Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.  
  
**History/Background and/or General Information**

Transcranial Magnetic Stimulation (TMS) is FDA approved for the treatment of
depression and obsessive-compulsive disorders.1-3 It is a non-invasive
procedure that uses pulsed magnetic fields to induce an electric current in a
localized region of the cerebral cortex.4-7 An electromagnetic coil is placed
on the scalp inducing a focal current into the brain that temporarily
modulates cerebral cortical function. A capacitor discharge provides
electrical current in an alternating on/off pulse. Based on stimulation
parameters this may be adjusted to alter the excitability of the targeted
structures in specific cortical regions.8 The electromagnetic current
parameters include cranial location, frequency, strength, width, and volume
dependent on the motor threshold that is individualized for each patient.1,2

TMS is delivered daily in an outpatient setting without anesthesia or
analgesia for up to six weeks and there are no restrictions related to
activities before or after treatment (e.g., driving, working, operating heavy
machinery).9  
  
 **Definitions**

**Major Depressive Disorder:** The diagnosis based on the definition in the
current Diagnostic and Statistical Manual of Mental Disorders (DSM). It is
based on symptoms, characteristics, and requirements that are needed in order
to be diagnosed with depression.

**Major Depressive Disorder - Severe: **A subcategory of major depressive
disorder as differentiated within the DSM manual from mild, moderate, and
severe. For example: "The number of symptoms is substantially in excess of
that required to make the diagnosis, the intensity of the symptoms is
seriously distressing and unmanageable, and the symptoms markedly interfere
with social and occupational functioning."10

**Failure of a trial of a pharmacological agent:** The failure of one or more
psychopharmacological medications that are administered at both an adequate
dose and adequate duration that are consistent with the FDA label and with a
duration that would elicit a favorable response.9,11-13

**Intolerance of a psychopharmacologic agent:** Intolerable side effect(s)
that are not expected to diminish or resolve with continued administration of
the medication.5,14,15

**Motor Threshold (MT) Intensity:** The minimum stimulator setting that
induces an observable motor response when applied to the patient.1

**Frequency:** The number of pulses delivered per second, measured in Hertz
(Hz).1

**Magnetic Field Strength:** The measurement of voltage induced to the
identified area.1

**Pulse Width:** The duration of time from the peak of a pulse to the peak of
the next pulse.1

**Stimulation Volume:** The region of cortical tissue that is stimulated based
on the Motor Threshold identified for the individual patient.1  
  
 **Covered Indications**

TMS of the brain for severe MDD, single or recurrent episode, is considered
medically reasonable and necessary for up to six weeks3,5,6,16-19 when the
following criteria are met:

  1. The patient has a confirmed diagnosis of severe MDD as defined by the current DSM.  
 **AND**

  2. The patient has demonstrated a failure of one or more trials of a pharmacological medication and/or demonstrates an intolerance to psychopharmacologic medications as defined in the definition section above.  
 **AND**

  3. The order for TMS procedure is written by a psychiatrist (MD or DO), who has examined the patient face to face and reviewed the record.20

  
**Limitations**

The following is considered an **ABSOLUTE CONTRAINDICATION:**

The presence of a medically implanted magnetic-sensitive device or other
implanted metal items including, but not limited to, a cochlear implant,
implanted cardiac defibrillator (ICD), pacemaker, vagus nerve stimulator
(VNS), metal aneurysm clips/coils, staples, or stents, that are located less
than or equal to 30 cm from the TMS magnetic coil.1,6,15  
  
The following are considered **RELATIVE CONTRAINDICATIONS:**

  1. The presence of a seizure disorder or any history of seizures (except those induced by Electroconvulsive therapy [ECT] or isolated febrile seizures in infancy without subsequent treatment or recurrence).
  2. The presence of acute or chronic psychotic symptoms or disorders in the current depressive episode.
  3. The presence of any neurological conditions including epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, history of repetitive or severe head trauma, or primary or secondary tumors in the central nervous system.

The following is considered not medically reasonable and necessary:

         All other uses of TMS, including the use of TMS for OCD.7,12,20-23  
  
 **Provider Qualifications**

Services will be considered medically reasonable and necessary when all
aspects of care are within the scope of practice of the provider's
professional licensure, when performed according to the supervision
requirements per state scope of practice laws, and when all procedures are
performed by appropriately trained providers in the appropriate setting.

**Notice:** Services performed for any given diagnosis must meet all the
indications and limitations stated in this LCD, the general requirements for
medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.

This summary of evidence focuses on the use of TMS in the treatment of MDD and
TMS in the treatment of OCD and the use of TMS following one or more failed
trials of pharmacological agents to determine whether the evidence is
sufficient to draw conclusions about improved health outcomes for the Medicare
population. In general, improved health outcomes of interest include patient
quality of life and function.

In addition to reviewing evidence presented at a Multi-jurisdictional CAC
Meeting and literature submitted with reconsiderations, a literature search
was conducted using the following key words and phrases: TMS and OCD; TMS
treatment for OCD; RCT of OCD TMS; OCD for deep transcranial magnetic
stimulation (dTMS); Non-invasive/non-pharmacological OCD/depression treatment;
and TMS as OCD treatment; scoring of Hamilton Rating Scale for Depression
(HAMD); Montgomery-Asberg Depression Scale (MARDS) treatment parameters; DSM
mild, moderate, severe depression. Along with various association guidelines.
The highest level of evidence consisting of large randomized controlled trials
(RCTs), multi-site RCTs, peer reviews and society endorsements were followed.  
  
**Clinical Trials**

Rush et al16 reviewed the protocol implemented by the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) that include a RCT that began with
3,671 patients who would receive the first of four levels of treatment
beginning with medication. At any time during the protocol, if a patient
achieved remission, they could then opt to be followed in a long-term
naturalistic review that would last 12 months. The study began with 41
clinical sites consisting of patients between 18-75 years of age, diagnosed
with MDD, and not previously exposed to any treatment protocol in the first
and second treatment steps.

Tools of depression measurement such as Hamilton Rating Scale of Depression
(HRSD17) and Inventory of Depressive Symptomatology (IDS-C30), Quick Inventory
of Depressive Symptomatology (QIDS-C16), Frequency, Intensity, and Burden of
Side Effects Rating, among others were implemented as a baseline and used to
gauge the effects of treatment throughout the study. Response was quantified
as a 50% reduction from baseline on the QIDS-SR16. Remission was defined as
QIDS-SR16 of 5 (HRSD17 7) and relapse defined as QIDS-SR16 11 (HRSD17 14).

The treatment steps outlined in the review consisted of the following levels:
Level one - involved administration of citalopram with the goal being a score
of 14 on the HRSD17 scale. The study excluded 2,232 patients during and after
the first level due to various reasons such as drop out and evaluation in
patient scores. Level two and three - treatments were based on equipoised
stratified random design. A choice of seven pharmacological or cognitive
behavior therapies (CBT) were provided to the remaining 1,439 patients. Level
three removed the option of CBT and continued with a pharmacological agent as
an augmentation option or the ability to switch medication treatment plans for
the 390 patients that continued to level four. Within level four - there were
123 patients that completed the final level. The overall results showed "QIDS-
SR16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first,
second, third, and fourth acute treatment steps, respectively."16(p1905)

The results and conclusions of the trial also identified some key areas:

Patients that had prior treatment for MDD had a lower rate of remission
(35.6%) in their current episode as compared to patients with no prior
treatment (42.7%). Remission appeared to occur at 5.4-7.4 weeks at each level
of treatment.

"Lower relapse rates were found among patients who were in remission at
follow-up entry than for those who were not after the first three treatment
steps."16(p1905)

Carpenter et al18 conducted a clinical trial of 42 clinic based TMS treatment
centers across the U.S. The trial consisted of 307 patients who underwent
acute treatment with TMS for six weeks. The patients ranged in age from 18-90
years, with one or more failed pharmacological treatments, no prior treatments
with TMS, and a confirmed diagnosis of major depression based on DSM-IV
criteria. Patients were treated per protocol with TMS up to six weeks and had
the opportunity to continue to a 52-week naturalistic continuation outcome
study. The goal of this study was to determine the outcomes of TMS treatment
for a large population of patients that were diagnosed with major depression.

The primary outcome measure was the amount of change from baseline to end-
point on the Clinical Global Impressions-Severity of Illness Scale (CGI-S)
with response being an end-point rating of three or less.

This study was initiated with 339 numerated patients, 307 met the criteria,
and of those 307 patients, one patient dropped out before the second week and
seven patients after two weeks of treatment 'completed' the study by
establishing remission or responding to treatment. Nineteen patients dropped
out and 280 continued treatments through the fourth week.

Within the fourth week,100 patients completed the study, 11 did not return and
169 continued through to the sixth week of treatment.

Within the sixth week, 91 patients completed the clinical trial and seven did
not return for various reasons. Seventy-one patients remained and continued
beyond the sixth week.

Beyond the sixth week, 67 patients completed the study while four remaining
did not return. Only one adverse effect of a seizure was noted and reported
during the study.

Acute phase treatment with continuous variables demonstrated a significant
improvement in CGI-S total scores from baseline (1.9  1.4, P < .0001).
Acute-phase treatment outcomes with categorical variables were consistent on
all outcome measures with over half of the patients achieving responder status
at the end of the acute treatment.

Since other research has suggested that there are several clinical variables
that may influence a patient's response to treatment, secondary analyses were
conducted in an effort to identify potential moderators of treatment outcome
with TMS.

The response rate was determined by the change in baseline based on CGI
testing tool. The authors, whom have a varied stake with Neuronetics, reported
that, in weeks two and six a total of 58% of patients were considered
responders while 37% were scored as in remission.

The study concluded that in the acute phase younger patients with lower pre-
treatment baseline scores fared better by identifying greater remission. The
authors note that "patients who had failed a minimum of one adequate
antidepressant trial were as likely to be TMS responders as those who had
failed two or more trials in the current episode" and that "more than half of
patients achieved responder status at the end of acute treatment, and
approximately one third of patients achieved remission."18

Fitzgerald et al24 provided a meta-analysis of 11 clinical trials (nine
published trials) over the course of 15 years. This analysis supported the
determination of response to rTMS, the rate of response and remission, and
touched on clinical and demographic predictors of responses. The compiled
studies were comprised of 1,132 (62.8% female and 37.1% male) patients that
were 18-89 years of age. Thirty-two percent of the patients were diagnosed
with a single episode of MDD, 53% were diagnosed with recurrence of MDD, 13%
were diagnosed with bipolar affective disorder and 1.7% were diagnosed with
schizoaffective disorders.

Twenty-nine percent of the patients were treated with high-frequency left-
sided rTMS; 45.4% of the patients received treatment with low-frequency right-
sided rTMS; and 25% of the patients received sequential bilateral rTMS.

The scales used to determine response rates were the HAMD17 and MADRS and
patients had to have an improved score(s) of 50% or better to be considered as
a 'responder' to the treatment provided. The result of the analysis determined
that there was a 57% reduction in depression rating scale scores, 46% of
patients achieved response criteria, and 31% completing rTMS treatment were in
remission.

There were additional items reviewed such as the treatment response or the
lower tolerance to biomedical interventions as it relates to patients that had
failed at least two or more medication trials. Results of the review indicate
a lower number of failed medication trials make patients more susceptible to
rTMS.

There is a noted left and right sided treatment difference and unilateral
versus bilateral treatment which may be related to 'priming stimulation' on
the right side. "It is less clear why bilateral treatment is associated with a
high response rate."24(p752)

In relation to age and improved response it was once thought that the distance
between the scalp and cortex was larger in the elderly causing an
'underdosing' at the time of treatment. Improvements in care and treatment
over the past 15 years seem to have corrected and compensated for the
individual's size, shape, and treatment intensity.

This meta-analysis concluded that 44% responded to treatment and 56% were
considered 'non-responders'. In addition, it was found that patients with a
shorter episodic illness and lower number of failed medication trials had a
better response to rTMS.

In summary "rTMS is an effective and useful clinical treatment for patients
with depression although questions remain as to the most effective way to
apply this intervention."24(p752)  
  
 **Randomized Control Trials**

Brakemeier et al25 provided a logistic regression review for an acute TMS
treatment phase of two weeks. The analysis was related to 70 patients with a
DSM-IV criteria for bipolar II or MDD. Within the study the characteristics of
the patients were as follows: 45% of patients had a single episode, 42% had
recurrent depression and 11% had a diagnosis of recurrent bipolar disorder. Of
those 70 patients, 55% were receiving antidepressants (four weeks prior to
review and constantly during study) and 44% were pharmacologically free. The
study determined that only 33% of the medication resistant patients responded
to TMS and 83% of the medication resistant patients did not respond to
treatment (non-responders).

Baseline scoring for HAMD17, CORE [elements of non-instructiveness], and Beck
Depression Inventory (BDI) were completed. The patients were evaluated again
after the first week of treatment and then again at the second week of rTMS
treatment.

The study was meant to evaluate the 'physiopathology of depression' therefore
patients were evaluated on a narrower response related to 'symptoms' to assist
as predictors for treatment for responders and non-responders.

The following five factors were based on HAMD17 to detail: Psychic depression,
Loss of motivation, Psychosis, Anxiety and Sleep disturbances. The patients
had to show a 50% reduction in these HAMD17 identified factors to be
considered a responder.

After two weeks of treatment 86% of the patients were responders and 14% were
categorized as non-responders. It was noted by the authors that "statistically
significant differences between responders and non-responders at baseline was
observed for the variables 'duration of current episode', total number of
antidepressant trials via the Antidepressant Treatment History Form (ATHF),
medication resistance, and the two CORE criteria 'agitation' and 'retardation'
[psychomotor slowing]."25(p398)

Regarding the five factors of the HAMD17 scoring there were notable
improvements in responders in relation to psychic depression, sleep
disturbances, and a loss of motivation. With this evidence, the authors
conclude that "the main predictors of response to rTMS were duration of the
Major Depressive Episode (MDE) less than five months."25(p398) It was also
noted that the patients with low treatment resistance had a higher response
rate than those with more than two medication trials.

Lisanby et al19 provides a prediction of acute outcomes in relation to the
degree of prior treatment in a multisite, randomized, double blinded,
controlled clinical trial that incorporated 23 clinical sites to include
multicultural nations such as the U.S., Australia, and Canada.

The trials were conducted between 2004-2005 and there were 301 patients that
were resistant to pharmaceutical antidepressants. The trial placed patients
into either an active or sham group with 155 patients in the active group and
146 patients in the sham group. Fifty-four percent of the 301 patients had
received one antidepressant treatment trial of adequate dose and duration in
the current episode, with the remainder of the patients (45.5%) receiving two
to four adequate treatment trials. The baseline HAMD17, HAMD24 and MARDS
scores averaged 22, 30 and 32 respectively, making patients moderately to
severely ill.

Treatment was provided at the following requirements: TMS = MT 120%, 10 rep,
10Hz, trains of four seconds duration, 26 seconds intertrain interval (40
pulses per train) for a total of 75 pulse trains (300 pulses) over the
Dorsolateral Prefrontal Cortex (DLPFC) for at least four weeks. Acute
treatment was extended to six weeks if the patient did not exhibit a response
or enter remission.

A total of 164 patients who failed to benefit from one adequate antidepressant
treatment in the current episode showed significantly greater improvement in
MADRS and HAMD24 total scores in comparison to patients who had failed two to
four adequate antidepressant treatments.

The MARDS score for one adequate antidepressant was 0.0018 in the second week
of treatment whereas the score for patients having more than one adequate
antidepressant trials was 0.377. At the end of the fourth week the results
were 0.0006 and 0.923 respectively and the evaluation at the end of the sixth
week resulted in 0.0063 and 0.547 respectively. Therefore, less treatment
resistance (TR) in the current episode and higher symptom severity at baseline
was associated with greater clinical benefit for the patient. The limitation
related to the study was related to only offering one TMS treatment protocol
and TR was limited to four treatment failures in the current episode.

Levkovitz et al5 conducted a review and additional research related to the use
of rTMS in acute treatment periods ranging from three to six weeks. This study
utilized the form of dTMS to investigate the efficacy and safety when applied
in five-day sequence (five days per week) for four weeks, as monotherapy for
patients with diagnosed MDD. In addition, these patients had either failed one
to four antidepressant trials or did not tolerate at least two antidepressant
treatments in the current episode. This double-blind randomized placebo-
controlled multicenter trial included patients that were 22-68 years of age
from October 2009 to January 2012 in collaboration with independent data and a
safety monitoring board.

This study focused on the subgenual cingulate gyrus which is a
pathophysiological region in the brain associated with MDD. The idea was to
"stimulate less focally and more deeply to reach connecting fiber
tracts"5(p65) and study the effects of a 12-week treatment protocol. The
H1-Coil was "developed for deeper and non-focal stimulation of dorsolateral
and ventrolateral prefrontal areas that also project into other areas of brain
reward system" and would be the type of device to deliver the dTMS protocol in
patients in the study.

The study design included three phases: a 'wash-out' phase (one to two weeks),
during which patients were tapered off all antidepressants, mood stabilizers
and antipsychotics; a four-week acute treatment phase (daily treatment from
Monday through Friday with dTMS or sham TMS), and a 12-week maintenance phase
(two treatments per week of dTMS or sham TMS).

The study used the Hamilton Depression Rating Scale (HDRS21) and the CGI-S as
scoring tools. The study resulted in 181 patients that were then divided into
two groups. One group had 89 patients that would receive the dTMS treatment
and 92 patients in the sham treatment group. At the end of the study (16
weeks) there were various dropouts or stages where the patients reached their
primary endpoint, resulting in 43 dTMS patients and 28 sham patients.

Results were reported with the primary endpoint being the change in HDRS21
from baseline. There was a noted change from baseline of -6.39 in the dTMS
group and -3.28 in the sham group. The secondary efficacy measures were
related to response and remission rates. At the fifth week the rate of
response for the dTMS group was 38.4% with the sham group reporting 21.4%, and
remission rates of 32.6% and 14.6% respectively.5

At the conclusion of the study (16 weeks) the third efficacy measure was
calculated resulting in the change in HDRS21 total scores from baseline. The
response results were statistically significant with the dTMS group reporting
44.3% improvement versus a 25.6% improvement in the sham group. While the
remission rates were 31.8% and 22.2% respectively.

There was also a subset analysis related to medication failures. The groups
were divided into subjects that failed one or two medication trials and those
who failed three or more. The results after the implementations of the
Analysis of Variance (ANOVA) model resulted in the first stratum being 36.6%
in the dTMS group and 16.7% in the sham group. The second stratum was 28.9%
and 12.2% respectively, indicating that patients that have a greater
medication failure rate are less likely to respond to dTMS.

As a result, this "randomized and placebo-controlled trial demonstrates that
dTMS is an effective and tolerable treatment for patients with MDD who have
not successfully responded to treatment with antidepressant medications in the
current episode"5(p72) but not without adverse events that were reported such
as nausea, vomiting, headache, site discomfort, insomnia, and muscle
twitching.

Fregni et al26 conducted an analysis of six randomized controlled trials that
provided five double blind studies and one study with an open label trial to
identify the predictors of antidepressant response to TMS. There were 195
patients ranging from 18-91 years of age with DSM-V diagnosis of MDD scoring
from 18-22 on the HAMD scoring tool. These studies used HAMD as a scoring
mechanism and the requirement to determine a response to treatment was the
reduction in base line score of 50% or remission as a post-treatment HAMD
baseline of 7\. Patients were given 10rTMS treatment sessions over a two-week
period and re-evaluated.

The evidence was analyzed by applying various linear regressions, univariate
analysis, logistic regression, and the removal of outliers. The evidence was
provided in comparison tables and the results of treatment refractoriness was
based on certain HAMD items (such as insomnia-early, work activities, fear,
anxiety, systematic somatic symptoms, and diminished insight), one table was
based on anxiety and work, and the third table in a linear regression model
that removed an outlier study.

The actual adjusted predictors of antidepressant response in treatment
refractoriness for scoring based on insomnia-early, work activities, fear,
anxiety, systematic somatic symptoms and diminished insight (Model 1) was
24%-52%, for items related to evaluation of anxiety and work (Model 2) was
22%-48% and for the linear regression (Model 3) removing an outlier study
resulted in refractoriness of 20%-46%.

The results provided a strong correlation to depression improvement after two
weeks of rTMS treatment.

Carmi et al27 studied 41 OCD patients who had failed two psychopharmacological
trials plus CBT. The study provided baseline of clinical and
electrophysiological measurements, a five-week treatment protocol, and a one-
month follow-up for patients with OCD. Entrance criteria included an age range
of 18-65 years old; a DSM-IV diagnosis of OCD; a score of 20 on the Yale-
Brown Obsessive Compulsive Scale (Y-BOCS); stable Selective Serotonin Reuptake
Inhibitor (SSRI) medications for eight weeks prior to enrollment and unchanged
during treatment; and CBT at maintenance phase (if conducted). Randomization
of treatment was provided to the patients at a certain frequency protocol. One
group received 1 Hz Low Frequency (LF), the second group received 20 Hz High
Frequency (HF) and the third group being the sham group. Treatment occurred
five times per week for five weeks. Primary and secondary outcomes were based
on the Y-BOCS and CGI-S scoring tools which were obtained at: pre-treatment;
prior to the second treatment session (weeks two to four); prior to the last
treatment session; one week post treatment; and at a one-month follow-up
evaluation.

The baseline characteristics of the three groups did not differ. Three of the
41 patients dropped out due to schedule conflicts and inconvenience. No
adverse events occurred beyond headache and when asked to guess the group to
which they were assigned, the vast majority of patients could not determine,
of the three groups, which one they were assigned.

No trend was reported in the low frequency and two of the eight patients had a
worsening Y-BOCS score; therefore, the low frequency group of the study was
omitted. Sixteen patients completed the study for the HF group and 14 patients
completed the study within the sham group. 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). Each remaining group 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.

Carmi11 conducted research based on a prospective, randomized double-blind
placebo-controlled trial to determine the benefits of dTMS to the medial
prefrontal cortex and the anterior cingulate cortex of patients suffering from
OCD.

The gage of improvement was based on YBOCS scored from baseline to post
treatment evaluation and extended to a one month follow up. A full response
was equivalent to a 30% reduction and a partial response was equivalent to a
20% reduction from the baseline scores. This study was conducted at 11
centers: nine in the U.S., one in Israel, and one in Canada. Each participant
had a Y-BOCS score of >20 and they must have failed at least one
pharmacological trial. Ninety-nine OCD patients were chosen for daily
treatment sessions of five days a week, for a total of 25 sessions at high-
frequency or sham dTMS for a period of six weeks (29 treatments).

The treatments provided the following results: post-treatment assessment at
the sixth week, demonstrated that the Y-BOCS score decreased significantly
from baseline in both the active (26.0 points, 95% CI=4.0, 8.1) and sham (23.3
points, 95% CI=1.2, 5.3) treatment groups (estimated slopes). The difference
in slopes of change in Y-BOCS score between the two groups was statistically
significant at the post-treatment assessment (2.8 points, p=0.01), for an
effect size of 0.69. The effect was also present at the fourth week post-
treatment follow-up assessment, at which point the mean Y-BOCS score had
decreased by 6.5 points (95% CI=4.3, 8.7) in the active treatment group and by
4.1 points (95% CI=1.9, 6.2) in the sham treatment group. The rate of full
response (a reduction >30% in Y-BOCS score) at the post-treatment assessment
in the active treatment group was 38.1% (16/42), compared with 11.1% (5/45) in
the sham treatment group (p=0.003).  
  
 **Systematic Review/Meta-Analysis**

Voigt et al's28 systematic review of the literature was to assess the clinical
efficacy for the use of rTMS in patients with MDD who have failed one or less
pharmacologic trial versus two or more pharmacologic trials. The level and
quality of evidence was assessed using the Center for Evidence-Based Medicine
(CEBM) and the Grading of Recommendations, Assessment, Development, and
Evaluation (GRADE) criteria. In addition, they used a Systematic Reviews and
Meta-Analyses (PRISMA) checklist to ensure the manuscript complied to minimum
accepted guidelines for review.

The mean average age was 41 years, with 1,339 patients. Six studies were
graded as 'high quality' by the GRADE and CEBM while the remaining four were
low quality, but all demonstrated a positive effect for patients with less
than one medication trial and the use of rTMS for treatments.

It has been noted within this analysis that the greater the medication
resistance the greater the resistance to other therapeutic modalities. It was
noted that 20-40% of patients cannot tolerate and do not benefit from repeated
trials of antidepressants. The literature shows that "with medication the
remission and response rates were: 30.6% and 28.5% after one failed medication
therapy; 13.7% and 16.8% after two failed medication therapies and 13 and
16.3% after three failed medication therapies."28(p8) The study also noted
that the response and remission rates for rTMS were "95% response and 63%
remission rate in treatment naive patients; 43% response rate after one failed
medication trial; 36.6% remission after one to two failed medication therapies
and; 28.9% remission after three to four failed medication therapies."28(p9)
Additional evidence exists that if TMS is used by itself or in combination
with an antidepressant for patients diagnosed with the first episode of MDD,
it may be more effective and shorten the treatment period than if
antidepressants were used alone.

Ma et al12 reviewed nine RCTs with 290 patients diagnosed with OCD. Most of
these patients were resistant to SSRI. Random assignments (not described
within the review) were made using rTMS or sham rTMS. 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 rTMS patients and 136 patients were in the sham rTMS
group. Study size ranged from 18 to 65 years of age. The Y-BOCSs were reported
to indicate improvement when rTMS was added to treatment with medication.
There were nine patients 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, and the 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 to rTMS.
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 greater at week two and week six, 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 monotherapy for OCD. No conflicts of
interest were reported.

Rehn et al23 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 (2014) 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 as rTMS. The total number of
patients was 484 with 262 receiving active rTMS and 222 receiving sham rTMS.
Patients ranged in age from 18 to 46 years of age. 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 Left
Dorsolateral Prefrontal Cortex (L-DLPFC) was not significant in relation to
the sham rTMS group. 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.

Lusicic et al21 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. The brain areas included in the review were
DLPFC, 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 showed that 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.  
  
**Societal Consensus**

Perera et al7 provides a peer and consensus review related to the effect of
rTMS on patients that are in an acute phase of clinical depression and
followed for six months to evaluate the durability of TMS. Within the
systematic review the authors included over 100 publications and used five
major levels of evidence to determine the greater emphasis of studies which
resulted in RCT and systematic reviews. The authors also requested additional
information such as scientific publication, manufactures' product manuals and
manufactures' Medical Technology Dossiers. One additional piece was a survey
conducted by the Clinical TMS Society.

The review detailed the first randomized, sham controlled multicenter trial
reported by O'Reardon et al (2007). This was a global 23 site study that
consisted of numerous phases such as one week, no treatment lead in, a four-
to-six-week acute monotherapy of TMS treatment, and then a four to six week
open-label trial for non-responders. This study concluded that in the patients
that failed one prior medication trial there was a robust effect from TMS
versus the sham group ( _p_ <0.001). The second sham controlled, randomized
multicenter trial was conducted by the National Institutes of Mental Health as
researched by George (2010). This eight-week study detailed a two-week lead-in
phase, three-week fixed TMS treatment protocol phase and a three-week
treatment extension phase. The results were summarized as "TMS as monotherapy
produced significant and clinically meaningful antidepressant therapeutic
effects greater than sham."7(p340) The third review consisted of the Brainsway
trial that involved 20 locations between the U.S., Canada, Europe, and Israel
as researched by Levkovitz (2015). This fully blinded, randomized-active sham
trial studied patients with MDD who had failed one to four pharmacological
trials. The patients were given TMS in the acute four-week phase and followed
with treatment for an additional 12 weeks. The total sample size was 703
patients. The results of this study demonstrated that 64%-90% of patients
showed acute TMS durability benefits, and most of the patients relapsing had
responded to more TMS treatments.

Additional reviews related to durability and maintenance studies were reviewed
and collected. The 'index/acute' course was defined as "the initial series of
treatment given to relieve acute symptoms."7(p340). Five meta-analyses were
referenced in the consensus information along with society endorsements such
as American Psychiatric Association and the World Federation of Societies for
Biological Psychiatry to name a few.

As a result of this review and research the following five recommendations
emerged: 1) TMS therapy is recommended as an acute treatment for symptomatic
relief of depression in the indicated patient population. 2) 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 (continuation or maintenance). 3) TMS therapy can be
administered with or without the concomitant administration of antidepressant
or other psychotropic medications. 4) TMS therapy can be used as a
continuation or maintenance treatment for patients who benefit from an acute
course. 5) TMS therapy can be reintroduced in patients who are relapsing into
depression after initially responding to TMS treatment.

McClintock et al17 provided a consensus statement concluding that "Repetitive
transcranial magnetic stimulation (rTMS) is a safe, noninvasive
neuromodulation therapy for major depressive disorder (MDD)."17(p2)
Furthermore, the expert opinion of the National Network of Depression Centers
(NNDC) in association with members from the American Psychiatric Association
(APA) determined that "rTMS is appropriate as a treatment in patients with MDD
even if the patient is medication resistant or has significant comorbid
anxiety as long as it is provided within treatment parameters."17(p5) The FDA
approved the use of rTMS in 2008 for MDD but limited treatment to adults
versus adolescents, females with perinatal depression or other
neuropsychiatric disorders.

The consensus statement was provided after the review and analysis of three
large RCTs, the meta-analyses of 29 RCTs, and review of 118 publications all
related to the use of rTMS for MDD as defined by DSM.

The three multicenter industry-sponsored studies in the treatment of MDD
resulted in a response rate of 24% and remission rate of 17% with active rTMS,
compared with 15% response and 8% remission with sham rTMS.

The meta-analysis of 29 RCTs resulted in 1,371 patients with a response rate
of 95%, and remission rate of 95%. The consensus provided a few examples of
the RCTs such as:

A systematic review and meta-analysis of 16 double-masked, parallel-design
resulted in a response rate of 95%.

The National Institute of Mental Health (NIMH) sponsored a study resulting in
a 15% response rate and 14% remission rate in comparison with a 5% response
and remission rates in the sham group.

Another industry-sponsored study resulted in a response rate of 37% and
remission rate of 30% compared to a 28% response rate and 16% remission rate
with sham group.

In conclusion "Practitioners are encouraged to implement rTMS based on
available evidence-guided recommendations and to employ systematic measurement
for documenting safety and efficacy".17(p16) It was also recommended that six
weeks of standard acute TMS treatment will "very likely be needed to achieve
results consistent with published regulatory rituals."17 (p8)

**The National Institute for Health and Care Excellence (NICE) 29 provided
guidelines for 'Repetitive transcranial magnetic stimulation for depression'
Interventional procedure guidelines:**

  * Support use of TMS as there are no major safety concerns when used for depression.
  * Efficacy is short-term with variable clinical responses.
  * Further evidence is needed based on regime type, stimulation used, long-term outcomes and maintenance treatment.

**U.S. Food and Drug Administration (FDA)**

The FDA provides information related to the marketing and Class II Special
Controls for Repetitive Transcranial Magnetic Stimulation (rTMS) in the
treatment of Major Depressive Disorders in 2008 and the treatment relates to
obsessive-compulsive disorders in 2011.1-3

**The following is a summary of the evidence submitted with a reconsideration
request to extend coverage to include 'moderate' in addition to severe major
depressive disorder diagnosis:**

Muller et al30 conducted a study to assess the depression severity of patients
with major depression as diagnosed by DSM-IV, by utilizing HAMD17, MARDS and
CGI scores. The study attempted to establish the cut off scores for moderate
and severe depression in MADRS by using cross-validation to a previous study
and by using CGI to correspond with MADRS and HAMD17. It was determined that
the correlation between mean MADRS, HAMD17, and CGI scores that were r>0.85;
P<0.0001. The author identified that "No empirically based MADRS cut-off
scores to separate 'moderate' from 'severe' depression were available so
far."30(p256)

Eighty-five hospitalized patients with a diagnosis of major depression were
evaluated by five psychiatrists that were trained and reviewed using the
interrater reliability coefficients that were >0.85. Patients were interviewed
and scored within one week of admission and before or the same day of
discharge. The Pearson's correlation coefficient and receiver operating
characteristic curves were calculated, and the level of statistical
significance was set at X=0.05.

MARDS and HAMD17 were based on a mean with confidence intervals of 95%.
'Moderate' was defined as 13.9 on MARDS versus 12.3 on HAMD17 for 15 patients.
'Severe' was defined as 35.9 on the MARDS versus 26.5 on the HAMD17 for 25
patients. This would conclude that a difference of  22 points on the MARDS
would separate 'moderate' from 'severe'. A difference of  13.5 points on the
HAMD17 would separate 'moderate' from 'severe'.

There were two noted limitations 1) the scoring psychiatrist was also the
patient's treating physician and 2) the role various antidepressants play in
the scoring for each patient. It was noted by the author that further studies
to validate groupings should include DSM-IV or ICD-10 CM diagnostic severity
categories.

Zimmerman et al31 concluded a severity classification based on the use and
derivatives of the HAMD17, CGI and correlates with the Schedule for Affective
Disorders and Schizophrenia (SAD) for 627 outpatients with current major
depression. The majority of the outpatients in the study were white females
that had health insurance. Additionally, 64% were females between the ages of
18 to 78 years of age. Sixty-two percent were college educated with 31%
completing a four-year college.

The data collected during the study was compared to the CGI severity scoring
and placed in the receiver operating curve (ROC) to determine the cutoff
scores for HAMD17. The results where then referenced as the mean scores with
HAMD mean being 18.8 (SD = 5.6) and a one-way analysis comparing HAMD17 to
CGI. The results on the HAMD17 were lower with mild depression than for
patients with moderate depression. The scores were as follows: 15.3 +4.9
vs.18.1+5.1, t= 3.7, p<.001 for mild and 18.1 +5.1 vs.23.0+5.7, t= 9.0,
p<.001 respectively. Resulting in the following depression severity HAMD17
range None = 0-7, mild 8-16, moderate 17-23 and severe 24.

It was noted that there are no "well-demarcated lines separating the severity
subtypes"31 and that the cutoffs are to be used to define severity categories
for interpreting studies of efficacy of antidepressants and the effect of
treatment selection.

**The following is a summary of the evidence submitted with two
reconsideration requests to provide coverage for the failure of one or more
psychopharmacological medications for MDD.**

Brakemeier et al32 conducted a study related to the review and proof of prior
studies as it relates to drug free patients. Within the study they chose 79
patients, 48 from Munich and 31 from Berlin all with MDD or Bipolar II that
were naive to rTMS and 35% were drug resistant with one to five treatment
trials.

The treatment trials of rTMS varied between location and was not uniform in
the protocol. The result demonstrated that 79 patients completed the treatment
session and after two weeks 34% showed an antidepressant response from
baseline HAMD scores. The mean reduction in the HAMD21 scores was 69% in
responders and 4% in non- responders. Additional models such as the logistic
regression, linear regression and statistical methods were applied to
determine response with all pointing back to "non-treatment resistant patients
with a short duration of episode were more likely to respond to rTMS than
medication resistant (43% vs. 18%) (P = 0.023)."28

Yang et al33 conducted a RTC that incorporated one clinical site. The trial
was conducted between 2016-2017 and there were initially 82 participants who
had the first episode of depression with no administration of any
antidepressant or antipsychotic medication. Forty-one patients were within the
active group and 41 patients were placed in the sham group. Four patients
dropped out with the remaining 78 patients having an average baseline HAMD17
score of 24 within the active group and a score of 25 for the patients in the
sham group making participants moderately to severely ill.

TMS treatment was provided at the following dose/time: exercise threshold
100%, ten repetitions, 1Hz, 1,200 total stimulations with a 20-minute session
over ten sessions. Patients were also treated with 10mg of Escitalopram
(Lexapro) during the acute treatment phase.

The HAMD17 scores at the end of two weeks drastically improved to an average
of 15 (compared to a baseline score of 24) on the HAMD scoring tool. The sham
group reported a mean scoring of 20 compared to 25 on the HAMD tool. At the
end of four weeks of treatment the active group's mean HAMD scoring was nine
in comparison to the patients in the sham groups that averaged 13 on the HAMD
tool. At the end of four weeks of acute treatment it was determined that 36
(87%) patients in the active group and 17 (41%) patients in the sham group
noted improvement in clinical symptoms.  
  
 **Consultation Summary**

**Contractor Advisory Committee (CAC) Evidentiary Summary - 09/29/2021**

Wisconsin Physicians Service Insurance Corporation (WPS) hosted a multi-
jurisdictional CAC meeting to review the evidence for reconsideration requests
to determine if coverage for OCD is warranted when a treatment plan has
included TMS as an option. Additionally, the CAC was tasked to determine if
TMS treatment should be reserved for treatment resistant patients if there is
a standard of managing severity and if the evidence supported a significant
portion of the Medicare population.

Subject matter experts (SMEs) from Psychiatry, Neurology, Emergency
Psychiatric Services, Geriatric Psychiatry, TMS Clinics, OCD/Neuromodulation
Programs, and Neuropsychopharmacology were represented. All literature
submitted by the SMEs to supplement the reference list was also reviewed.

The panel of SMEs determined that while confidence in coverage of TMS in OCD
was noted it did not support treatment within the Medicare population and the
studies suffered from small sample sizes, bias, poor design, limited follow-
up, and inconsistent results. Many questions remain in terms of the efficacy,
location of device application, frequency and duration of use, and the
clinical presentation of the patient at the time TMS treatment is initiated.

Coverage of items and services in the Medicare program is provided based on
what is reasonable and necessary for the Medicare population. This concept is
operationalized by the application of evidentiary standards, clinical
validity, and clinical utility. Through the process of review and
reconsideration the focus remains on patient outcomes that demonstrate reduced
mortality and morbidity, and that will improve patient quality of life and
function. The evidence thresholds for coverage are a careful balance of
benefits and harms in the consideration of net health outcomes.

The level of treatment resistance related to the failure of medication trials
and intolerance to psychopharmacologic medications shows direct correlation
with the level of treatment resistance and aids in the success of TMS
treatment, for patients with MDD. The clear and reported treatment success was
identified in studies related to the failure of at least one pharmacological
trial and/or an intolerance of a psychopharmacologic medication. Two
consensuses' statements from the neurological societies indicate an improved
status and follow up for the patients that received TMS treatment with only
having failed one or more trials.

The FDA provided special controls and guidance in 2008 for the use of TMS in
MDD. Within the clinical manifestations of MDD there are varying degrees of
depression (mild, moderate, and severe). There are various clinical evaluation
and rating tools such as Quick Inventory of Depressive Symptomatology - Self
Rating (QIDS-SR)16, Inventory of Depressive Symptomatology - Self Rating (IDS-
SR30), HAMD17, HAMD21 and HAMD24, available to assist the provider in
diagnosing major depressive disorders per the DSM.

The evaluations and rating tools can provide guidance to severity, but there
is no defined standard of measurement or classification to determine mild,
moderate, or severe. This hinders any standardized treatment protocols,
expected outcomes or benefits to the patient but aids the healthcare
professional in diagnosing MDD.

The clinical trials, RCTs, Meta-analyses, societal recommendations, and
literature provided in this LCD demonstrated different standards for entry
into the studies, different rating/evaluation tools, different outcome
standards and differences in post treatment follow up. With the varied
protocol standards, clinical validity, and clinical utility there is no
existing evidence that meets the requirement of reasonable and necessary to
expand the criteria of MDD to other than 'severe' as defined by the most
current DSM criteria when diagnosed by the psychiatrist that examined the
patient face to face.

In 2018, the FDA expanded the use of TMS in OCD based on a RCT multi-center
study with 100 patients and reviewed the 'Brainsway' device through the de
nova premarket pathway. Even though TMS was determined to be safe in the
treatment of OCD, the current evidence has not been standardized or replicated
to the standard and quality needed in providing a balance of benefits and harm
when considering net health outcomes for the beneficiary.

Within the literature available, limitations include a lack of standardized
protocol and a lack of high-quality studies. Current studies have small sample
sizes, bias, poor design, limited follow-up, and inconsistent results. The
authors agree there is a low risk associated with treatment, but the
literature suggests safety and long-term data has not been obtained. There is
a trend towards a benefit, as noted in the meta-analysis and randomized
control trials, that suggest there may be a role in refractory OCD. However,
many questions remain in terms of the efficacy, location of the device
application, and the frequency/duration of the treatment. Several systematic
reviews/meta-analyses conclude that TMS demonstrated a range from no-response
to modest effect on the reduction of OCD symptoms. Further research is
required to determine optimal frequency, total pulses per session, and
duration of treatment. This will be closely monitored for any future research.
At this time, TMS treatment for OCD has been determined to be not medically
reasonable and necessary.

Following extensive literature review, discussions with CAC members, and SMEs
it has been determined that TMS treatment will be considered medically
reasonable and necessary for patients with a confirmed diagnosis of severe
major depressive disorder and that have demonstrated a failure of one or more
pharmacological medications and/or intolerance to psychopharmacologic
medications. At this time TMS treatment for OCD has been determined to be not
medically reasonable and necessary.