Transcranial Magnetic Stimulation (TMS)

Title XVIII of the Social Security Act (SSA) §1862(a)(1)(A). This section allows coverage and payment for only those services that are considered to be medically reasonable and necessary.

Title XVIII of the Social Security Act (SSA) §1833(e). This section prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physician examinations.

Title XVIII of the Social Security Act (SSA) §1862(a)(1)(D), and (E). Investigational or Experimental.

Repetitive Transcranial Magnetic Stimulation (rTMS) in Adults with Treatment Resistant Major Depressive Disorder

Transcranial Magnetic Stimulation (TMS) is a non-invasive treatment that uses pulsed magnetic fields to induce an electric current in a localized region of the cerebral cortex. An electromagnetic coil placed on the scalp induces focal current in the brain that temporarily modulates cerebral cortical function. Capacitor discharge provides electrical current in alternating on/off pulses. Stimulation parameters may be adjusted to alter the excitability of the targeted structures in specific cortical regions. Repetitive TMS (rTMS) has been investigated as treatment for pharmacoresistant depression.

TMS parameters include cranial location, stimulation frequency, duration, and intensity. TMS is delivered in outpatient settings without anesthesia or analgesia. Typically for the treatment of depression, the coil is located over the left prefrontal cortex. The rTMS is performed daily (weekdays) for 6 weeks. There is no need for anesthesia or analgesia and there are no restrictions about activities before or after treatment (e.g. driving, working, operating heavy machinery).

When used as an antidepressant therapy, TMS produces a clinical benefit without the systemic side effects attendant with standard oral medications. TMS does not have adverse effects on cognition. Unlike electroconvulsive therapy (ECT), rTMS does not induce amnesia or seizures.

Indications for Coverage

CGS considers TMS therapy reasonable and necessary when it is furnished in accordance with the accepted standards of medical practice, when it is furnished in a setting appropriate to the patient’s medical needs and condition, when it meets but does not exceed the patient’s medical need and when it is ordered and furnished by qualified personnel. It is expected that TMS therapy will be ordered by, and furnished under, the direct supervision of a psychiatrist who has experience administering TMS therapy.

TMS therapy not ordered by and furnished under direct supervision, by a psychiatrist will be considered not medically reasonable and necessary and not subject to coverage.

Initial Treatment

Left Prefrontal rTMS of the brain is considered medically necessary for use in an adult who meets all four of the following criteria:

1. Has a confirmed diagnosis of severe major depressive disorder (MDD) single or recurrent episode; and

2. One or more of the following:

• Resistance to treatment with psychopharmacologic agents as evidenced by a lack of a clinically significant response to two trials of psychopharmacologic agents in the current depressive episode from at least two different agent classes.
• At least one of the treatment trials must have been administered at an adequate course of mono- or poly-drug therapy; or
  
  
• Inability to tolerate psychopharmacologic agents as evidenced by four 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.

Resistance to treatment is defined by a failure to achieve a 50% reduction in depressive symptoms, in accordance with objective measures such as PHQ-9 and/or HAM-D, from a pharmacologic trial where the medication is administered at the recommended adult dose, per the FDA label, for a period of not less than 6 weeks.

Psychopharmacologic agent side effects will be considered intolerable, when those side effect are of a nature where they are not expected to diminish or resolve with continued administration of the drug

AND

3. 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

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

Coverage 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.

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. (e.g., GDS, PHQ-9, BDI, HAM-D, MADRS, QIDS or IDS-SR scores).

All other uses of Transcranial Magnetic Stimulation, including "maintenance therapy" are experimental and are not covered including TMS for the Treatment of Obsessive-Compulsive Disorder (OCD).

Summary of Evidence for Transcranial Magnetic Stimulation (TMS) for the Treatment of Obsessive-Compulsive Disorder (OCD)

Background

Transcranial Magnetic Stimulation (TMS) is a non-invasive treatment that uses pulsed magnetic fields to induce an electric current in a localized region of the cerebral cortex. An electromagnetic coil placed on the scalp induces focal, patterned current in the brain that temporarily modulates cerebral cortical function. Capacitor discharge provides electrical current in alternating on/off pulses. Stimulation parameters may be adjusted to alter the excitability of the targeted structures in specific cortical regions. TMS parameters include cranial location, stimulation frequency, pattern, duration, intensity and the state of the brain under the coil.¹ 

Systematic Review/Meta-Analysis

A number of SR/MA ^2-16 conclude rTMS demonstrates a range from none to modest effect on the reduction of OCD symptoms, but further research is required to determine optimal frequency, total pulses per session, and duration of treatment.

Two recent meta-analyses reviewed rTMS for the treatment of OCD. Ma et al¹² reviewed nine randomized controlled trials (RCTs) with 290 subjects with OCD. Most were selective serotonin reuptake inhibitor (SSRI) resistant. Using undescribed random assignment 154 were in the active r-TMS group and 136 to sham rTMS group. Primary outcome was Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores and secondary outcome was response rate determined by the RCT’s definition. Study size ranged from 18 to 65. The Y-BOCSs showed 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 numbers were not 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 lack of data in most of the included studies at four weeks’ length may precluded accurate assessment. Additional limitations include stimulus parameters and follow-up data was not 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 al¹³ 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. study¹². Selected studies had patients ages 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; low-frequency (LF) </= 1 Hz) or high frequency (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 bilateral dorsolateral prefrontal cortex (B-DLPFC), right dorsolateral prefrontal cortex (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.¹⁷ performed a systematic review on the effect of rTMS and dTMS on different brain targets in OCD. Twenty studies met the 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. Of 16 studies evaluated, nine had Y-BOCS score reductions with rTMS versus sham while eight showed no significant difference. 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.

Randomized Control Trials

RCTs comprised of thirty or fewer subjects were not included in this summary.

Carmi¹⁸ studied forty-one 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 reported. 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 forty-one 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 the study was partially supported by Brainsway, which produces the deep TMS H-coil systems.

A second study by Carmi et al¹⁹ was a prospective multicenter randomized double-blind placebo-controlled trial following the pilot described immediately above. One hundred patients with OCD and Y-BOCS score >/= 20 between the ages of 22-68 receiving treatment in an outpatient setting were recruited. Subjects were on a therapeutic dosage of a serotonin uptake inhibitor (SRI) for least two months with limited response or if not on an SRI, in CBT maintenance therapy with failure to respond adequately. Medications to treat depression 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 three-to-five-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 medical prefrontal cortex (mPFC) and anterior cingulate cortices (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 fourteen authors reported some financial relationship with Brainsway.

Elbeh et al.²⁰ performed a double-blind randomized trial to evaluate the impact of different frequencies of rTMS over right dorsolateral prefrontal cortex (DLPFC) in OCD. 45 subjects with OCD were enrolled and evaluated using: Yale-Brown obsessive-compulsive scale (Y-BOCS), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impression-Severity scale (CGI-S). They were randomized into one of three groups: 1st group received 1 Hz rTMS; 2nd group received 10 Hz rTMS; and 3rd group received sham stimulation all at 100% of the resting motor threshold for 10 sessions. Follow-up assessment were after the final treatment and three months later. The group receiving 1 Hz versus 10 Hz groups showed a significant improvement in Y-BOCS and HAM-A scores (P<0.001 and 0.0001 respectively) and significantly larger percentage change in GCI-S, as well as greater clinical benefit than the 10 Hz. The authors conclude that 1 Hz-rTMS, targeting right DLPFC is a promising tool for treatment of OCD.

Dutta et al.²¹ conducted a randomized placebo-controlled study to evaluate the effect of novel continuous Theta Burst Stimulation (cTBS) targeting OFC in OCD subjects. Thirty-three patients were randomly allocated to active cTBS (n= 18) or sham (n= 15). Each subject received 10 TBS sessions, 2 per day (total of 1200 pulses: intensive protocol) for 5 days in a week. The Y-BOCS, HAM-D, HAM-A, and CGI-S scores were assessed at baseline, after last session and at 2 weeks post-rTMS. They reported a significant improvement from pretreatment to two weeks post TBS for obsessions, compulsions, HAM-A, HAM-D, and CGI scores, but when controlled for confounding variables, only HAM-A scores and CGI retained statistical significance. The authors conclude that intensive OFC cTBS (iOFcTBS) in OCD results in clinically significant improvements in anxiety symptoms and global severity, while acknowledging that improvement in anxiety symptoms could be due to “modulations of state dependent dysregulation in OCD.”

Badawy et al.²² reported on 60 OCD patients to evaluate rTMS as monotherapy vs. add-on treatment in patients with poor response to SSRIs. Of 40 un-medicated patients 20 received sham treatment and 20 TMS. An additional 20 patients with poor response to SSRI received rTMS. With two-to-four-week follow-up they found TMS was not effective as monotherapy, but was useful as add-on therapy. Study was limited by lack of control for the poor responder group, short follow-up, and small sample size. The authors conclude further studies regarding the site of stimulation, frequency and rate of stimulation and the number of sessions is needed.

A post marketing analysis of 219 patients who underwent TMS for OCD from 22 sites were included. A response was defined as at least a 30% reduction in Yale Brown Obsessive Compulsive Scale (YBOCS) score from baseline. They reported first and sustained response rates were 72.6% and 54.4% respectively. The authors state that in real world clinical practice the majority of OCD patients benefited from TMS with improvement usually occurring within 20 sessions. They also advocate the extension of treatment beyond 29 weeks reporting continued reduction in OCD symptoms suggesting value in extended treatment protocols. Limitations include multiple uncontrolled variables including comorbidities, medication use, incomplete data set, variations in duration and protocol of treatment used at different sites and risk of bias.²³

Harmelech et al. conducted a sub-analysis of a previous multicenter randomized sham-controlled trial of Deep TMS for OCD funded by Brainsway focusing on the durability of treatment with TMS. Sixty subjects from the original study had “durability” defined as time from end of last treatment with TMS until change in treatment occurred from the original study. They report the average durability of Deep TMS is 1.98 years. Fifty-two patients reported at least 1 year durability and 26 reported ≥ 2 years. Twenty-eight patients had functional disability data collected and reported reduction in disability scores after TMS.^24,25  Limitations include incomplete data sets or lack of follow-up after treatment, small sample size, challenges applying to real world practice as the scoring system used is not routinely used in clinical practice.

A 2021 meta-analysis of RCTs on treatment strategies for serotonin reuptake inhibitor-resistant obsessive-compulsive disorder included 55 studies with 19 treatments or placebo.²⁶  The investigators reported four interventions studied which included Ondansetron, deep TMS, cognitive behavioral therapy, and ariprazole were ranked the best treatments using Surface Under the Cumulative Ranking percentage values (85.4%, 83.2%, 80.3% 65.9% respectively). In a sensitivity analysis deep TMS was ranked as the best strategy for SRI-resistant OCD. While this trend is favorable meta-analysis is only reliable if the included studies are high quality studies with low heterogenicity which is not the case with this literature. Small sample sizes, high confidence interval limits and wide prediction interval are acknowledged by the authors as limitations contributing their acknowledgment of the need for “cautious interpretation”. Additional limitations include inability to directly compare interventions because no studies were designed for direct comparison, high risk of bias in many of the included studies, and study design weaknesses including lack of blinding, randomization and control in the majority of the randomized control trials.

Summary of Evidence for Repetitive Transcranial Magnetitic Stimulation (rTMS) in Adults with Treatment Resistant Major Depressive Disorder

Several studies evaluated the efficacy and safety of TMS in the treatment of major depression that included patients with major depression (MDD) and a previous trial of one or more anti-depressive psychotherapies. In George et al. the average was 3-6 clinical antidepressant medications for current episode treatment and diagnosis of major depressive disorder single or recurrent.²⁷ In Levkovitz et al. a multicentered RCT sponsored Brainsway which included subjects with major depressive disorder with previous antidepressant use in the current episode ranging from 1 or more agents. Twenty-five subjects in the treatment group had one antidepressant agent used while the remaining 76 had 2 or more. They found a higher response rate (38.4% versus 21.4%; p=0.013) and remission rates (32.6% versus 14.6%; p=0.05) with TMS than sham at 16 weeks. These findings are limited by small sample size.²⁸ Kaster et al is a single center RCT with 52 patients with late life depression. Twenty-five received TMS and 27 sham and they report higher remission with active treatment than sham of 40% versus 14.8% concluding high dose deep TMS is safe and effective.²⁹ Limitations include small sample size below target, short term follow-up and dropout rate higher in treatment group than sham group.

Several meta-analyses to evaluate safety and effectiveness of TMS have been conducted.^30-32 The challenges facing the meta-analysis is that the results of meta-analysis are limited by the overall low quality of available literature. Literature ranging from RCT, prospective, retrospective, observational and case series has been included and the high rate of heterogenicity between the studies limits the effect of meta-analysis. One meta-analysis reports rated with Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) however risk of bias assessment was not performed on the individual studies, so the GRADE quality evidence rating of moderate quality is inconclusive.³² Based on ECRI risk of bias assessment 6/8 studies reviewed were subject to high risk of bias due to small sample sizes, and serious flaws in study design such as lack of controls, blinding and randomization.³³ No studies compared TMS with other treatment options and all studies were short term with longest follow-up of 6 months. Studies also had high variability of diagnosis and not all were MDD with some in bipolar disorder patients exclusively.³⁰ The demographic for age listed for each of the studies is younger than the Medicare population. Additionally, the parameters for the TMS administered varied greatly from study to study without standardized treatment protocol or response criteria across studies, and some studies had high dropout rate or patients not treated by the intensity defined within the protocols. Finally, many studies were funded by makers of TMS equipment with associated risk of bias. One meta-analysis reported promise for TMS but acknowledge the need for well-designed sham-controlled studies. One large retrospective registry study included 5010 participants in the intent-to-treat sample with MDD, and PHQ-9 assessment before and after TMS and reported response rate of 58-83%. However, this study is limited by study design, incomplete data, lack of clear diagnostic criteria and assessment limited to PHQ-9 which is a screening too.³⁴

Weissman et al. performed a secondary analysis of patients enrolled in the STAR*D trial for the effects of antidepressants on suicidal ideation. Of significance SI measured by HRSD suicide item score was low in the population with only those patients classified as level 4 having SI at baseline.³⁵ While mean SI decreased across all four levels the decrease in level 4 was not significant (α = 0.0125); and degree of SI correlated with degree of depression and was more common in treatment resistant depression. Limitations of this study includes the primary outcome of STAR*D trial was not SI but rather remission from MDD so study was not designed to measure this endpoint, low baseline level of SI, limited to outpatients therefore not reflecting real world population where suicidal patients are likely inpatients, lack of blinding, and risk of bias as the funding was from makers of deep TMS equipment.

A 2022 systematic review and meta-analysis of 3,273 subjects RCT on TMS for MDD reports high rate of non-serious adverse events (ADE’s) including headache (22.6%), discomfort (10.9%) and pain (23.8%) in the stimulation sites in treatment group compared to sham. However, most ADE’s were mild and transient with a low risk of serious adverse events including seizures and mood switches and reported no increased risk of drop out due to adverse events supporting safety.³⁶

A small RCT (n=81) of deep TMS as monotherapy for medication resistant depression administered TMS treatments 5 days a week for 4 weeks and 33 were non-responders. This group had 4 additional weeks of twice weekly TMS and they reported 61% (24/33) responded to the additional TMS on at least one of the weekly assessments, however 12/33 (36.4%) dropped out of the study before completion and follow-up was limited to 16 weeks.³⁷ In an open-label, crossover trial 42 patients who did not respond to initial TMS treatment received an additional 30 sessions and 26% achieved a response. The rate of response based on number or prior treatments was analyzed and authors suggest more treatment resistant patients may take longer to respond to TMS. Limitations were small sample size, lack of blinding with high risk of placebo effect, uncontrolled study design and data limited to 6 weeks due to cross-over.³⁸  A small pilot study with 49 patients reports on once monthly maintenance therapy after initial treatment for 19 subjects while 24 received observation alone once initial treatment completed. 16/49 completed the 53 weeks of the study indicating high discontinuation rate. The authors reported “they did not find an advantage for once-monthly maintenance TMS treatment over observation, since it did not significantly delay the time until reintroduction TMS was needed or reduce the proportion of patients who needed retreatment”.³⁹  In another small trial 29 subjects received 4 weeks of TMS for MDD followed by 18 weeks of continuation treatment (twice weekly for 16 sessions and once weekly during the final 10 weeks). The authors report “probability of remission at the end of the acute phase was 26.92% (SE " 8.70%) and 71.45% (SE " 10.99%) at the end of the study” however this must be balanced by high dropout rate with 15/29 finishing the protocol, low initial response rate of 12/29 and no comparison to observation alone.⁴⁰ Overall, the literature regarding continuation or maintenance therapy is challenged by small sample size, lack of standardized protocols, lack of blinding, randomization and controls in study designs and longest outcome reported of 12 months therefore lack long-term safety and outcome data. This is summarized in a 2022 meta-analysis reports on 30 papers (n=1494) regarding ‘maintenance, continuation, preservation or rescue TMS’. This included four randomized control trials (one sham controlled), 14 open trials and 12 case series. The authors conclude that while there is evidence to support the use of preservation it is based on largely uncontrolled, low quality studies with lack of standardized protocols and calls for more studies to establish the role of continuation TMS.⁴¹

In contrast several studies suggest “durability” of treatment meaning the effects last after the treatment has finished. An observational study in 257 non-medicated patients with MDD reported on 120 subjects who responded to initial TMS treatment 75 (62.5%) had prolonged response. 93 (36.2%) received reintroduction of TMS with mean number of TMS treatment days of 16.2. The authors conclude there is a statically and clinically meaningful durability of acute benefit over 12 months. This study is limited by observational design but strengthened by 12 month follow-up and use of standardized questionnaires throughout the study time frame.⁴² A meta-analysis of 19 studies reported 65.5% after 3 months and 46.3% maintained response 1 year after induction treatment.³⁰

Additional studies have shown a positive response to retreatment for relapse of symptoms for the majority of those who initially respond.⁴³

Society Guidance/Technology Analysis



TMS for OCD

NICE Guidance -Transcranial magnetic stimulation for obsessive-compulsive disorder.⁴⁴ Recommendations conclude that evidence on the safety of transcranial magnetic stimulation for obsessive-compulsive disorder raises no major safety concerns. However, evidence on its efficacy is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research.

UpToDate - Technique for performing transcranial magnetic stimulation (TMS) mentions for use in patients with major depression.⁴⁵ There was no mention of TMS for OCD.

ECRI - Transcranial Magnetic Stimulation for Treating Adults with Obsessive-compulsive Disorder executive summary evidence was inconclusive based on too few data on outcomes of interest.⁴⁶

TMS for Depression

Agency for Healthcare Research and Quality (AHRQ) Final Technology Assessment - No agreed-upon definition of Treatment-Resistant Depression (TRD) exists.⁴⁷ 

McClintock Consensus statement of the National Network of Depression Centers (NNDC) and the American Psychological Association (APA) Council - “rTMS is appropriate as a treatment in patients with MDD even if the patient is medication resistant or has significant comorbid anxiety.”⁴⁸ 

Perera Consensus review from the TMS Society - TMS therapy is recommended as an acute treatment for symptomatic relief of depression in the indicated patient population & TMS therapy is recommended for use as a subsequent option in patients who previously benefited from an acute treatment course and are experiencing a recurrence of their illness.⁴⁹

APA Practice guideline includes TMS as an option for treatment-resistant depression.⁵⁰

Contractor  Advisory Committee (CAC) Summary

 CGS Administrators co-hosted a CAC Meeting with multiple other contractors on 9/29/2021. The panelist 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 so 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 panelist felt that there was not clarity regarding the degree of improvement in scores 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.

The is existing literature reporting on TMS for management of OCD is low quality. Limitations include small sample sizes, high risk of bias, lack of high-quality studies and long-term follow-up, and inconsistent results. Studies do suggest a low risk associated with treatment; however long-term data is lacking. There is a trend towards benefit in the meta-analysis and in the randomized control trial suggesting there may be a role in refractory OCD. However, many questions remain in terms of the efficacy, location that the device should be applied, the frequency that should be used, how often treatment should be given and over what duration. For a treatment to be considered medically reasonable and necessary per 1862(a)(1)(A) of The Act²⁶ the treatment must be appropriate, including duration and frequency furnished in accordance with accepted standards of medical practice for the condition. CGS Administrators determines that the existing evidence and lack of accepted standards of medical practice for dTMS for OCD does not meet the requirement of medically reasonable and necessary. CGS Administrators will continue to monitor scientific developments and may adjust this coverage policy in accordance.

There remains a need for high quality randomized control trials and comparison studies for the use of TMS in the setting of depression. However, there is a volume of evidence as well as safety data to support the use as an option for treatment resistant or recurrent depression in select patients. Based on new literature submitted the requirement for four failed pharmacological agents prior to TMS will be reduced to two. Further reduction has not been consistently supported in the literature as very few studies included patients with one or less prior failed pharmacological agent. While the STAR*D supports patients with more treatment steps have lower acute remission rate this is likely correlated to the severity of disease.^{51, 52} There is no evidence that TMS is superior to standard treatment in this higher risk population to support earlier use of TMS or that earlier treatment with TMS improves outcomes. The literature on the use of TMS treatment for induction beyond 36 weeks, maintenance (also called preservation or continuation) therapy beyond the initial treatment phase in patients who do not respond by at least 25% to the initial to treatment is challenged by small samples sizes, study design flaws with lack of control groups, blinding and risk of bias, and lack of long-term data for safety and effectiveness therefore is considered investigational. There is not clear benefit of prolongation of TMS past the induction phase to prevent relapse or maintain remission in current literature especially since up to half of patients demonstrate durability, and patient selection, role of antidepressant in maintenance and protocol for this treatment have not been established. However, retreatment (reintroduction/TMS rescue) for relapse in in appropriately selected previous responders is considered reasonable and necessary.

N/A

N/A

1. Clinical TMS Society: Coverage Guidance for TMS for OCD. 2021;https://www.clinicaltmssociety.org/sites/default/files/ctmss_recommended_ocd_coverage_policy_0.pdf Accessed Nov. 11, 2021.
2. Perera MPN, Mallawaarachchi S, Miljevic A, et al. Repetitive Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Meta-analysis of Randomized, Sham-Controlled Trials. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;6(10):947-960.
3. Liang K, Li H, Bu X, et al. Efficacy and tolerability of repetitive transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis. Transl Psychiatry. 2021;11(1):332.
4. Homan S, Muscat W, Joanlanne A, et al. Treatment effect variability in brain stimulation across psychiatric disorders: A meta-analysis of variance. Neuroscience and biobehavioral reviews. 2021;124:54-62.
5. Acevedo N, Bosanac P, Pikoos T, et al. Therapeutic Neurostimulation in Obsessive-Compulsive and Related Disorders: A Systematic Review. Brain sciences. 2021;11(7).
6. Bijanki KR, Pathak YJ, Najera RA, et al. Defining functional brain networks underlying obsessive-compulsive disorder (OCD) using treatment-induced neuroimaging changes: a systematic review of the literature. Journal of neurology, neurosurgery, and psychiatry. 2021;92(7):776-786.
7. Rapinesi C, Kotzalidis GD, Ferracuti S, et al. Brain Stimulation in Obsessive-Compulsive Disorder (OCD): A Systematic Review. Curr Neuropharmacol. 2019;17(8):787-807.
8. Marques RC, Vieira L, Marques D, Cantilino A. Transcranial magnetic stimulation of the medial prefrontal cortex for psychiatric disorders: a systematic review. Revista brasileira de psiquiatria (Sao Paulo, Brazil: 1999). 2019;41(5):447¬457.
9. Zhou DD, Wang W, Wang GM, Li DQ, et al. An updated meta-analysis: Short-term therapeutic effects of repeated transcranial magnetic stimulation in treating obsessive-compulsive disorder. J Affect Disord. 2017;215:187-196.
10. Euser AM, Stapert AF, Oosterhoff M, et al. Transcranial magnetic stimulation in obsessive compulsive disorder: a systematic review. Tijdschr Psychiatr. 2017;59(10):617-625.
11. Trevizol AP, Shiozawa P, Cook IA, et al. Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: An Updated Systematic Review and Meta-analysis. The journal of ECT. 2016;32(4):262-266.
12. Ma ZR, Shi LJ. Repetitive transcranial magnetic stimulation (rTMS) augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant obsessive-compulsive disorder (OCD): a meta-analysis of randomized controlled trials. Int J Clin Exp Med. 2014;7(12):4897-4905.
13. Rehn S, Eslick GD, Brakoulias V. A Meta-Analysis of the Effectiveness of Different Cortical Targets Used in Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Obsessive-Compulsive Disorder (OCD). Psychiatr Q. 2018;89(3):645-665.
14. Berlim MT, Neufeld NH, Van den Eynde F. Repetitive transcranial magnetic stimulation (rTMS) for obsessive-compulsive disorder (OCD): an exploratory meta-analysis of randomized and sham-controlled trials. J Psychiatr Res. 2013;47(8):999-1006.
15. Martin JL, Barbanoj MJ, Perez V, et al. Transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder. Cochrane Database Syst Rev. 2003(3):CD003387.
16. Fontenelle LF, Coutinho ES, Lins-Martins NM, et al. Electroconvulsive therapy for obsessive-compulsive disorder: a systematic review. J Clin Psychiatry. 2015;76(7):949-957.
17. Lusicic A, Schruers KR, Pallanti S, et al. Transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder: current perspectives. Neuropsychiatr Dis Treat. 2018;14:1721-1736.
18. Carmi L, Alyagon U, Barnea-Ygael N, et al. Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patients. Brain Stimul. 2018;11(1):158-165.
19. Carmi L, Tendler A, Bystritsky A, et al. Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial. Am J Psychiatry. 2019;176(11):931-938.
20. Elbeh KAM, Elserogy YMB, Khalifa HE, et al. Repetitive transcranial magnetic stimulation in the treatment of obsessive-compulsive disorders: Double blind randomized clinical trial. Psychiatry Res. 2016;238:264-269.

21. Dutta P, Dhyani M, Garg S, et al. Efficacy of intensive orbitofrontal continuous Theta Burst Stimulation (iOFcTBS) in Obsessive Compulsive Disorder: A Randomized Placebo Controlled Study. Psychiatry Res. 2021;298:113784.
22. Badawy A, El Sawy H, El Hay MA et al. Efficacy of repetitive transcranial magnetic stimulation in the management of obsessive compulsive disorder. Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 2010: 47, 393¬-397.

23. Roth Y, Tendler A, Arikan MK, et al. Real-world efficacy of deep TMS for obsessive-compulsive disorder: post-marketing data collected from twenty-two clinical sites. Journal of Psychiatric Research. 2021;137:667-672.
24. Carmi L, Tendler A, Bystritsky A, et al. Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial. Am J Psychiatry. 2019;176(11):931-938.
25. Harmelech T, Tendler A, Arikan MK, et al. Long-term outcomes of a course of deep TMS for treatment-resistant OCD. Brain Stimulation: Basic, Translational Clinical Research in Neuromodulation 2022;15(1):226-228.
26. Suhas S, Malo PK, Kumar V, et al. Treatment strategies for serotonin reuptake inhibitor-resistant obsessive-compulsive disorder: A network meta-analysis of randomized controlled trials. The World Journal of Biological Psychiatry. 2022(just-accepted):1-75.
27. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Archives of general psychiatry. 2010;67(5):507-516.
28. Levkovitz Y, Isserles M, Padberg F, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. J World Psychiatry. 2015;14(1):64-73.
29. Kaster TS, Daskalakis ZJ, Noda Y, et al. Efficacy, tolerability, and cognitive effects of deep transcranial magnetic stimulation for late-life depression: a prospective randomized controlled trial. Neuropsychopharmacology. 2018;43(11):2231-2238.
30. Senova S, Cotovio G, Pascual-Leone A, Oliveira-Maia AJ. Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systematic review and meta-analysis. Brain stimulation. 2019;12(1):119-128.
31. Rachid F. Maintenance repetitive transcranial magnetic stimulation (rTMS) for relapse prevention in with depression: A review. Psychiatry Research. 2018;262:363-372.
32. Voigt J, Carpenter L, Leuchter A. A systematic literature review of the clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) in non-treatment resistant patients with major depressive disorder. BMC psychiatry. 2019;19(1):1-11.
33. ECRI Institute. Deep Transcranial Magnetic Stimulation System (Brainsway, Ltd.) for Treating Major Depressive Disorder. 2020; (Custom Product Brief). Available at: https://www.ecri.org/components/ProductBriefs/Pages/28482.aspx?tab=2. Accessed 8/30/2022.
34. Sackeim HA, Aaronson ST, Carpenter LL, et al. Clinical outcomes in a large registry of patients with major depressive disorder treated with transcranial magnetic stimulation. Journal of Affective Disorders. 2020;277:65-74.
35. Weissman CR, Hadas I, Yu D, et al. Predictors of change in suicidal ideation across treatment phases of major depressive disorder: analysis of the STAR*D data. Neuropsychopharmacology. 2021;46(7):1293-1299.
36. Wang W-L, Wang S-Y, Hung H-Y, Chen M-H, Juan C-H, Li C-T. Safety of transcranial magnetic stimulation in unipolar depression: A systematic review and meta-analysis of randomized-controlled trials. Journal of Affective Disorders. 2022.
37. Yip AG, George MS, Tendler A, Roth Y, Zangen A, Carpenter LL. 61% of unmedicated treatment resistant depression patients who did not respond to acute TMS treatment responded after four weeks of twice weekly deep TMS in the Brainsway pivotal trial. Brain Stimulation. 2017;10(4):847-849.
38. Avery DH, Isenberg KE, Sampson SM, et al. Transcranial magnetic stimulation in the acute treatment of major depressive disorder: clinical response in an open-label extension trial. Journal of Clinical Psychiatry. 2008;69(3):441-451.
39. Philip NS, Dunner DL, Dowd SM, et al. Can medication free, treatment-resistant, depressed patients who initially respond to TMS be maintained off medications? A prospective, 12-month multisite randomized pilot study. Brain stimulation. 2016;9(2):251-257.
40. Harel EV, Rabany L, Deutsch L, Bloch Y, Zangen A, Levkovitz Y. H-coil repetitive transcranial magnetic stimulation for treatment resistant major depressive disorder: an 18-week continuation safety and feasibility study. The World Journal of Biological Psychiatry. 2014;15(4):298-306.
41. Wilson S, Croarkin PE, Aaronson ST, et al. Systematic review of preservation TMS that includes continuation, maintenance, relapse-prevention, and rescue TMS. Journal of Affective Disorders. 2022;296:79-88.
42. Dunner DL, Aaronson ST, Sackeim HA, et al. A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period. The Journal of clinical psychiatry. 2014;75(12):12379.
43. 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. 2010;3(4):187-199.
44. NICE: Transcranial magnetic stimulation for obsessive-compulsive disorder | Interventional Procedures Guidance. 2020; https://www.nice.org.uk/guidance/ipg676/resources/transcranial-magnetic-stimulation-for-obsessivecompulsive-disorder-pdf-1899874288332997. Accessed Nov. 10, 2021.
45. Holtzheimer, P. Technique for performing transcranial magnetic stimulation (TMS). Up To Date. UpToDate; 2022. Accessed Nov. 10, 2021.
46. ECRI. Transcranial magnetic stimulation for treating adults with obsessive-compulsive disorder. Plymouth Meeting (PA): ECRI; 2021 May. (Clinical Evidence Assessment). Accessed Nov. 11, 2021.
47. AHRQ Program. Definition of Treatment-Resistant Depression in the Medicare Population 2/9/2018; https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id105TA.pdf. Accessed 8/30/22.
48. McClintock SM, Reti IM, Carpenter LL, et al. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. 2017;79(1):3651.
49. Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TSJBs. The clinical TMS society consensus review and treatment recommendations for TMS therapy for major depressive disorder. 2016;9(3):336-346.
50. Gelenberg AJ, Freeman M, Markowitz J, et al. American Psychiatric Association practice guidelines for the treatment of patients with major depressive disorder. Am J Psychiatry. 2010;167(Suppl 10):9-118.
51. Rush, A. J., C. South, M. K. Jha, S. B. Jain and M. H. Trivedi (2020). "What to expect when switching to a second antidepressant medication following an ineffective initial SSRI: a report from the randomized clinical STAR* D study." The Journal of clinical psychiatry 81(5): 20565.
52. Rush, A. J., M. H. Trivedi, S. R. Wisniewski, A. A. Nierenberg, J. W. Stewart, D. Warden, G. Niederehe, M. E. Thase, P. W. Lavori and B. D. J. A. J. o. P. Lebowitz (2006). "Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR* D report." 163(11): 1905-1917.

Additional literature reviewed but not cited

1. Repetitive Transcranial Magnetic Stimulation Position Statement 79. 2018; https://www.ranzcp.org/news-policy/policy-and-advocacy/position-statements/repetitive-transcranial-magnetic-stimulation. Accessed Nov. 23, 2021.
2. Hamani C, Pilitsis J, Rughani AI, et al. Deep brain stimulation for obsessive-compulsive disorder: systematic review and evidence-based guideline sponsored by the American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons (CNS) and endorsed by the CNS and American Association of Neurological Surgeons.
   Neurosurgery. 2014;75(4):327-333; quiz 333.
3. Reddy JYC, Sundar AS, Narayanaswamy JC, et al. Clinical practice guidelines for Obsessive-Compulsive Disorder. Indian J Psychiatry. 2017;59(Suppl 1):S74-S90.
4. Koran LM, Hanna GL, Hollander E, et al. Practice Guideline for the Treatment of Patients with Obessive-Compulsive Disorder. 2007; https://psychiatryonline.org/guidelines. Accessed Nov. 24, 2021.
5. Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. 2014;14(1):1-83.
6. Rossi S, Antal A, Bestmann S, et al. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clinical Neurophysiology. 2021;Volume 132, Issue 1:269-306.
7. Allan CL, Herrmann LL, Ebmeier KP. Transcranial Magnetic Stimulation in Management of Mood Disorders. Neuropsychobiology. 2011;64(3)163-9.

Original References for TMS for Depression

1. Carpenter LL, Janicak PG, Aaronson ST, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012;29:587–596. [Industry-sponsored post market approval study of TMS in general psychiatric practice. The results showed efficacy with few side effects and low dropouts. Daily prefrontal TMS for treating acute depression appears to have clinical effectiveness in a practice setting.]
2. Connolly RK, Helmer A, Cristancho MA, O’Reardon JP. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry. 2012;73:e567–e573. [Study for Philadelphia clinic, again showing effectiveness as an adjunctive treatment to antidepressant medications in the first 100 patients treated at their university-based TMS clinical service following FDA approval.
3. Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry. Oct 2003;60(10):1002-8. [Early study with some evidence of efficacy.]
4. Gaynes BN, Lux LJ, Lloyd SW, et al. Comparative Effectiveness Review Number 33. Effective Health Care Program. Nonpharmacologic interventions for treatment-resistant depression in adults AHRQ Publication No. 11-EHC056-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. (The evidence for ECT was good, TMS vs sham was moderate and all others insufficient.) Accessed 1/20/2015
5. George MS, Taylor JJ, Short EB. The expanding evidence base for rTMS treatment of depression. Curr Opin Psychiatry. Jan 2013;26:13-8. [Review]
6. 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;67:507–516.[190 patients NIMH-sponsored multicenter, randomized controlled trial demonstrated that rTMS, as drug-free monotherapy, produced statistically significant antidepressant effects with a remission rate 4x that of the sham patients. Industry-independent evidence of safety and efficacy.
7. George MS, Wassermann EM, Williams WE, et al. Mood improvements following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry. 1997;154:1752–1756. [Early study with preliminary evidence.]
8. Mantovani A, Pavlicova M, Avery D, et al. Long-term efficacy of repeated daily prefrontal transcranial magnetic stimulation (TMS) in treatment-resistant depression. Depress Anxiety. 2012;29:883–890. [The effects appear durable, at least at 3 and 6 months.]
   McDonald WM, Durkalski V, Ball ER, et al. Improving the antidepressant efficacy of transcranial magnetic stimulation: maximizing the number of stimulations and treatment location in treatment-resistant depression. Depress Anxiety. 2011;28:973-980. [Open-label extension of the OPT-TMS randomized trial showed that about 30% of patients remit, but that in many this can take up to 6 weeks of therapy.
9. McDonald WM, Durkalski V, Ball ER, et al. Improving the antidepressant efficacy of TRANSCRANIAL MAGNETICSTIMULATION: maximizing the number of stimulations and treatment location in treatment-resistantdepression. Depress Anxiety. 2011;28:973-980. [Open-label extension of the OPT-TMS randomized trialshowed that about 30% of patients remit, but that in many this can take up to 6 weeks of therapy.
10. 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.

• rTMS
• TMS