations, delusions, and disorganized speech and behavior) did not find a significant effect of TMS. Four meta-analyses that looked specifically at auditory hallucinations showed a significant effect of TMS. It was noted that outcomes were evaluated at the end of treatment, and the durability of the effect is unknown. The Assessment concluded that the available evidence is insufficient to demonstrate that TMS is effective in the treatment of schizophrenia.
A 2012 meta-analysis included 17 randomized double-blind sham-controlled trials (n=337) of the effect of rTMS on auditory hallucinations (Slotema, 2012). A 2013 meta-analysis by Zhang et al included 17 RCTs (N=398) that evaluated low-frequency rTMS of the left temporoparietal cortex for the treatment of auditory hallucinations. A small (n=18) double-blind randomized sham-controlled trial from 2012 found no significant effect of deep rTMS with an H1 coil on auditory hallucinations (Rosenberg, 2012).
A 2015 Cochrane review by Dougall et al included 41 studies with a total of 1473 participants. Based on very low-quality evidence, there was a significant benefit of temporoparietal TMS compared with sham for global state (7 RCTs) and positive symptoms (5 RCTs). The evidence on the cognitive state was equivocal. For prefrontal rTMS compared with sham, the evidence on global state and cognitive state was of very low quality and equivocal. The review concluded that there is insufficient evidence to support or refute the use of TMS to treat symptoms of schizophrenia and, although some evidence suggests that temporoparietal TMS may improve certain symptoms (eg, auditory hallucinations, positive symptoms of schizophrenia), the results were not robust enough to be unequivocal.
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. For 1-Hz rTMS, 13 studies were included. Compared with sham, the rTMS group showed greater improvement in auditory hallucinations (standard mean difference, -0.29; 95% CI, -0.57 to -0.01). However, significant heterogeneity across the studies was found (p=0.06). 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<0.001). The review was further limited by the small number of articles included and by the lack of original data for some studies.
Several additional small, single center RCTs of rTMS for the treatment of schizophrenia have been published since the systematic reviews described above (Guan et al, 2020; Zhuo et al, 2019; Kumar et al, 2020) Due to study limitations, the studies do not provide sufficient evidence to draw conclusions about the effectiveness of the technology in patients with schizophrenia.
PARKINSON DISEASE
Li et al conducted a meta-analysis of 32 sham controlled RCTs of rTMS in patients with Parkinson disease and motor dysfunction (N=1048 patients) (Li, 2022). 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.
A systematic review from 2009 included 10 randomized controlled trials with a total of 275 patients with Parkinson disease (Elahi, 2009). Seven of the studies were double-blind, one was not blinded and 2 of the studies did not specify whether the raters were blinded. In studies that used high-frequency rTMS there was a significant improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) with a moderate effect size of -0.58. For low-frequency rTMS, the results were heterogeneous and did not significantly reduce the UPDRS. The analyzed studies varied in outcomes reported, rTMS protocol, patient selection criteria, demographics, stages of Parkinson disease and duration of follow-up, which ranged from immediate to 16 weeks after treatment
In 2012, Benninger et al reported a randomized double-blind sham-controlled trial of brief (6 sec) very-high-frequency (50 Hz) rTMS over the motor cortex in 26 patients with mild to moderate Parkinson disease. Eight sessions of 50 Hz rTMS did not improve gait, bradykinesia, or global and motor scores on the UPDRS compared to the sham-treated group. Activities of daily living were significantly improved a day after the intervention, but the effect was no longer evident at 1 month after treatment. Functional status and self-reported well-being were not affected by the treatment. No adverse effects of the very-high-frequency stimulation were identified.
Another study from 2012 randomized 20 patients with Parkinson disease to 12 brief sessions (6 min) of high-frequency (5-Hz) rTMS or sham rTMS over the leg area of the motor cortex followed by treadmill training (Yang, 2013). Blinded evaluation showed a significant effect of rTMS combined with treadmill training on neurophysiological measures, and change in fast walking speed and the timed up and go task. Mean treadmill speed improved to a similar extent in the active and sham rTMS groups.
Additional study with a larger number of subjects and longer follow-up is needed to determine if rTMS improves motor symptoms in patients with Parkinson disease.
STROKE
Qiao et al performed a meta-analysis of RCTs that assessed the effect of rTMS in 433 patients with post-stroke dysphagia (Qiao, 2022). 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.
A 2013 Cochrane review included 19 RCTs with a total of 588 participants on the effect of TMS for improving function after stroke (Hao et al, 2013). The 2 largest trials (N=183) showed that rTMS was not associated with a significant improvement in the Barthel Index. Four trials (N=73) found no significant effect for motor function. Subgroup analysis for different stimulation frequencies or duration of illness also did not show a significant benefit of rTMS when compared with sham rTMS or no treatment. The review concluded that current evidence does not support the routine use of rTMS for the treatment of stroke.
Hsu et al (2012) reported a meta-analysis of the effect of rTMS on upper limb motor function in patients with stroke. Eighteen randomized controlled trials with a total of 392 patients were included in the meta-analysis. Most of the studies were double blind (n=11) or single blind (n=3). Eight studies applied low frequency (1 Hz) rTMS over the unaffected hemisphere, 5 applied high frequency (5 Hz) rTMS over the affected hemisphere, and 2 used both low- and high-frequency stimulation. Outcomes included kinematic motion analyses (5 trials), hand grip (2 trials), and the Wolf Motor Function Test (2 trials). Meta-analysis of results showed a moderate effect size (0.55) for rTMS on motor outcome, with a greater effect size of rTMS in patients with subcortical stroke (mean effect size, 0.73) compared to non-specified lesion sites (mean effect size, 0.45), and for studies applying low-frequency rTMS (mean effect size, 0.69) compared to high-frequency rTMS (effect size, 0.41). Effect size of 0.5 or greater was considered to be clinically meaningful.
Hand Function
A 2014 meta-analysis assessed the effect of rTMS on the recovery of hand function and excitability of the motor cortex after stroke.33 Eight RCTs (total N=273 participants) were included in the review. The quality of the studies 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 (1-25 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 potential (n=43) or motor threshold (n=62).
Aphasia
A 2015 meta-analysis included 4 RCTs on rTMS over the right pars triangularis for patients (total N=137 patients) with aphasia after stroke (Li et al, 2015). All studies used double-blinding, but therapists were not blinded. Every study used a different outcome measure, and sample sizes were small (range, 12-40 patients). Meta-analysis showed a medium effect size for naming (p=0.004), a trend for a benefit on repetition (p=0.08), and no significant benefit for comprehension (p=0.18). Additional study in a larger number of patients is needed to determine with greater certainty the effect of this treatment on aphasia after stroke.
Upper-Limb
Zhang et al (2017) published a systematic review and meta-analysis evaluating the effects of rTMS on upper-limb motor function after stroke. A search through October 2016 yielded 34 RCTs with a total of 904 participants (range, 6-108 participants). Pooled estimates found improvement with rTMS for both short-term (SMD=0.43; p<0.001) and long-term (SMD=0.49; p<0.001) 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.
In 2016, Graef et al reported a meta-analysis of rTMS combined with upper-limb training for improving function after stroke. Included were 11 sham-controlled randomized trials with 199 patients that evaluated upper-limb motor/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).
SUBSTANCE ABUSE AND CRAVING
Chang et al conducted a meta-analysis of 7 double-blind RCTs (N=462) that used rTMS to treat methamphetamine use disorder (Chang, 2022). 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.
Jansen et al reported a 2013 meta-analysis of the effect of rTMS and transcranial direct current stimulation (tDCS) of the DLPFC on substance dependence (alcohol, nicotine, cocaine, marijuana) or craving for high palatable food. Seventeen double-blind, sham-controlled RCTs that used high frequency stimulation were included in the analysis. The standardized effect size was 0.476, indicating a medium effect size for active stimulation over sham, although there was significant heterogeneity in the included studies. No significant differences were found in the effectiveness of rTMS versus tDCS, the different substances, or the side of stimulation.
SUMMARY OF EVIDENCE
For individuals who have TRD who receive rTMS, the evidence includes a large number of sham-controlled randomized trials and meta-analyses of these trials. Relevant outcomes are symptoms, functional outcomes, and quality of life. The meta-analyses found a clinical benefit associated with rTMS for TRD with improved response rates and rates of remission compared with sham. The most recent meta-analyses have concluded that the effect of rTMS, on average depression scores, is smaller than the effect of ECT on TRD and that the mean improvement in depression scores with rTMS 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 rTMS is in accelerating or enhancing the response to antidepressant medications, and 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. The effect of rTMS 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 rTMS decreases with longer follow-up, though some studies have reported 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 rTMS appear to be minimal. While the most recent meta-analyses have reported that the effect of rTMS is smaller than the effect of ECT on TRD, because rTMS does not require general anesthesia or induce seizures, some individuals may decline ECT so the balance of incremental benefits and harms associated with rTMS may be a 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, rTMS may be considered a treatment option in patients with TRD who meet specific criteria. The evidence for theta burst stimulation includes a large randomized trial showing noninferiority with another method of rTMS; no significant differences were noted in the number of adverse events. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have migraine headache who receive rTMS, the evidence includes a sham controlled RCT of 201 patients conducted for submission to the FDA for clearance in 2013.The trial results were limited by the 46% dropout rate and use of a post hoc analysis. No recent studies have been identified with these devices. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have obsessive compulsive disorder (OCD) who receive rTMS, the evidence includes a number of small-to-moderate sized sham-controlled RCTs and a meta-analyses of these studies. The meta-analysis of 15 RCTs (total N=483 patients, range 18-65 patients) 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. A more recent RCT compared deep rTMS to sham in 99 patients for 6 weeks, with an additional 4 weeks of followup as a secondary outcome. Using a modified ITT analysis(N=94), there was a larger mean change from baseline on the primary efficacy outcome; Yale-Brown Obsessive Compulsive Scale (YBOCS)score in the active treatment group (-6.0 points) than the sham group (-2.8 points), translating to a moderate effect size of 0.69. At 6 weeks, the response rate was 38.1% in the active treatment group compared to 11.1% in the sham group (P=0.003), as measured by a 30% or greater decrease in the YBOCS. The difference on the primary outcome measure between active and sham groups was not statistically significant inthe 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 followup duration are needed to confirm these results. The evidence is insufficient to determine the effect of the technology on health outcomes.
For individuals who have psychiatric or neurologic disorders other than depression, migraine, or obsessive-compulsive disorder (eg, amyotrophic lateral sclerosis, chronic pain, epilepsy, fibromyalgia, panic disorder, Parkinson disease, posttraumatic stress disorder, schizophrenia, stroke, substance abuse and craving) who receive rTMS, 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 the effects of the technology on health outcomes.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov registry identified several currently unpublished trials that might influence this policy.
PRACTICE GUIDELINES AND POSITION STATEMENTS
American Psychiatric Association
In 2018, the American Psychiatric Association published consensus recommendations on rTMS for the treatment of depression (McClintock et al, 2017). The guidelines state, "Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy." The recommendations include information on the following variables: clinical environment, operator requirements, documentation, coils, cortical targets, coil positioning methods, determination of motor threshold, number of treatment sessions for acute treatment, and allowable psychotropic medications during TMS treatment.
The Association’s guidelines on the treatment of patients with obsessive-compulsive disorder (2007, reaffirmed in 2012) have indicated that “findings of the four published trials of repetitive TMS (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.”
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 (Murphy et al, 2013). The Academy did not recommend rTMS, citing the limited evidence on the safety, ethics, and long-term impact on development.
Veteran's Affairs/Department of Defense
The 2022 Veteran's Affairs/Department of Defense 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) (VA/DoD Clinical Practice Guideline, 2022). 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.
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 (NICE, 2020).
National Institute for Health and Care Excellence
In 2015, the National Institute for Health and Care Excellence 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 (NICE, 2015).
In 2014, the Institute provided guidance on the use of rTMS for treating and preventing migraine (NICE, 2014). The guidance stated that evidence on the efficacy of TMS for the treatment of a migraine was limited in quantity and for the prevention of a 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.
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 (Leung, 2020). 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.
Regulatory Status
Devices for transcranial stimulation have been cleared for marketing by the U.S. Food and Drug Administration (FDA) for diagnostic uses (FDAProduct Code: GWF). A number of devices subsequently received FDA clearance for the treatment of major depressive disorders 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 headache. The device differs from the predicate Cerena™ TMS device with the addition of an LCD screen, a use authorization feature, lithium battery pack, and 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 novo510(k) classification by FDA (DEN170078). The new classification applies to this device and substantially equivalent devices of this generic type. The Brainsway Deep TMS System is cleared for treatment of adults with obsessive-compulsive disorder. FDA product code: QCI.
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 2013, the Cerena™ TMS device (Eneura Therapeutics) received de novo marketing clearance 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.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.
Selected devices that are FDA cleared are listed below. For major depressive disorder (Product Code: OBP), migraine headache pain (Product Code: OKP), and obsessive-compulsive disorder (Product Code: QCI)
Repetitive TMS Devices Cleared by FDA for Major Depression, Migraine, or Obsessive-Compulsive Disorder
(listed by Device, Manufacturer, Indication, FDA Clearance No., FDA Clearance Date)
- Horizon 3.0 TMS Therapy. System Magstim. Major depressive disorder and obsessive-compulsive disorder K222171 01/13/2023
- ALTMS Magnetic Stimulation Therapy System. REMED Co., Ltd. Major depressive disorder K220625 04/06/2022
- Neurostar Neuronetics Major Depressive Disorder K083538 12/16/2008
- Brainsway Deep TMS System Brainsway Major Depressive Disorder K122288 01/07/2013 Obsessive-Compulsive Disorder K183303 03/08/2019
- Springtms Total Migraine System Eneura Migraine headache with aura K140094 05/21/2014
- Rapid Therapy System Magstim Major Depressive Disorder K143531 05/08/2015
- Magvita Tonica Elektronik Major Depressive Disorder K150641 07/31/2015
- Mag Vita TMS Therapy System w/Theta Burst Stimulation Tonica Elektronik Major Depressive Disorder K173620 8/14/2018
- Neurosoft TeleEMG Major Depressive Disorder K160309 12/22/2016
- Horizon Magstim Major Depressive Disorder K171051 09/13/2017
- Horizon TMS Therapy System (Theta Burst Protocol) Magstim Major Depressive Disorder K182853 03/15/2019
- Nexstim Nexstim Major Depressive Disorder K171902 11/10/2017
- Apollo Mag & More Major Depressive Disorder K180313 05/04/2018