Transcranial Magnetic Stimulation

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Abstract:

Transcranial magnetic stimulation (TMS) is a noninvasive method of brain stimulation. The technique involves placement of a small coil over the scalp and passing a rapidly alternating current through the coil wire which produces a magnetic field that passes unimpeded through the brain. Depending on stimulation parameters (frequency, intensity, pulse duration, stimulation site), repetitive TMS (rTMS) to specific cortical regions can either increase or decrease the excitability of the affected brain structures. The procedure is usually carried out in an outpatient setting and does not require anesthesia or analgesia.

Transcranial magnetic stimulation has been investigated in the treatment of various disorders, primarily depression. In 2008 the U.S. Food and Drug Administration (FDA) granted 510(k) marketing clearance as a “de novo” device (assessed as low risk, no predicate device) for NeuroStar® TMS to be utilized as a Class II rTMS device for the treatment of major depressive disorder in patients who had not responded to one adequate trial of antidepressant medication. 

The FDA first allowed marketing of deep transcranial magnetic stimulation (d-TMS) for the treatment of obsessive-compulsive disorder in August 2018. [FDA.gov (dTMS)] Deep transcranial magnetic stimulation (d-TMS) uses magnetic pulses to target specific areas of the brain that have been implicated in certain conditions.

Indications and Limitations:

Indications:

Repetitive transcranial magnetic stimulation (rTMS) is only considered medically necessary in adults who have a confirmed diagnosis of major depressive disorder (MDD), single or recurrent episode and meet the following criteria:

One or more of the following:

• Resistance to treatment with psychopharmacologic agents as evidenced by a lack of a clinically significant response to one trial of psychopharmacologic agents in the current depressive episode from at least two different agent classes. Each agent in the treatment trial must have been administered at an adequate course of mono- or poly-drug therapy; or
• Inability to tolerate psychopharmacologic agents as evidenced by two trials of psychopharmacologic agents from at least two different agent classes, with distinct side effects; or
• History of response to rTMS in a previous depressive episode; or
• If patient is currently receiving electro-convulsive therapy, rTMS may be considered reasonable and necessary as a less invasive treatment option.

AND
A trial of an evidence-based psychotherapy known to be effective in the treatment of MDD of an adequate frequency and duration without significant improvement in depressive symptoms as documented by standardized rating scales that reliably measure depressive symptoms.

AND
The order for treatment (or retreatment) is written by a psychiatrist (MD or DO) who has examined the patient and reviewed the record. The physician will have experience in administering TMS therapy. The treatment shall be given under direct supervision of this physician (physician present in the area but does not necessarily personally provide the treatment).

• NPPs providers may order treatment (or retreatment) if it is within the scope of practice of the NPP in the State they are licensed. It is expected that the NPP has examined the patient, reviewed the record and has experience administering TMS therapy. The treatment shall be given under direct supervision of this NPP.

AND
The rTMS treatment is delivered by a device that is FDA-approved or –cleared for the treatment of MDD in a safe and effective manner. rTMS treatment should generally follow the protocol and parameters specified in the manufacturer’s user manual, with modifications only as supported by the published scientific evidence base.

Limitations:

The benefits of TMS use must be carefully considered against the risk of potential side effects in patients with any of the following:

• Seizure disorder or any history of seizures (except those induced by ECT or isolated febrile seizures in infancy without subsequent treatment or recurrence); or
• Presence of acute or chronic psychotic symptoms or disorders (such as schizophrenia, schizophreniform or schizoaffective disorder) in the current depressive episode; or
• Neurological conditions that include epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, history of repetitive or severe head trauma, or primary or secondary tumors in the central nervous system, or
• Presence of an implanted magnetic-sensitive medical device located less than or equal to 30 cm from the TMS magnetic coil or other implanted metal items including, but not limited to a cochlear implant, implanted cardiac defibrillator (ICD), pacemaker, Vagus nerve stimulator (VNS), or metal aneurysm clips or coils, staples or stents. (Dental amalgam fillings are not affected by the magnetic field and are acceptable for use with TMS).
• Maintenance therapy is not currently supported by evidence from clinical trials and therefore, is considered not reasonable and necessary.
• All other conditions not included in the above list of “Indications.”

Deep TMS (d-TMS) is not considered reasonable and necessary for Obsessive Compulsive Disorder (OCD). 

Retreatment

Retreatment may be considered for patients who met the guidelines for initial treatment and subsequently developed relapse of depressive symptoms if the patient responded to prior treatments as evidenced by a greater than 50% improvement in standard rating scale measurements for depressive symptoms.

Blue Cross Blue Shield TEC Assessments. Transcranial Magnetic Stimulation for Depression (October 2009, In Press, April 2011): The Blue Cross and Blue Shield Association performed an extensive literature review to evaluate the efficacy of transcranial magnetic stimulation for depression and published its findings as a TEC Assessment in 2009. The Blue Cross and Blue Shield Association Medical Advisory Panel concluded that “transcranial magnetic stimulation for the treatment of depression does not meet the TEC criteria.” In 2011 an updated report was issued. Literature was reviewed through January 2011 and meta-analyses of sham-controlled studies of TMS were selected for review to determine whether TMS therapy was effective for the treatment of depression.

The authors concluded that although the meta-analyses and recent clinical trials of TMS generally show statistically significant effects on depression outcomes at the end of the TMS treatment period (1–4 weeks), there is a lack of rigorous evaluation beyond the period of treatment. Therefore, the Advisory Panel concluded that “the available evidence does not permit conclusions regarding the effect of TMS on health outcomes or compared with alternatives.” (Blue Cross Blue Shield TEC Assessment, Transcranial Magnetic Stimulation for Depression. In Press, April 2011)

O’Reardon (2007) conducted a study under an Investigational Device Exemption (IDE) from the U.S. Food and Drug Administration (FDA) to determine whether repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) was effective and safe.

Three hundred and one (301) patients with major depressive disorder (MDD) were enrolled at 23 study sites and randomized to either active or sham rTMS. Treatment and rating personnel were blinded to patient assignments. Eligible patients were antidepressant medication-free, aged 18-70, with a single or recurrent MDD episode and a current MDD episode duration of three (3) years or less. Treatments occurred daily five days a week for six (6) weeks followed by a tapering period of three additional weeks during which time patients were begun on an antidepressant. Subjects achieving less than a 25% reduction on the Hamilton Depression Rating Scale-17 (HAMD-17) at four weeks could crossover to an open-label, acute treatment extension study. The primary outcome was the difference between active and sham TMS using the last visit Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale and response and remission rates using the MADRS and HAMD.

At the primary efficacy point of four weeks, the baseline to endpoint change on both the HAMD-17 and the HAMD-24 but not the MADRS showed a significant improvement for the active rTMS group. The result was sustained at six weeks. Significant response rates (> 50% improvement from baseline) were present at four and six weeks for the active treatment group using each of the three scales (HAMD-17, HAMD-24, and MARDS). A significant difference in remission rates did not occur at four weeks but was higher for the active group at six weeks for the MARDS and HAMD-24.

Limitations of the study included the period of randomization lasting only through the first four weeks of the study with 74 (47.7%) in the active group and 92 (63.0%) in the sham group electing to enter the open-label extension study; no follow-up after the study; and the study was supported by the manufacturer.

Avery (2008) reported on the results of the open-label study summarized immediately above [O’Reardon (2007)]. Non-responders at four weeks could enroll in a second six-week extension trial of open-label rTMS at each of the 23 treatment sites. The first six-week phase of the study was anti-depressant free followed by a three-week rTMS taper phase with initiation of one of 15 different antidepressants. During the taper phase rTMS was delivered three, two and one time in the first, second and third weeks, respectively. As noted above, 166 patients entered the study but only 158 were present for at least one post-baseline observation, 73 of whom had been in the active arm and 85 in the sham. The primary efficacy outcome was the change in total score on the MADRS from the start of the open-label phase to six weeks or study endpoint. Secondary outcome measures included the HAMD-17 and HAMD-24. Remission was defined as a score 50% reduction from baseline. Remission at the end of the taper phase was achieved by 30.6% using MARDS and 36.7% using the HADM-24. Study limitations included its open-label design and a probabilistic surface anatomy approach for magnet positioning.

George et al (2010) conducted a National Institutes of Health-sponsored, industry-independent sham controlled randomized trial to test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder. This was a prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatments (fixed-dose phase) followed by continued blinded treatment for up to 3 weeks for improvers. Study participants were all antidepressant drug-free with unipolar nonpsychotic major depressive disorder. One hundred ninety patients entered the intention-to-treat group from approximately 860 screened patients. The group had an average of 1.5 failed research-quality adequate treatment trials and study participants were considered to be moderately treatment resistant. The major goal of this study was to assess whether active, compared with sham rTMS increased the remission rate during phase 1 of the rTSM. Authors concluded:

Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.21-13.24). The number needed to treat was 12.

Study strengths included the successful blinding of patients, treaters, and clinical raters to the randomization status of the study participants; the rigorous rater certification process; and methodological improvements over previous studies including MRI adjustment for coil placement in approximately one-third of patients. Study limitations noted included failure to enroll the projected 240 individuals suggested by the original power analysis; a patient population that was antidepressant medication free (not using rTMS in conjunction with pharmacotherapy which may have increased the positive response rate); and a treatment protocol which assessed patients after 3 weeks to determine whether there was substantial improvement. No one received treatment for a full six weeks which was the point at which O’Reardon et al (2007) found a significant difference in remission rates.

Martin et al (2003) published a systematic review and meta-analysis of data from 14 randomized controlled trials with similar rTMS delivery that compared rTMS with sham in patients with depression. The goal of the study was to assess the efficacy of rTMS in treating depression. The authors concluded:

Current trials are of low quality and provide insufficient evidence to support the use of rTMS in the treatment of depression. Systematic and large-scale studies will be needed to identify patient populations most likely to benefit from its use and treatment parameters most likely to establish sustained response.

Schutter (2007) conducted this meta-analysis to provide an update on the clinical efficacy of fast-frequency rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) for the treatment of depression. The meta-analysis included all available published clinical trials that have studied the antidepressant effects of rTMS; applied at least five treatment sessions of high-frequency rTMS over the left DLPFC; and were double-blind sham-controlled designs. Thirty double-blind sham-controlled parallel studies with 1164 patients comparing the percentage change in depression scores from baseline to endpoint of active versus sham treatment were included. Study participants’ treatment must have been completed within 6 weeks after the first session. The goal of this study was to determine whether DLPFC can be considered an effective treatment method for depression. The author concluded that:

High frequency rTMS over the left DLPFC is superior to sham in the treatment of depression and the effect is comparable to at least a subset of commercially available antidepressant drug agents.

The author noted that the integrity of blinding and lack of a proper control condition, age bias, medication, suboptimal stimulation parameters, and lack of biological information and follow up assessment are study limitations which warrant caution and need to be addressed in future studies.

Lam (2008) performed a systematic review and meta-analysis of randomized controlled trials of active versus sham rTMS for patients with treatment-resistant depression (TRD). A total of 24 studies with 1092 patients were reviewed. The primary outcome was clinical response defined as either a percentage improvement on a continuous score from a depression rating scale, or by a global rating scale. Secondary outcomes included clinical remission, defined as either a score within the normal range of a depression rating scale or a global rating of not depressed or an equivalent. The definitions of TRD were not uniform. Treatment duration varied. Most studies used one to two weeks of rTMS, three used three weeks and two used four weeks. Anti-depressant medication was used in all but four studies. Follow-up was described in only eight studies. The author concluded:

For patients with TRD, rTMS appears to provide significant benefits in short-term treatment studies. However, the relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggest that further studies are needed before rTMS can be considered as a first-line monotherapy treatment for TRD.

Daskalakis et al (2008) reviewed existing literature evaluating the efficacy of rTMS for MDD and neurophysiological literature describing mechanisms through which rTMS may exert its therapeutic effect. They summarized the most important studies in 5 broad categories: first-generation studies that have evaluated the efficacy of 10 rTMS sessions (that is, 2 weeks) for TRD; second-generation studies that have evaluated the efficacy of rTMS for more than 10 rTMS sessions; third-generation studies that evaluate the efficacy of rTMS using several novel treatment approaches (for example, bilateral rTMS): meta-analytic studies of rTMS for TRD; and future studies proposing novel methods to optimize the efficacy of treatment resistant depression (TRD).

Efficacy studies evaluating HFL-rTMS to date suggest that rTMS is therapeutically effective, but the magnitude of this clinical effect remains in question. All meta-analyses reviewed by the authors included treatment studies with several limitations including an inconsistent means of defining and quantifying treatment resistance; inconsistency regarding the maintenance, and diagnostic heterogeneity. Additional factors limiting current rTMS trials in MDD to date were that most of the studies involved left-sided treatment alone with the DLPFC; suboptimal methods used to target the DLPFC; treatment durations that were typically short (2-4weeks); and stimulation intensity might have been insufficient by not taking into consideration coil-to-cortex distance which is of particular importance when considering that this parameter may contribute significantly to the rTMS-induced antidepressant response. Another concern was the link between the severity of the MDD symptoms and placebo response. There is evidence to suggest that when subjects with more severe depressive symptoms have lower placebo response rates, in studies that include subjects experiencing mild-to-moderate depressive symptoms, placebo response rates are anticipated to be as high as 50%, potentially undermining the benefits of rTMS. The authors concluded:

Although rTMS was demonstrated in several studies and meta-analyses to be a promising and effective treatment tool for resistant depression, the clinical efficacy is often modest and varies widely between treatment studies. Future studies designed to directly target brain regions associated with depression, to further evaluate bilateral stimulation and to optimize treatment duration intensity are necessary to optimize the efficacy of this treatment for resistant depression.

Janicak et al. (2010) studied 99 patients for 24 weeks who agreed to participate and had met the criteria for at least partial response in either the randomized [O’Reardon et al. (2007)] or open-label extension [Avery et al. (2008)] trials. Individual site investigators and their clinical and research staff were blinded to the original patient assignment (active or sham rTMS). All patients underwent a three-week transition off rTMS while being started on maintenance antidepressant therapy. Only dose adjustments of the antidepressant were allowed during the study period without switching or augmentation of the drugs. Reintroduction of rTMS was allowed if the patient had a Clinical Global Impressions Severity of Illness (CGI-S) score change of at least one point observed over two successive weeks. The rTMS was discontinued when the CGI-S score returned to baseline.

There were 121/142 patients who completed the transition phase and thus eligible for the 24-week study. Ninety-nine (81.8%) agreed to participate. Twenty-one (21.2%) had received a total of 12 weeks of active rTMS. Seventy of the 99 (70.7%) completed the 24-week “durability” study. Approximately 75% maintained a full response and >50% maintained remission using either the MADRS or HAMD24 scores. Thirty-eight (38.4%) had symptom worsening and received rTMS; 32 of these 38 (84.2%) responded. A second period of reintroduction occurred for 15 patients and five (5) had a third round of rTMS.

Twenty-one additional patients who had benefited from sham rTMS also entered the durability study and received anti-depressants. Relapse occurred in three (16.0%). Eleven of the 21 (52.4%) had reintroduction of rTMS and 5/11 (45.5%) responded.

The authors note the strength of this article is that it is the only prospective, follow-up study of rTMS acute antidepressant effects with maintenance antidepressants. Limitations noted included the lack of a controlled comparison. Since the two groups of patients were no longer fully randomized after entry into the long-term trial, the authors noted that inferential statistical comparisons were not appropriate. In addition, the number of sham rTMS only patients was small.

The Agency for Healthcare Research and Quality finalized and published a comparative effectiveness review entitled, “Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults” (Gaynes et al., 2011). Modalities reviewed included ECT, rTMS, vagal nerve stimulation and psychotherapy. Conclusions were as follows:

Our review suggests 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. Interpretation of the data is substantially hindered by varying definitions of TRD and the paucity of relevant studies. The greatest volume of evidence is for ECT and rTMS. However, even for the few comparisons of treatments that are supported by some evidence, the strength of evidence is low for benefits, reflecting low confidence that the evidence reflects the true effect and indicating that further research is likely to change our confidence in these findings. This finding of low strength is most notable in two cases: ECT and rTMS did not produce different clinical outcomes in TRD, and ECT produced better outcomes than pharmacotherapy. No trials directly compared the likelihood of maintaining remission for nonpharmacologic interventions. The few trials addressing adverse events, subpopulations, subtypes, and health-related outcomes provided low or insufficient evidence of differences between nonpharmacologic interventions. The most urgent next steps for research are to apply a consistent definition of TRD, to conduct more head-to-head clinical trials comparing nonpharmacologic interventions with themselves and with pharmacologic treatments, and to delineate carefully the number of treatment failures following a treatment attempt of adequate dose and duration in the current episode.

Carpenter et al. (2012) reported short-term outcomes on 307 patients with major depressive disorder (MDD) who were treated primarily with high-frequency left-sided rTMS in 42 various clinical settings. A Clinical Global Impressions-Severity of Illness Scale (CGI-S) score of ≥ 4 (signifying moderate or worse depression) was found in 99% of the patients at baseline. The primary outcome measure was the change from baseline to end-point on the CGI-S scale. Response was defined as achieving a CGI-S score of ≤ 3 (mildly ill or better) and remission was determined as ≤ 2 (borderline mentally ill or normal/not mentally ill). Psychotropic medicines could be continued. Clinical assessments after rTMS treatment showed 58% response and 37% remission rates, with a statistically significant change of -1.9 ± 1.4. Benefit was noted to be better in those ≤ 55 years of age. The CGI-S was obtained at baseline, two weeks, and at the end of the acute phase with a 42 day average length of treatment. There was no long-term follow-up.

Connolly et al. (2012) studied the first 100 consecutive patients with diagnoses of major depression, bipolar disorder in a current major depressive episode, or depressive disorder not otherwise specified (NOS) treated with rTMS in an academic medical center. Numbers were 65, 20, and 3 respectively. A retrospective analysis of the medical records occurred. Psychotropic medicines were held fixed as long as possible. The rTMS treatments lasted six (6) weeks in the acute treatment with six (6) weeks of tapered maintenance treatment. Patients in the earlier period had the TMS applied over the left DLPFC using the 5-cm rule, but later the F3 electroencephalogram (EEG) – based method was used. A variety of treatment regimens was used. Six (6) patients switched to electroconvulsive treatment (ECT). The primary outcome was the Clinical Global Impressions-Improvement (CGI-I). Patients were followed for six (6) months or until they left treatment. At the endpoint of up to 30 adjunctive sessions, the CGI-I response rate was 50.6% and the remission rate was 24.7%, but the criteria for these determinations were not reported. Limitations of the study were reported as treatment being open-label and adjunctive to existing medications. Detailed characterization of prior ECT trials was not available, there was no control group, and the sample size from a single treatment center would not allow generalization to rTMS treatments more globally.

The New England Comparative Effectiveness Public Advisory Council Public Meeting held December 9, 2011 sought new evidence published after the Agency Healthcare Research and Quality (AHRQ) report. Ten articles were evaluated. The report noted no randomized controlled trials identified, and most of the studies were small, single-center case series of relatively poor quality. One case-series described 15 patients and focused on quality of life improvements for patients receiving rTMS. A cost-effectiveness analysis of rTMS or usual care over a period of five (5) years for the New England commercial and Medicaid populations was performed. Votes of council members occurred on the comparative effectiveness of the four (4) depression treatment options discussed: rTMS, ECT, vagus nerve stimulation, and cognitive behavioral therapy/interpersonal therapy. Pharmacotherapy alone was not addressed. Ten (10) of 15 council members thought evidence was available to demonstrate that rTMS provides a net health benefit equivalent to usual care (i.e., general supportive psychotherapy with or without continued use of antidepressant medication) with five (5) considering it equivalent and five (5) considering it superior.

Janicak et al. (2013) described the quality of life (QOL) and functional status for depressed patients after an acute course of rTMS reported by Carpenter et al. (2012). Functional status outcomes were measures with the Medical Outcome Study Short-Form Health Survey (SF-36). Patient-reported QOL was reported using the EuroQol 5-Dimension Questionnaire (EQ-5D). Patients considered remitters had a higher improvement in the mental component summary (MCS). The EQ-5D also showed better results in the remitters. As noted above, all results were short-term.

Mantovani et al. (2012) reported on a 12-week follow-up study of patients enrolled in a randomized double-blind sham-controlled trial or from an open-label extension trial. Eighteen (18) patients from the first (13 active, 5 sham) and 43 from the second referenced trials were followed for 12 weeks. The primary outcome for relapse was a score of ≥ 20 on the 24-item Hamilton Depression Rating Scale (HDRS-24). Five (5) entered naturalistic follow-up and were in remission at three (3) months. Fifty (50) entered the rTMS taper; six (6) refused follow-up. Twenty-nine (29) of the initial 50 remitters in the taper protocol maintained remission at three (3) months. Two (2) of the five (5) sham remitters were in remission at three (3) months, and one (1) was not; one (1) was still in remission at a one-month follow-up, and there was no information provided for the other sham remitter. One-third of the patients were lost to follow-up. The author’s noted study limitations were the small sample size that completed the three-month follow-up and the relatively low medication levels in those patients who agreed to continued pharmacotherapy.

McDonald et al. (2011) studied strategies for improving the response to rTMS. Patients were allowed to receive up to 12 weeks of fast left rTMS and a maximum of 180,000 pulses. It also looked at the outcomes of switching fast left rTMS nonresponders to low frequency stimulation (1 Hz) over the right DLPFC of slow right rTMS. Patients were part of a larger trial (George et al., 2010) and Phase 1 patients are reported in that paper. Phase 2 patients (McDonald et al., 2011) could receive open label fast left rTMS if they had improved but were not in remission after the first six (6) weeks in the Phase 1 trial. Patients not satisfactorily improving were given the option of being switched to slow right rTMS. Sixteen percent (16%) (n= 22/141) remitted with the open fast left treatments. The percent of remission for the 21/81 was 26% for those receiving slow right treatments. The authors noted the remission rates in the open label phase 2 study were more than double the remission rate of patients receiving active treatment in the sham-controlled trial (14.1% active rTMS versus 5.1% sham/P<0.2. However, they also noted limitations of the study were its being open label and the practical consideration of some patients needing six (6) to nine (9) weeks of rTMS.

Gaynes et al. (2014) recently published a systematic review and meta-analysis which included 18 good- to fair-quality studies. The definition of treatment resistant depression (TRD) used by the authors was two or more prior antidepressant failures following adequate dose and duration (at least four weeks). Studies with up to 20% of patients with bipolar disorder were also included. TMS compared to sham was found to be beneficial producing a greater decrease in depression severity and averaging a clinically meaningful decrease on the Hamilton Depression Rating Scale. Average remission rates were 30% and were five times more likely to be achieved with treatment compared to sham. The authors stated no information about maintenance therapy was found following completion of TMS and noted longer trials or follow-up periods would be helpful to determine whether treatment responses are maintained.

Janicak et al. (2014) reviewed the evidence for TMS both as a monotherapy and as adjunctive therapy in major depression. Stimulation parameters; randomized, sham controlled trials including one for a new TMS device; randomized trial of TMS versus electroconvulsive therapy (ECT); and durability of acute TMS antidepressant effects were described. The authors concluded HF-TMS studies support efficacy for acute antidepressant benefit but note the ideal TMS maintenance schedule is yet to be defined.

Based on a reconsideration request received in February 2018, the following analyses were added:

Fregni F et al. (2006) pooled the data from six independently conducted clinical trials to evaluate the effects of rapid rTMS performed on the left dorsolateral prefrontal cortex given for 10 days. Data for 195 patients were collected. Analysis showed age and treatment refractoriness were significant negative predictors of depression improvement. The authors listed a number of methodological issues, among which was that the six studies each had different methodologies and stated that the study results should be interpreted with caution.

Brakemeier E-L et al. (2007) studied whether specific biographical, clinical and psychopathological parameters were associated with the antidepressant response to rTMS. Seventy patients were included. Patients with major depression and bipolar II disorder were included with 32 (45.7%) having a single episode and 30 (42.9%) recurrent; 8 (11.4%) had a bipolar II disorder. Medication prior to the rTMS was maintained at a constant dose four weeks before rTMS and during the rTMS therapy. Thirty-nine (55.7% were on psychotropic medications and31 (44.3%) were not. Ten rTMS treatments were given. A high level of sleep disturbances was a predictor for a significant response as was a low score of treatment resistance and a short duration of the depressive episode. The authors noted the study had no control patients and that there was a large inter-individual difference in add-on pharmacotherapy. They recommended future studies with large numbers of non-medicated patients to validate the predictive value of their model.

Brakemeier et al. (2008) reported on 79 patients enrolled in two open clinical trials evaluating the effect of rTMS treatments delivered over the left dorsolateral prefrontal cortex. Forty-eight patients were treated at the Munich center and 31 in the Berlin facility. Twenty-three (29.1%) had a single episode of major depression, 52 (65.8%) had recurrent depression and 4 (5.1%) had a bipolar disorder. Patients were free of psychotropic medication for seven days (and 30 days if fluoxetine had been used) prior to the rTMS. An average of 12 sessions of rTMS were provided. The groups were significantly different regarding gender, duration of episode, therapy resistance, baseline HAMD, retardation scale, agitation scale, and HAMD Factors 2 & 4. There was a trend for the patients at Munich to respond (41.70%) better than at Berlin (22.60%). Overall, there were 27 (34%) responders and 52 (66%) non-responders. Results showed that non-treatment resistant patients with a short duration of episode were much more likely to respond to rTMS that patient who are labeled as treatment resistant. Patients with guilt also seemed to benefit less from rTMS. Limitations of the study were a lack of a control/placebo group and the authors stated the identified predictors in this or in previous open trials could not be accepted until the results are duplicated in a placebo-controlled study. The authors concluded that this study failed to confirm previously reported clinically valid and robust studies being predictive for rTMS response, but that in combination with other studies shows efficacy is greater in less therapy-resistant patients.

Lisanby SH et al (2009) was also referenced in the current LCD, but was not summarized. Predictors of acute outcome in the study population immediately above (O-Reardon JP et al. (2007) was examined. Univariate predictor analyses showed the degree of prior treatment resistance in the current episode was a predictor of positive response in both the controlled study and the open-label extension. One antidepressant treatment of adequate dose in the current episode had been received by 164 (54.5%) of the patients with the remainder receiving from two to four adequate treatment trials. The predictive effect of prior treatment resistance was not observed in the Extended TMS group which received more than six weeks of treatment in the open-label study. One limitation of the study noted by the authors was that only one dosage of TMS was used.

Cohen RB et al. (2010) retrospectively reviewed 56 patients with bipolar depression type I or II who were successfully treated with rTMS and sustained remission for six months. All had failure to have remission of symptoms after two or more antidepressant/mood stabilizer trials. Treatment until achievement of remission or 30 rTMS sessions, whichever came first, occurred. The study aim was to identify the patient characteristics associated with the greater number of sessions required to attain remission. Unadjusted analysis showed refractoriness, severe baseline depression, age, and number of past depressive episodes were associated with more than 15 sessions. Multivariate analysis showed that refractoriness and baseline severity remained significantly associated with more sessions. The authors noted there was no control group, that false positive results might have occurred since there were many variables analyzed, and that the goal of the study was to generate hypotheses for future trials.

Huang M et al (2012) performed a two-week double-blind trial with a two-week extended antidepressant phase enrolling 60 first-episode young patients with major depression who were randomized to citalopram in combination with two weeks of either active or sham rTMS. The citalopram was continued for two weeks following.  Fifty-six patients completed the study. The 17-item Hamilton Depression Rating Scale (HAMD-17) and the Montgomery-Asberg depression rating scale (MADRS) were used to judge the severity of depression. Although there was a greater number of early improvers in the active rTMS group at two weeks, there was no significant difference in responder or remission rates at four weeks.

Wang Y-M et al. (2017) studied the use of sham versus active rTMS for four weeks in 43 first-episode depressed patients who were concomitantly taking paroxetine for four weeks followed by another four weeks of paroxetine therapy alone. Response was defined as a >50% response on the total Hamilton Depression Rating Scale (HDRS) from baseline and remission was defined as an HDRS total residual score <8. The patients were randomly assigned to sham versus active rTMS, but the operators knew the assignment at the start of therapy. At the end of the 4th week, the active rTMS response rate was 95.5% and the 71.4% with sham; remission rates were 68.2% and 38.1% respectively. However, these differences disappeared by the end of the study Follow-up was limited to the eight weeks.

Yang H et al. (2017) conducted a randomized controlled trial of right low frequency TMS combined with 10 mg escitalopram per day for 82 patients with their first episode of depression. Each group received sham or active rTMS treatment for two weeks as well as the medication. The study was completed by 78 (95%) of the patients. HAMD-17 scores were significantly reduced in the active treatment group compared to the sham group at two and four weeks. Follow-up was limited to the four- week period.

Wang H-N et al. (2017) designed a study to measure the potential for rTMS to prevent depression relapse in patients who have achieved stable full or partial remission after six months of antidepressant therapy. A total of 281 patients were randomly assigned to rTMS alone (n = 91), antidepressant (ADP) alone (n = 208), or a combination (rTMS + ADP). Clustered treatments of rTMS occurred with 10 sessions over a five-day period for the first three months and five sessions over a three-day period thereafter. Evaluators of the patients were blinded to group assignment but the patients were not. Completion rate was 71.2% (200/281). The combination of rTMS + ADP and the rTMS alone significantly reduced the risk of relapse compared to ADP alone. 

Voigt J et al. (2017) published a cost-effectiveness analysis comparing rTMS to antidepressant medications after a first treatment failure for major depression in newly diagnosed patients’ project costs over a lifetime. The lifetime Markov simulation modeling was used to compare the direct costs and quality adjusted life years (QALYs) (ages 20-59) for individuals who had failed one pharmacotherapy treatment. The literature was used to determine life expectancies, rates of response and remission and quality of life outcomes. Treatment costs were based on Medicare fees. The authors concluded that rTMS was the dominant therapy compared to drug therapy given the costs of treatment. Given the current state of the literature we would question the validity of the variables used in the model. In addition, the age range excludes the majority of the Medicare population.

Based on a reconsideration request received April 2019 to allow coverage of dTMS for obsessive compulsive disorder (OCD), the following literature has been reviewed and added. In addition, literature to examine the use of rTMS for OCD has also been included.

Two recent meta-analyses reviewed rTMS for the treatment of OCD. Ma et al. (2014) reviewed nine randomized controlled trials (RCTs) with 290 subjects who had OCD. Most were selective serotonin reuptake inhibitor (SSRI) resistant. Random assignment (not described) was made using rTMS or sham rTMS. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores were used as the primary outcome and response rate as the secondary outcome. The latter was determined by the RCT’s definition. Drop-out rates were also evaluated. There were 154 active r-TMS subjects and 136 who had sham rTMS. Study size ranged from 18 to 65. The Y-BOCSs were said to show improvement when rTMS was added to treatment with medication. There were nine subjects in two studies that did not have SSRI-resistant OCD, but the improvement continued to be shown when these RCTs were excluded from the Y-BCOS analysis. Actual Y-BCOS scores were not provided. It was noted that the active rTMS patients had higher baseline Y-BOSC scores, but no actual numbers were provided. Response rates were available for eight of the nine trials. Fifty-five of 139 active patients (39.6%) and 27 of the 122 sham patients (22.1%) responded. There was no difference in the drop-out rate between the active 8/207 (3.8%) and sham 7/94 (7.4%) subjects. Mean duration of rTMS treatment was 3.8 weeks with a range of two to six weeks. A sub-group analysis suggested treatment effects were larger at two and six weeks’ duration, but the small number of studies with four weeks’ length may have precluded an accurate assessment. Stimulus parameters were not reported. No follow-up data were reported. The authors noted that future large–scale studies are needed to assess the long-term effect of rTMS as augmentation and mono-therapy for OCD. No conflicts of interest were reported.

Rehn et al. (2018) conducted a systematic review and meta-analysis of rTMS used to treat OCD and focused on whether certain TMS parameters were associated with higher treatment effectiveness. Eighteen RCTs were included, six of which were also included in the Ma et al. study. Selected studies had patients aged 18-75 years with DSM-IV diagnosis of OCD; had randomized rTMS or sham treatment with either single- or double-blinding or parallel or cross-over design; more than five OCD subjects per arm; LF(</= 1 Hz) or HF-rTMS (>/=5 Hz) for >/= 5 sessions either as mono- or augmentation strategy; and pre- and post- reporting of Y-BOCS scores. Studies were excluded if patients were starting a new medication at the same time of rTMS. Total number of subjects was 484 with 262 receiving active rTMS and 222 sham rTMS. Study size ranged from 18 to 46. All trials used rTMS as an augmentation therapy with most of the patients having some degree of treatment resistance. The last Y-BOCS measurement obtained was used as the post-treatment score. Pre-and post-treatment Y-BOCS were available from each of the 18 studies, but the actual scores were not provided. Overall, active rTMS was significantly superior to sham rTMS. Cortical targets over the B-DLPFC, R-DLPFC and the supplementary motor area (SMA) yielded significantly superior Y-BOCS scores over sham treatments. Active rTMS directed at the L-DLPFC was not significantly improved over sham rTMS. Six trials had Y-BOCS scores at four weeks or less post-treatment and three had scores 12 weeks post-treatment. Improvements in scores were maintained. The authors stated that the clinical utility of rTMS in the treatment of OCD requires further investigation to discern the most optimal stimulation parameters. No conflicts of interest were reported.

Lusicic et al. (2018) performed a systematic review on the effect of rTMS and dTMS on different brain targets in OCD. Twenty studies met inclusion criteria with 19 using rTMS and one dTMS. All but one of the rTMS trials are included in the meta-analyses described above. Included brain areas were the dorsolateral prefrontal cortex (DLPFC), supplementary motor area (SMA), orbitofrontal/medial prefrontal cortex (OFC), and anterior cingulate cortex (ACC). Frequency stimulation was low (1 Hz) or high (>/=5 Hz). Treatment duration varied from two to six weeks with follow-up ranging from none to three months. Three tables listed 16 of the studies, nine had Y-BOCS score reductions with rTMS versus sham; eight showed no significant difference. Summaries of dTMS studies follow. The authors concluded treatment of OCD with neurostimulation shows promise, but it is yet to be determined how best to optimize the approach using rTMS or dTMS to achieve clinically relevant results.

Carmi et al. (2018) studied 41 OCD patients who had failed two SRI trials plus cognitive behavioral therapy (CBT). Baseline clinical and electrophysiological measurements, a five-week treatment, and a one month follow-up were performed. The medial prefrontal cortex (mPFC) and the anterior cruciate cortex (ACC) were targeted. Entrance criteria included an age range of 18-65 years old; a DSM-IV diagnosis of OCD; a score of >/=20 on the Y-BOCS; stable SSRI medications for eight weeks prior to enrollment and unchanged during treatment; and CBT at maintenance phase (if conducted). Exclusion criteria included any other Axis-I psychopathology or a current depressive episode. Randomization to treatment with 1 Hz (LF), 20 Hz (HF) or sham occurred using a computer program. Treatment occurred five times per week for five weeks. Primary and secondary outcomes were Y-BOCS and Clinical Global Impressions of Severity (CGI-S) which were obtained pre-treatment, prior to the second treatment session in weeks two to four, prior to the last treatment session (post-treatment) and at one-week and one-month follow-up beginning with an exposure to personalized obsessive-compulsive cues.

Electroencephalograms (EEGs) during a Stroop task were performed at pre- and post-treatment time-points and analyzed by the condition (congruent or non-congruent) and whether the response was correct or a mistake. Most of the mistakes (93%) were made under incongruent conditions. Individuals who made more than 90% mistakes were excluded from analysis (2 HF and 3 sham). Error-related negativity (ERN) showed an increase in the HF group and a decrease in the sham group with treatment. (An ERN occurs when an individual makes a behavioral error.)

The baseline characteristics of the three groups did not differ. Three of the 41 participants dropped out, one in the sham group due to schedule conflicts and two from the HF group due to inconvenience. No adverse events occurred beyond headache in three from the HF group and one from sham. Asked to guess the group to which they were assigned, 75% of the LF, 88% of the HF, and 86% indicated they did not know. An interim analysis revealed a near significant effect for HF but not LF. Although no trend was reported in the group and two of the eight had a worsening Y-BOCS score the LF arm of the study was omitted. Completion by 16 HF and 14 sham participants occurred. The percent change in Y-BOCS scores was significant at weeks four and five and a higher proportion of the HF group compared to the sham group (7/16 vs 1/14) reached the predefined response rate (30%) after five weeks. Using the more restrictive criterion of 35%, 5/16 HF and 1/14 sham individuals achieved the higher rate. Significant differences at one week occurred but not at one month follow-up. Similarly, the CGI-I results were significant after treatment and one week but not at four weeks.

The authors concluded the study showed the treatment was safe and effective immediately after treatment but not significant four weeks later. Limitations were noted to be that the study was considered as a pilot and had a small number of subjects; the provocation was not controlled and the number of pulses differed for the HF and LF groups. A need for further studies was noted. A financial disclosure noted one of the authors is a co-inventor of the TMS H-coils, serves as a consultant for, and has financial interests in BrainsWay and potential conflicts of interest. The study was partially supported by BrainsWay, which produces the deep TMS H-coil systems.

A prospective multicenter randomized double-blind placebo-controlled trial (Carmi et al., 2019) followed the pilot described immediately above. One hundred patients with OCD and Y-BOCS score >/= 20 between the ages of 22 and 68 receiving treatment in an outpatient setting were recruited. A limited response to previous treatments and maintenance treatment with a therapeutic dosage of a serotonin uptake inhibitor (SRI) for least two months before randomization; or if not on an SRI, in CBT maintenance therapy with failure to respond adequately to an SRI and other antidepressants. SRIs and other antidepressants and D2 or D2/5-HT2 antagonist medications were allowed but could not be changed for at least two months before enrollment. Exclusion criteria were any primary axis I disorder other than OCD, severe neurological impairment, and any condition associated with an increased risk for seizures. Patients were randomized 1:1 into an active dTMS or sham group. A 3 – 5 minute individualized symptom provocation occurred before each treatment session. The medial prefrontal cortex and anterior cingulate cortex were targeted with 20 Hz dTMS. Patients, operators, and raters were blinded to treatment group. Subjects were queried regarding the group to which they had been assigned after the first treatment with 66% of the active and 69% of the sham group giving an incorrect answer. The treatment phase lasted six weeks with one day for assessment and had three phases – a three-week screening phase, a six-week treatment of five treatments per week, and a four-week follow-up phase.

The primary outcome measure was a change in Y-BOCS score from baseline to post-treatment. A full response was defined as a >/=30% reduction and a partial response as >/=20%. At six weeks post-treatment, the Y-BOCS score significantly decreased in each group with the treatment group considered to have a statistically significant slope of change. At four weeks post-treatment, the treatment group had a statistically significant change in full response but not in the partial response rate. Clinical Global Impression Severity scales (CGI-S) and a modified version of the improvement scale (CGS-I) measurements were made post-treatment. The CGI-I scores were divided into improved (moderately to very much improved) and not improved (minimally to not improved). The active group had 20/41 (49%) compared to 9/43 (21%) reporting feeling moderate to “very much improved’ (P=0.011). The CGS-S scores also showed a significant difference in the treatment group post-treatment. No significant differences between groups were found for the Sheehan Disability Scale or the Hamilton Depression Rating Scale (HAM-D) scores. The drop-out rate was around 12% for each group (6/48 and 6/51). Adverse event rates did not differ between groups. One patient reported suicidal ideation (which was unreported and present before study entry) requiring inpatient treatment after two active dTMS treatments.

Limitations noted by the authors were that the provocations were uncontrolled and functional brain imaging of the mPFC and ACC was not performed. A different mechanism for dTMS compared to pharmaceuticals and CBT was suggested as well as the need to determine which patients might respond to dTMS. Further studies were recommended. Twelve of the 14 authors reported some financial relationship with BrainsWay.

A reconsideration request to cover dTMS for individuals with treatment-resistant obsessive compulsive disorder was received in March 2021. Seven articles eligible for consideration are summarized below listed in alphabetical order of the senior authors’ name. Following guidelines in the Medicare Program Integrity Manual 100-08, Chapter 13, submitted poster presentations and abstracts are not included.

Alyagon U et al. (2021) wrote an editorial reporting on 12 active patients (7 females and 10 sham (7 females) who participated in the Carmi et al study (2019) and had pre- and post-treatment Stroop data available. Only active dTMS significantly reduced reaction times. Post-error slowing was also reduced in the dTMS patients but not in the sham patients. The author felt the results supported the observed clinical improvements suggested dTMS of the mPFC and ACC could induce long-term changes in cognitive functioning associated with error monitoring. The author noted size limitation in number of subjects and the analysis methods which could be subject to potential drift bias. He is an inventor of dTMS technology and has financial interest in BrainsWay Ltd.

Carmi et al. (2018) and Carmi et al, (2019) were reviewed and summarized during the most recent reconsideration request. Please see above.

More than 50% of patients with OCD have a comorbid major depressive disorder (MDD) or dysthymia. Performing a post-hoc analysis of the Carmi et al. (2019) trial data, Harmelech T et al. (2020) pulled treatment results for nine (9) active and ten (10) sham treatment OCD patients who also had MDD comorbidity. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and Hamilton Depression Rating Scale (HDRS) of the two groups were compared. A statistically significant decrease in YBOCS and HDRS scores occurred at all time points including the end of the trial in the active but not the sham treatment groups. The HDRS decreases between the active and sham groups were not statistically significant. Although the author acknowledged further research is needed, he recommended comorbid OCD-MDD patients be treated with just the OCD protocol (H7PFC/ACC). BrainsWay funded the study. The first author is a BrainsWay employee. The second author is the BrainsWay chief medical officer with financial interests in BrainsWay and ownership interests in Advanced Mental Health Care, Inc. Financial interests in BrainsWay were also reported by the third and fourth authors who are also key inventors d-TMS technology.

Roth et al. (2020) studied whether a high number of medication trials and/or cognitive behavioral therapy (CBT) influence the potential effectiveness of dTMS in OCD. Participants in the Carmi et al. (2019) trial were divided into two groups – those with an insufficient response to one or two medications (1-2) and those who had an insufficient response to three or more medications. The principle investigator made the group assignment based on a patient interview and usually records showing two months of medication prescribed above the minimum dosage required for OCD. The majority were in the 3+ group (63%, 53/84). Patients were also divided into two cohorts based on whether they had received prior CBT. At post-treatment, responses were significantly higher in the TMS group compared to sham in the larger cohorts of 3+ medications and of past CBT. Limitations of this study included not having enough patients to show significance in each cohort and some treatment histories may have been inaccurate due missing records or faulty memories. The senior author is a key inventor of deep TMS as is the second author and each have financial interests in BrainsWay.

Treatment data under naturalistic conditions were collected by Roth et al. (2021). There were 22 clinics which were paid for participation. Response was defined as a >30% reduction in YBOCS score. At the endpoint (29 sessions), response rate was determined. In addition, the first time the YBOCS scores met criteria, the number of sessions and days required to reach first response and sustained response were noted. There were 219 patients who had at least one d-TMS session and one YBOCS score. Seventy of the 219 patients (32%) reached a response and 51 of 219 (23%) did not. Completion of the prescribed 29 sessions was accomplished by 121 patients whose response rates were 70/121 (58%) achieving a response and 51/121 (42%) no response. The authors stated that the results of this multicenter trial demonstrated that real-world clinical practice could achieve success. Concern was expressed that the primary limitation of studies in these settings is the limited amount of information collected due to competing staff priorities. The study was supported by BrainsWay. The first, second, and third authors have financial interests in BrainsWay. All other authors except one declared a financial interest in commercial TMS.

Storch et. al. (2021) looked at moderators and predictors of response to deep transcranial magnetic stimulation for obsessive-compulsive disorder. Approximately 20% of individuals do not respond to combined treatment where first line interventions include cognitive behavioral therapy with exposure and response prevention, serotonin reuptake inhibitor medications or their combination. Deep transcranial magnetic stimulation has emerged as another treatment option. 100 adults, ages 22-68 years, with primary OCD participated in a randomized, sham controlled study of deep TMS. Additional eligibility criteria includes: Y-BOCS score greater than or equal to 20 and stable on any medications for two months prior to study entry. Exclusion criteria included non-OCD primary disorder, severe neurological impairment, and increased risk of seizures. Twenty-nine treatments were given over 6 weeks in both the active control group and the sham control group. Older age, lower baseline OCD severity and lower baseline functional disability significantly predicted greater OCD symptom reduction post treatment. Only age was a significant predictor at 10 week follow-up. Study limitations include the sample was mostly white and non-Hispanic and no information on socioeconomic status were obtained limiting ability to generalize the findings. Further studies should include an ethnically more diverse population among other things.

Tzirini et. al. (2022) H7 and D-B80 coils, were measured in an experimental phantom of the human filled with physiologic saline solution with EF characteristics including amplitude and orientation. Limitations of the study obviously include interindividual variability among patients and individual anatomical and physiologic characteristics that would affect the results. Future studies based on individual human brains would be needed to further investigate the effects of the two coils for treatment of OCD.

Contractor advisory committee (CAC) Meeting Summary

NGS co-hosted a CAC Meeting with multiple other contractors on 9/29/2021. The panelists reviewed the literature that was submitted as part of an LCD reconsideration request to expand the policy to include coverage for OCD. The panel shared the lack of good treatment options for refractory OCD and a priority to develop new and effective treatments. The literature was reviewed and noted to be challenged by small sample sizes, high risk of bias, many studies with lower quality study design (lack of control arm/blinding), short follow-up (4-5 weeks for most studies) with lack of long-term outcome data, and lack of real-world application of the technology. There was a discussion of risk of co-morbid depression and OCD and different coil locations with some potential overlap, which brought up the potential impact of treatment for both conditions. One paper reviewed low vs. high frequency showing improvement with high frequency but not low. Another challenge addressed was which region of the brain should be targeted for OCD as the studies varied in the location treated. The panelists felt that there was not clarity regarding the degree of improvement in scores that would result in meaningful clinical improvement, but even small change would be significant in refractory OCD. In the study on predictors to response, the panel did consider the secondary analysis that those with more severe disease had greater response to treatment. Overall, the panel felt there was potential improvement for OCD with TMS and it appears to be safe, but limitations in literature are substantial as described.

Effective 01/01/2012:

A number of studies have shown a short-term treatment benefit for patients with a major depressive disorder receiving active versus sham rTMS. “Treatment benefit” has been defined by response or remission rates using depression rating scales. The literature has the following limitations:

• The dorsal lateral prefrontal cortex (DLPFC) is presumed to be the treatment target area of the brain. There is some question whether the “standard procedure” used for coil placement is sufficiently precise (Herwig, 2001). Recent work is exploring methods to address coil placement (Fitzgerald, (2009; Herbsman, 2009).
• Stimulation parameters vary and the optimal treatment has not been determined.. High-frequency left-sided TMS (HFL-TMS), high-frequency right-sided TMS (HFR-TMS), low-frequency right-sided TMS (LFR-TMS), low-frequency left-sided TMS (LFL-TMS) and bilateral TMS involving LFR-TMS and HFL-TMS have been used.
• Definitive patient selection criteria have not been determined. Non-response to one or more six-week trials of antidepressant therapy as well as duration of major depressive episode has varied among study participants.
• Study populations have usually been small, <100 patients.
• Studies vary in the concomitant use of anti-depressants.
• The optimal treatment duration is not known. Most studies have short treatment periods, varying from one to four weeks. More recently there have been studies of six weeks or longer.
• Very few studies have included patient follow-up and when performed, is short.

Therefore, the evidence is insufficient to determine rTMS improves health outcomes in the Medicare or general population.

Effective 08/15/2014:

The accumulated literature as well as consultation with researchers led to a decision to allow coverage as shown above in the “Indications and Limitations” sections. 

Effective 06/15/2018:

Several publications were provided to support a reconsideration request received in February 2018 to revise the LCD to allow rTMS for use after one failed pharmacologic therapy (versus the current four). However, none of the provided literature had as its purpose to study use of rTMS after one failed pharmacologic therapy and show that it is superior to changing psychotherapeutic agents with or without psychotherapy.

Analysis based on reconsideration request received April 29, 2019

There is currently insufficient evidence to show use of rTMS or dTMS for OCD as reasonable and necessary for the treatment of illness or injury [SSA § 1862 (a)(1)(A)] in the Medicare population. Medical policies of commercial insurers also find the treatment not medically necessary. The rTMS studies have heterogenous populations, vary in frequency and site of stimulation, have mixed results, and short follow-ups. The dTMS investigations are in their infancy with one randomized double-blind controlled trial studying 99 patients, with a 12% drop-out rate, and a four-week follow-up. The ability of rTMS or dTMS to improve outcomes in patients with OCD is yet to be determined.

Analysis based on reconsideration request received March 2021.

There is currently insufficient evidence to show use of dTMS for OCD as reasonable and necessary for the treatment of illness or injury [SSA § 1862 (a)(1)(A)] in the Medicare population. TMS studies have heterogenous populations, vary in frequency and site of stimulation, have mixed results, and short follow-ups. The d-TMS investigations are in their infancy with one randomized double-blind controlled trial studying 99 patients, with a 12% drop-out rate, and a four-week follow-up. (Carmi et al.,2019). With the exception of Roth et al, 2021, the patients in the literature submitted for LCD reconsideration were participants in the Carmi et al, 2019 trial. There was insufficient information to support coverage of d-TMS to treat OCD. The ability of d-TMS to improve outcomes in patients with OCD is yet to be determined.

This bibliography presents those sources that were obtained during the development of this policy. National Government Services is not responsible for the continuing viability of Web site addresses listed below.

Aetna Clinical Policy Bulletin No 0469. Transcranial Magnetic Stimulation and Cranial Electrical Stimulation. http://www.aetna.com. Accessed 04/18/2011 and 05/01/2018.

American Psychiatric Association (APA). Practice Guideline for the Treatment of Major Depressive Disorder. Published 2010. http://www.psych.org/guidelines/mdd2010. Accessed 11/10/2011.

Anthem Medical Policy BEH.00002. Transcranial Magnetic Stimulation. Accessed 05/02/2018.

Avery DH, Isenberg KE, Sampson SM, et al. Transcranial magnetic stimulation in the acute treatment of major depression: clinical response in an open-label extension trial. J Clin Psychiatry. 2008;6(3):441-451.

Blue Cross Blue Shield Association (BCBSA). Technology Evaluation Center (TEC). Transcranial magnetic stimulation for depression. TEC Assessment Program. Chicago, IL:BCBSA. 2009:24(5). http://www.bcbs.com/blueresources/TEC/press/transcranial-magnetic.html. Accessed 04/28/2011.

Blue Cross Blue Shield Association (BCBSA). Technology Evaluation Center (TEC). Transcranial magnetic stimulation for depression. TEC Assessments in Press. April 2011. http://www.bcbs.com/blueresources/TEC/press/transcranial-magnetic.html. Accessed 04/28/2011.

CIGNA Medical Coverage Policy 0383 – Transcranial Magnetic Stimulation – Accessed 01/15/2011 and 05/02/2018.

Clinical Trials Search of Transcranial Magnetic Stimulation/Depression found 9 new studies with 8 recruiting patients and 1 study not yet recruiting. http://www.clinicaltrias.gov. Accessed 04/26/2011.

Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci. 2005;30(2):83-90.

Daskalakis ZJ, Levinson AJ, Fitzgerald PB. Repetitive transcranial magnetic stimulation for major depressive disorder. A review. Can J Psychiatry. 2008;53(9):555-566.

Demitrack MA, Thase M. Clinical significance of transcranial magnetic stimulation in the treatment of pharmacoresistant major depression: synthesis of recent data. Psychopharmacology Bulletin. 2009; 42(2): 5-38.

Eranti S, Mogg A, Pluck G, et al. A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry. 2007;164:73-81.

Fitzgerald PB, Hoy K, McQueen S, et al. A randomized trial of rTMS targeted with MRI based neuro-navigation in treatment-resistant depression. Neuropsycholpharmacology. 2009;34(5):1255-1262.

Gaynes BN, Lux L, Hansen RA, et al. Nonpharmacologic interventions for treatment-resisitant depression in adults. Comparative effectiveness review no. 33. (prepared by RTI International-University of North Carolina (RTI-UNC). Evidence-based practice center under contract no. 290-02=0016I.) AHRQ publication no. 11-EHCO56-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed 09/28/2011.

Gelenberg AJ, Freeman MP, Markowitz JC, et al. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. Third Edition 2010.

George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. A sham-controlled randomized trial. Arch Gen Psychiatry. 2010;60(5)5007-516.

Gross M, Nakamura L, Pascual-Leone A, Fregni F. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr Scand. 2007;116:165-73.

Hamilton Depression Rating Scale.

Hayes Inc. Evaluating the efficacy of transcranial magnetic stimulation to treat major depression. Hayes Overview. Lansdale, PA; Hayes, May 25, 2010.

Herbsman T, Avery D. Ramsey D, et al. More lateral and anterior prefrontal coil location is associated with better repetitive transcranial magnetic stimulation antidepressant response. Biol Psychiatry. 2009;66(5):509-515.

Herwig U, Padberg F, Unger J, Spitzer M, and Schonfeldt-Lecuona S. Transcranial magnetic stimulation in therapy studies: examination of the reliability of “standard” coil positioning by neuronavigation. Biol Psychiatry. 2001;50:58-61.

Humana Medical Coverage Policy HCS-0457-013 Transcranial Magnetic Stimulation (TMS) and Cranial Electrical Stimulation (CES). Accessed 05/01/2018.

Janicak PG, Nahas Z, Lisanby SH, et al. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study. Brain Stimulation. 2010;3:187-199.

Janicak PG, O’Reardon JP, Sampson SM, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry. 2008;69(2): 222-232.

Kim DF, Pesiridou A, O’Reardon JP. Transcranial magnetic stimulation in the treatment of psychiatric disorders. Current Psychiatry Reports. 2009;11:447-452.

Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can J Psychiatry. 2008;53:621-631.

Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology. 2009;34:522-534.

Loo CK, McFarquhar TF, Mitchell PB. A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. Int J Neuropsychopharmacol. 2008;11(1):131-147.

Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. Br J Psychiatry. 2003;182:480-491.

Montgomery-Asberg Depression Rating Scale.

O’Reardon JP, Solvason HB, Janicak PG et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208-1216.

Other Medicare contractors’ Non-Covered Services LCDs - First Coast Service Options (L29023); Noridian Administrative Services, LLC (L24471); Trailblazer Health Enterprises, LLC (L26811).

Prudic J, Olfson M, Marcus SC, Fuller RB, Sackeim HA.. Effectiveness of electroconvulsive therapy in community settings. Biol Psychiatry. 2004;55:301-312.

Rodriguez-Martin JL, Barbanoj JM, Schlaepfer TE, Clos SSC, Pérez V, Kulisevsky J, Gironelli A. Transcranial magnetic stimulation for treating depression. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD003493. DOI:10.1002/14651858.CD003493. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. http://www.thecochranelibrary.com. Accessed 04/28/2011.

Rush AJ, Trivedi MY, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.

Schutter DJ. Antidepressant efficacy of high frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham controlled designs: a meta-analysis. Psychol Med. 2009;39:65-75.

Slotema CW, Blom JD, Hoek HW, Sommer IE. Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS): A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry. 2010;71(7): 873-884.

The Regance Group. Medical Policy -Transcranial Magnetic Stimulation as a Treatment of Depression and Other Disorders. Policy No. 17. Updated 03/01/2011.

Triggs WJ, Ricciuti N, Ward He, et al. Right and left dorsolateral pre-frontal rTMS treatment of refractory depression: A randomized, sham-controlled trial. Psychiatry Research. 2010;178:467-474.

UnitedHealthcare Commercial Medical Policy 2018T0536K Transcranial Magnetic Stimulation. https://www.unitedhealthcareonline.com. Accessed 04/28/2011 and 05/02/2018.

U.S. Food and Drug Administration (2007) Neurological Devices Panel of the Medical Devices Advisory Committee. January 26, 2007. FDA Executive Summary. http://www.fda.gov. Accessed 04/28/2011.

WHO Collaborating Centre in Mental Health, Psychiatric Research Unit. Major (ICD-10) Depression Inventory.

Zung. A self-rating depression scale. Arch Gen Psychiatry. 1965;12:653-70.

References reviewed and/or cited for a reconsideration request October 2013:

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• Depression