**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 transmagnetic 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.

**The following additional literature was reviewed.**

Elbeh et al. (2016) 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 assessments were after
the final treatment and 3 months later. The group receiving 1 Hz versus the 10
Hz group 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. (2021) 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
Yale Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Rating
Scale (HAM-D), Hamilton Anxiety Rating Scale (HAMA), and Clinical Global
Impression-Severity (CGI-S) scores were assessed at+z baseline, after last
session and at 2 weeks post-rTMS. They reported significant improvements from
pretreatment to 2 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. (2010) 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 are needed.

**Contractor advisory committee (CAC) Meeting Summary**

NGS 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, 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 panelist 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.