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

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

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

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

  
**Indications for Coverage**

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

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

  
_Initial Treatment_  
  
Left Prefrontal rTMS of the brain is considered medically necessary for use in
an adult who meets all four of the following criteria:  
  
1\. Has a confirmed diagnosis of severe major depressive disorder (MDD) single
or recurrent episode; **and**

2\. One or more of the following:  
  

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

  * Inability to tolerate psychopharmacologic agents as evidenced by four trials of psychopharmacologic agents from at least two different agent classes, with distinct side effects; or  
  

  * History of response to rTMS in a previous depressive episode; or   
If patient is currently receiving electro-convulsive therapy, rTMS may be
considered reasonable and necessary as a less invasive treatment option.

Resistance to treatment is defined by a failure to achieve a 50% reduction in
depressive symptoms, in accordance with objective measures such as PHQ-9
and/or HAM-D, from a pharmacologic trial where the medication is administered
at the recommended adult dose, per the FDA label, for a period of not less
than 6 weeks.  
  
Psychopharmacologic agent side effects will be considered intolerable, when
those side effect are of a nature where they are not expected to diminish or
resolve with continued administration of the drug  
  
 **AND**  
  
3\. A trial of an evidence-based psychotherapy known to be effective in the
treatment of MDD of an adequate frequency and duration without significant
improvement in depressive symptoms as documented by standardized rating scales
that reliably measure depressive symptoms.  
  
**AND**  
  
4\. The order for treatment (or retreatment) is written by a psychiatrist (MD
or DO) who has examined the patient and reviewed the record. The psychiatrist
will have experience in administering TMS therapy. The treatment shall be
given under direct supervision of this psychiatrist (physician present in the
area and immediately available but does not necessarily personally provide the
treatment).  
  
 **Coverage Limitations**  
  
The benefits of TMS use must be carefully considered against the risk of
potential side effects in patients with any of the following:

  * Seizure disorder or any history of seizures (except those induced by ECT or isolated febrile seizures in infancy without subsequent treatment or recurrence); or  
  

  * Presence of acute or chronic psychotic symptoms or disorders (such as schizophrenia, schizophreniform or schizoaffective disorder) in the current depressive episode; or  
  

  * Neurological conditions that include epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, history of repetitive or severe head trauma, or primary or secondary tumors in the central nervous system, or   
  

  * Presence of an implanted magnetic-sensitive medical device located less than or equal to 30 cm from the TMS magnetic coil or other implanted metal items including, but not limited to a cochlear implant, implanted cardiac defibrillator (ICD), pacemaker, Vagus nerve stimulator (VNS), or metal aneurysm clips or coils, staples or stents.  
  

  * Dental amalgam fillings are not affected by the magnetic field and are acceptable for use with TMS.

  
**Retreatment**  
  
Retreatment may be considered for patients who met the guidelines for initial
treatment and subsequently developed relapse of depressive symptoms if the
patient responded to prior treatments as evidenced by a greater than 50%
improvement in standard rating scale measurements for depressive symptoms.
(e.g., GDS, PHQ-9, BDI, HAM-D, MADRS, QIDS or IDS-SR scores).

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



**Summary of Evidence** **for Transcranial Magnetic Stimulation (TMS) for the
Treatment of Obsessive-Compulsive Disorder (OCD)**  
  
 _Background_  
  
Transcranial Magnetic Stimulation (TMS) is a non-invasive treatment that uses
pulsed magnetic fields to induce an electric current in a localized region of
the cerebral cortex. An electromagnetic coil placed on the scalp induces
focal, patterned current in the brain that temporarily modulates cerebral
cortical function. Capacitor discharge provides electrical current in
alternating on/off pulses. Stimulation parameters may be adjusted to alter the
excitability of the targeted structures in specific cortical regions. TMS
parameters include cranial location, stimulation frequency, pattern, duration,
intensity and the state of the brain under the coil.1  
  
 _Systematic Review/Meta-Analysis_  
  
A number of SR/MA 2-16 conclude rTMS demonstrates a range from none to modest
effect on the reduction of OCD symptoms, but further research is required to
determine optimal frequency, total pulses per session, and duration of
treatment.  
  
Two recent meta-analyses reviewed rTMS for the treatment of OCD. Ma et al12
reviewed nine randomized controlled trials (RCTs) with 290 subjects with OCD.
Most were selective serotonin reuptake inhibitor (SSRI) resistant. Using
undescribed random assignment 154 were in the active r-TMS group and 136 to
sham rTMS group. Primary outcome was Yale-Brown Obsessive-Compulsive Scale
(Y-BOCS) scores and secondary outcome was response rate determined by the
RCT's definition. Study size ranged from 18 to 65. The Y-BOCSs showed
improvement when rTMS was added to treatment with medication. There were nine
subjects in two studies that did not have SSRI-resistant OCD, but the
improvement continued to be shown when these RCTs were excluded from the
Y-BCOS analysis. Actual Y-BCOS scores were not provided. It was noted that the
active rTMS patients had higher baseline Y-BOSC scores, but numbers were not
provided. Response rates were available for eight of the nine trials. Fifty-
five of 139 active patients (39.6%) and 27 of the 122 sham patients (22.1%)
responded. There was no difference in the drop-out rate between the active
8/207 (3.8%) and sham 7/94 (7.4%) subjects. Mean duration of rTMS treatment
was 3.8 weeks with a range of two to six weeks. A sub-group analysis suggested
treatment effects were larger at two- and six-weeks' duration, but lack of
data in most of the included studies at four weeks' length may precluded
accurate assessment. Additional limitations include stimulus parameters and
follow-up data was not reported. The authors noted that future large-scale
studies are needed to assess the long-term effect of rTMS as augmentation and
mono-therapy for OCD. No conflicts of interest were reported.  
  
Rehn et al13 conducted a systematic review and meta-analysis of rTMS used to
treat OCD and focused on whether certain TMS parameters were associated with
higher treatment effectiveness. Eighteen RCTs were included, six of which were
also included in the Ma et al. study12. Selected studies had patients ages
18-75 years with DSM-IV diagnosis of OCD; had randomized rTMS or sham
treatment with either single- or double-blinding or parallel or cross-over
design; more than five OCD subjects per arm; low-frequency (LF) </= 1 Hz) or
high frequency (HF)-rTMS (>/=5 Hz) for >/= 5 sessions either as mono- or
augmentation strategy; and pre- and post- reporting of Y-BOCS scores. Studies
were excluded if patients were starting a new medication at the same time of
rTMS. Total number of subjects was 484 with 262 receiving active rTMS and 222
sham rTMS. Study size ranged from 18 to 46. All trials used rTMS as an
augmentation therapy with most of the patients having some degree of treatment
resistance. The last Y-BOCS measurement obtained was used as the post-
treatment score. Pre-and post-treatment Y-BOCS were available from each of the
18 studies, but the actual scores were not provided. Overall, active rTMS was
significantly superior to sham rTMS. Cortical targets over the bilateral
dorsolateral prefrontal cortex (B-DLPFC), right dorsolateral prefrontal cortex
(R-DLPFC) and the supplementary motor area (SMA) yielded significantly
superior Y-BOCS scores over sham treatments. Active rTMS directed at the
L-DLPFC was not significantly improved over sham rTMS. Six trials had Y-BOCS
scores at four weeks or less post-treatment and three had scores 12 weeks
post-treatment. Improvements in scores were maintained. The authors stated
that the clinical utility of rTMS in the treatment of OCD requires further
investigation to discern the most optimal stimulation parameters. No conflicts
of interest were reported.  
  
Lusicic et al.17 performed a systematic review on the effect of rTMS and dTMS
on different brain targets in OCD. Twenty studies met the inclusion criteria
with 19 using rTMS and one dTMS. All but one of the rTMS trials are included
in the meta-analyses described above. Included brain areas were the
dorsolateral prefrontal cortex (DLPFC), supplementary motor area (SMA),
orbitofrontal/medial prefrontal cortex (OFC), and anterior cingulate cortex
(ACC). Frequency stimulation was low (1 Hz) or high (>/=5 Hz). Treatment
duration varied from two to six weeks with follow-up ranging from none to
three months. Of 16 studies evaluated, nine had Y-BOCS score reductions with
rTMS versus sham while eight showed no significant difference. The authors
concluded treatment of OCD with neurostimulation shows promise, but it is yet
to be determined how best to optimize the approach using rTMS or dTMS to
achieve clinically relevant results.  
  
 _Randomized Control Trials_  
  
RCTs comprised of thirty or fewer subjects were not included in this summary.  
  
Carmi18 studied forty-one OCD patients who had failed two SRI trials plus
cognitive behavioral therapy (CBT). Baseline clinical and electrophysiological
measurements, a five-week treatment, and a one-month follow-up were reported.
The medial prefrontal cortex (mPFC) and the anterior cruciate cortex (ACC)
were targeted. Entrance criteria included an age range of 18-65 years old; a
DSM-IV diagnosis of OCD; a score of >/=20 on the Y-BOCS; stable SSRI
medications for eight weeks prior to enrollment and unchanged during
treatment; and CBT at maintenance phase (if conducted). Exclusion criteria
included any other Axis-I psychopathology or a current depressive episode.
Randomization to treatment with 1 Hz (LF), 20 Hz (HF) or sham occurred using a
computer program. Treatment occurred five times per week for five weeks.
Primary and secondary outcomes were Y-BOCS and Clinical Global Impressions of
Severity (CGI-S) which were obtained pre-treatment, prior to the second
treatment session in weeks two to four, prior to the last treatment session
(post-treatment) and at one-week and one-month follow-up beginning with an
exposure to personalized obsessive-compulsive cues.  
  
Electroencephalograms (EEGs) during a Stroop task were performed at pre- and
post-treatment time-points and analyzed by the condition (congruent or non-
congruent) and whether the response was correct or a mistake. Most of the
mistakes (93%) were made under incongruent conditions. Individuals who made
more than 90% mistakes were excluded from analysis (2 HF and 3 sham). Error-
related negativity (ERN) showed an increase in the HF group and a decrease in
the sham group with treatment. (An ERN occurs when an individual makes a
behavioral error.)  
  
The baseline characteristics of the three groups did not differ. Three of the
forty-one participants dropped out, one in the sham group due to schedule
conflicts and two from the HF group due to inconvenience. No adverse events
occurred beyond headache in three from the HF group and one from sham. Asked
to guess the group to which they were assigned, 75% of the LF, 88% of the HF,
and 86% indicated they did not know. An interim analysis revealed a near
significant effect for HF but not LF. Although no trend was reported in the
group and two of the eight had a worsening Y-BOCS score the LF arm of the
study was omitted. Completion by 16 HF and 14 sham participants occurred. The
percent change in Y-BOCS scores was significant at weeks four and five and a
higher proportion of the HF group compared to the sham group (7/16 vs 1/14)
reached the predefined response rate (30%) after five weeks. Using the more
restrictive criterion of 35%, 5/16 HF and 1/14 sham individuals achieved the
higher rate. Significant differences at one week occurred but not at one month
follow-up. Similarly, the CGI-I results were significant after treatment and
one week but not at four weeks.  
  
The authors concluded the study showed the treatment was safe and effective
immediately after treatment but not significant four weeks later. Limitations
were noted to be that the study was considered as a pilot and had a small
number of subjects; the provocation was not controlled, and the number of
pulses differed for the HF and LF groups. A need for further studies was
noted. A financial disclosure noted one of the authors is a co-inventor of the
TMS H-coils, serves as a consultant for, and has financial interests in
Brainsway and the study was partially supported by Brainsway, which produces
the deep TMS H-coil systems.  
  
A second study by Carmi et al19 was a prospective multicenter randomized
double-blind placebo-controlled trial following the pilot described
immediately above. One hundred patients with OCD and Y-BOCS score >/= 20
between the ages of 22-68 receiving treatment in an outpatient setting were
recruited. Subjects were on a therapeutic dosage of a serotonin uptake
inhibitor (SRI) for least two months with limited response or if not on an
SRI, in CBT maintenance therapy with failure to respond adequately.
Medications to treat depression were allowed but could not be changed for at
least two months before enrollment. Exclusion criteria were any primary axis I
disorder other than OCD, severe neurological impairment, and any condition
associated with an increased risk for seizures. Patients were randomized 1:1
into an active dTMS or sham group. A three-to-five-minute individualized
symptom provocation occurred before each treatment session. The medial
prefrontal cortex and anterior cingulate cortex were targeted with 20 Hz dTMS.
Patients, operators, and raters were blinded to treatment group. Subjects were
queried regarding the group to which they had been assigned after the first
treatment with 66% of the active and 69% of the sham group giving an incorrect
answer. The treatment phase lasted six weeks with one day for assessment and
had three phases - a three-week screening phase, a six-week treatment of five
treatments per week, and a four-week follow-up phase.  
  
The primary outcome measure was a change in Y-BOCS score from baseline to
post-treatment. A full response was defined as a >/=30% reduction and a
partial response as >/=20%. At six weeks post-treatment, the Y-BOCS score
significantly decreased in each group with the treatment group considered to
have a statistically significant slope of change. At four weeks post-
treatment, the treatment group had a statistically significant change in full
response but not in the partial response rate. Clinical Global Impression
Severity scales (CGI-S) and a modified version of the improvement scale
(CGS-I) measurements were made post-treatment. The CGI-I scores were divided
into improved (moderately to very much improved) and not improved (minimally
to not improved). The active group had 20/41 (49%) compared to 9/43 (21%)
reporting feeling moderate to "very much improved' (P=0.011). The CGS-S scores
also showed a significant difference in the treatment group post-treatment. No
significant differences between groups were found for the Sheehan Disability
Scale or the Hamilton Depression Rating Scale (HAM-D) scores. The drop-out
rate was around 12% for each group (6/48 and 6/51). Adverse event rates did
not differ between groups. One patient reported suicidal ideation (which was
unreported and present before study entry) requiring inpatient treatment after
two active dTMS treatments.  
  
Limitations noted by the authors were that the provocations were uncontrolled
and functional brain imaging of the medical prefrontal cortex (mPFC) and
anterior cingulate cortices (ACC) was not performed. A different mechanism for
dTMS compared to pharmaceuticals and CBT was suggested as well as the need to
determine which patients might respond to dTMS. Further studies were
recommended. Twelve of the fourteen authors reported some financial
relationship with Brainsway.  
  
Elbeh et al.20 performed a double-blind randomized trial to evaluate the
impact of different frequencies of rTMS over right dorsolateral prefrontal
cortex (DLPFC) in OCD. 45 subjects with OCD were enrolled and evaluated using:
Yale-Brown obsessive-compulsive scale (Y-BOCS), Hamilton Anxiety Rating Scale
(HAM-A), and Clinical Global Impression-Severity scale (CGI-S). They were
randomized into one of three groups: 1st group received 1 Hz rTMS; 2nd group
received 10 Hz rTMS; and 3rd group received sham stimulation all at 100% of
the resting motor threshold for 10 sessions. Follow-up assessment were after
the final treatment and three months later. The group receiving 1 Hz versus 10
Hz groups showed a significant improvement in Y-BOCS and HAM-A scores (P<0.001
and 0.0001 respectively) and significantly larger percentage change in GCI-S,
as well as greater clinical benefit than the 10 Hz. The authors conclude that
1 Hz-rTMS, targeting right DLPFC is a promising tool for treatment of OCD.  
  
Dutta et al.21 conducted a randomized placebo-controlled study to evaluate the
effect of novel continuous Theta Burst Stimulation (cTBS) targeting OFC in OCD
subjects. Thirty-three patients were randomly allocated to active cTBS (n= 18)
or sham (n= 15). Each subject received 10 TBS sessions, 2 per day (total of
1200 pulses: intensive protocol) for 5 days in a week. The Y-BOCS, HAM-D,
HAM-A, and CGI-S scores were assessed at baseline, after last session and at 2
weeks post-rTMS. They reported a significant improvement from pretreatment to
two weeks post TBS for obsessions, compulsions, HAM-A, HAM-D, and CGI scores,
but when controlled for confounding variables, only HAM-A scores and CGI
retained statistical significance. The authors conclude that intensive OFC
cTBS (iOFcTBS) in OCD results in clinically significant improvements in
anxiety symptoms and global severity, while acknowledging that improvement in
anxiety symptoms could be due to "modulations of state dependent dysregulation
in OCD."  
  
Badawy et al.22 reported on 60 OCD patients to evaluate rTMS as monotherapy
vs. add-on treatment in patients with poor response to SSRIs. Of 40 un-
medicated patients 20 received sham treatment and 20 TMS. An additional 20
patients with poor response to SSRI received rTMS. With two-to-four-week
follow-up they found TMS was not effective as monotherapy, but was useful as
add-on therapy. Study was limited by lack of control for the poor responder
group, short follow-up, and small sample size. The authors conclude further
studies regarding the site of stimulation, frequency and rate of stimulation
and the number of sessions is needed.  
  
A post marketing analysis of 219 patients who underwent TMS for OCD from 22
sites were included. A response was defined as at least a 30% reduction in
Yale Brown Obsessive Compulsive Scale (YBOCS) score from baseline. They
reported first and sustained response rates were 72.6% and 54.4% respectively.
The authors state that in real world clinical practice the majority of OCD
patients benefited from TMS with improvement usually occurring within 20
sessions. They also advocate the extension of treatment beyond 29 weeks
reporting continued reduction in OCD symptoms suggesting value in extended
treatment protocols. Limitations include multiple uncontrolled variables
including comorbidities, medication use, incomplete data set, variations in
duration and protocol of treatment used at different sites and risk of bias.23  
  
Harmelech et al. conducted a sub-analysis of a previous multicenter randomized
sham-controlled trial of Deep TMS for OCD funded by Brainsway focusing on the
durability of treatment with TMS. Sixty subjects from the original study had
"durability" defined as time from end of last treatment with TMS until change
in treatment occurred from the original study. They report the average
durability of Deep TMS is 1.98 years. Fifty-two patients reported at least 1
year durability and 26 reported  2 years. Twenty-eight patients had
functional disability data collected and reported reduction in disability
scores after TMS.24,25  Limitations include incomplete data sets or lack of
follow-up after treatment, small sample size, challenges applying to real
world practice as the scoring system used is not routinely used in clinical
practice.  
  
A 2021 meta-analysis of RCTs on treatment strategies for serotonin reuptake
inhibitor-resistant obsessive-compulsive disorder included 55 studies with 19
treatments or placebo.26  The investigators reported four interventions
studied which included Ondansetron, deep TMS, cognitive behavioral therapy,
and ariprazole were ranked the best treatments using Surface Under the
Cumulative Ranking percentage values (85.4%, 83.2%, 80.3% 65.9% respectively).
In a sensitivity analysis deep TMS was ranked as the best strategy for SRI-
resistant OCD. While this trend is favorable meta-analysis is only reliable if
the included studies are high quality studies with low heterogenicity which is
not the case with this literature. Small sample sizes, high confidence
interval limits and wide prediction interval are acknowledged by the authors
as limitations contributing their acknowledgment of the need for "cautious
interpretation". Additional limitations include inability to directly compare
interventions because no studies were designed for direct comparison, high
risk of bias in many of the included studies, and study design weaknesses
including lack of blinding, randomization and control in the majority of the
randomized control trials.  
  
Summary of Evidence for Repetitive Transcranial Magnetitic Stimulation (rTMS)
in Adults with Treatment Resistant Major Depressive Disorder  
  
Several studies evaluated the efficacy and safety of TMS in the treatment of
major depression that included patients with major depression (MDD) and a
previous trial of one or more anti-depressive psychotherapies. In George et
al. the average was 3-6 clinical antidepressant medications for current
episode treatment and diagnosis of major depressive disorder single or
recurrent.27 In Levkovitz et al. a multicentered RCT sponsored Brainsway which
included subjects with major depressive disorder with previous antidepressant
use in the current episode ranging from 1 or more agents. Twenty-five subjects
in the treatment group had one antidepressant agent used while the remaining
76 had 2 or more. They found a higher response rate (38.4% versus 21.4%;
p=0.013) and remission rates (32.6% versus 14.6%; p=0.05) with TMS than sham
at 16 weeks. These findings are limited by small sample size.28 Kaster et al
is a single center RCT with 52 patients with late life depression. Twenty-five
received TMS and 27 sham and they report higher remission with active
treatment than sham of 40% versus 14.8% concluding high dose deep TMS is safe
and effective.29 Limitations include small sample size below target, short
term follow-up and dropout rate higher in treatment group than sham group.  
  
Several meta-analyses to evaluate safety and effectiveness of TMS have been
conducted.30-32 The challenges facing the meta-analysis is that the results of
meta-analysis are limited by the overall low quality of available literature.
Literature ranging from RCT, prospective, retrospective, observational and
case series has been included and the high rate of heterogenicity between the
studies limits the effect of meta-analysis. One meta-analysis reports rated
with Grading of Recommendations, Assessment, Development, and Evaluation
(GRADE) however risk of bias assessment was not performed on the individual
studies, so the GRADE quality evidence rating of moderate quality is
inconclusive.32 Based on ECRI risk of bias assessment 6/8 studies reviewed
were subject to high risk of bias due to small sample sizes, and serious flaws
in study design such as lack of controls, blinding and randomization.33 No
studies compared TMS with other treatment options and all studies were short
term with longest follow-up of 6 months. Studies also had high variability of
diagnosis and not all were MDD with some in bipolar disorder patients
exclusively.30 The demographic for age listed for each of the studies is
younger than the Medicare population. Additionally, the parameters for the TMS
administered varied greatly from study to study without standardized treatment
protocol or response criteria across studies, and some studies had high
dropout rate or patients not treated by the intensity defined within the
protocols. Finally, many studies were funded by makers of TMS equipment with
associated risk of bias. One meta-analysis reported promise for TMS but
acknowledge the need for well-designed sham-controlled studies. One large
retrospective registry study included 5010 participants in the intent-to-treat
sample with MDD, and PHQ-9 assessment before and after TMS and reported
response rate of 58-83%. However, this study is limited by study design,
incomplete data, lack of clear diagnostic criteria and assessment limited to
PHQ-9 which is a screening too.34  
  
Weissman et al. performed a secondary analysis of patients enrolled in the
STAR*D trial for the effects of antidepressants on suicidal ideation. Of
significance SI measured by HRSD suicide item score was low in the population
with only those patients classified as level 4 having SI at baseline.35 While
mean SI decreased across all four levels the decrease in level 4 was not
significant ( = 0.0125); and degree of SI correlated with degree of
depression and was more common in treatment resistant depression. Limitations
of this study includes the primary outcome of STAR*D trial was not SI but
rather remission from MDD so study was not designed to measure this endpoint,
low baseline level of SI, limited to outpatients therefore not reflecting real
world population where suicidal patients are likely inpatients, lack of
blinding, and risk of bias as the funding was from makers of deep TMS
equipment.  
  
A 2022 systematic review and meta-analysis of 3,273 subjects RCT on TMS for
MDD reports high rate of non-serious adverse events (ADE's) including headache
(22.6%), discomfort (10.9%) and pain (23.8%) in the stimulation sites in
treatment group compared to sham. However, most ADE's were mild and transient
with a low risk of serious adverse events including seizures and mood switches
and reported no increased risk of drop out due to adverse events supporting
safety.36  
  
A small RCT (n=81) of deep TMS as monotherapy for medication resistant
depression administered TMS treatments 5 days a week for 4 weeks and 33 were
non-responders. This group had 4 additional weeks of twice weekly TMS and they
reported 61% (24/33) responded to the additional TMS on at least one of the
weekly assessments, however 12/33 (36.4%) dropped out of the study before
completion and follow-up was limited to 16 weeks.37 In an open-label,
crossover trial 42 patients who did not respond to initial TMS treatment
received an additional 30 sessions and 26% achieved a response. The rate of
response based on number or prior treatments was analyzed and authors suggest
more treatment resistant patients may take longer to respond to TMS.
Limitations were small sample size, lack of blinding with high risk of placebo
effect, uncontrolled study design and data limited to 6 weeks due to cross-
over.38  A small pilot study with 49 patients reports on once monthly
maintenance therapy after initial treatment for 19 subjects while 24 received
observation alone once initial treatment completed. 16/49 completed the 53
weeks of the study indicating high discontinuation rate. The authors reported
"they did not find an advantage for once-monthly maintenance TMS treatment
over observation, since it did not significantly delay the time until
reintroduction TMS was needed or reduce the proportion of patients who needed
retreatment".39  In another small trial 29 subjects received 4 weeks of TMS
for MDD followed by 18 weeks of continuation treatment (twice weekly for 16
sessions and once weekly during the final 10 weeks). The authors report
"probability of remission at the end of the acute phase was 26.92% (SE "
8.70%) and 71.45% (SE " 10.99%) at the end of the study" however this must be
balanced by high dropout rate with 15/29 finishing the protocol, low initial
response rate of 12/29 and no comparison to observation alone.40 Overall, the
literature regarding continuation or maintenance therapy is challenged by
small sample size, lack of standardized protocols, lack of blinding,
randomization and controls in study designs and longest outcome reported of 12
months therefore lack long-term safety and outcome data. This is summarized in
a 2022 meta-analysis reports on 30 papers (n=1494) regarding 'maintenance,
continuation, preservation or rescue TMS'. This included four randomized
control trials (one sham controlled), 14 open trials and 12 case series. The
authors conclude that while there is evidence to support the use of
preservation it is based on largely uncontrolled, low quality studies with
lack of standardized protocols and calls for more studies to establish the
role of continuation TMS.41  
  
In contrast several studies suggest "durability" of treatment meaning the
effects last after the treatment has finished. An observational study in 257
non-medicated patients with MDD reported on 120 subjects who responded to
initial TMS treatment 75 (62.5%) had prolonged response. 93 (36.2%) received
reintroduction of TMS with mean number of TMS treatment days of 16.2. The
authors conclude there is a statically and clinically meaningful durability of
acute benefit over 12 months. This study is limited by observational design
but strengthened by 12 month follow-up and use of standardized questionnaires
throughout the study time frame.42 A meta-analysis of 19 studies reported
65.5% after 3 months and 46.3% maintained response 1 year after induction
treatment.30  
  
Additional studies have shown a positive response to retreatment for relapse
of symptoms for the majority of those who initially respond.43  
  
 ** _Society Guidance/Technology Analysis_**  
  
 __  
  
**TMS for OCD**  
  
NICE Guidance -Transcranial magnetic stimulation for obsessive-compulsive
disorder.44 Recommendations conclude that evidence on the safety of
transcranial magnetic stimulation for obsessive-compulsive disorder raises no
major safety concerns. However, evidence on its efficacy is inadequate in
quantity and quality. Therefore, this procedure should only be used in the
context of research.  
  
UpToDate - Technique for performing transcranial magnetic stimulation (TMS)
mentions for use in patients with major depression.45 There was no mention of
TMS for OCD.  
  
ECRI - Transcranial Magnetic Stimulation for Treating Adults with Obsessive-
compulsive Disorder executive summary evidence was inconclusive based on too
few data on outcomes of interest.46  
  
 **TMS for Depression**  
  
Agency for Healthcare Research and Quality (AHRQ) Final Technology Assessment
- No agreed-upon definition of Treatment-Resistant Depression (TRD) exists.47  
  
McClintock Consensus statement of the National Network of Depression Centers
(NNDC) and the American Psychological Association (APA) Council - "rTMS is
appropriate as a treatment in patients with MDD even if the patient is
medication resistant or has significant comorbid anxiety."48  
  
Perera Consensus review from the TMS Society - TMS therapy is recommended as
an acute treatment for symptomatic relief of depression in the indicated
patient population & TMS therapy is recommended for use as a subsequent option
in patients who previously benefited from an acute treatment course and are
experiencing a recurrence of their illness.49  
  
APA Practice guideline includes TMS as an option for treatment-resistant
depression.50  
  
 **Contractor   Advisory Committee (CAC) Summary**  
  
 CGS Administrators co-hosted a CAC Meeting with multiple other contractors on
9/29/2021. The panelist reviewed the literature that was submitted as part of
an LCD reconsideration request to expand the policy to include coverage for
OCD. The panel shared the lack of good treatment options for refractory OCD
and a priority to develop new and effective treatments. The literature was
reviewed and noted to be challenged by small sample sizes, high risk of bias,
many studies with lower quality study design (lack of control arm/blinding),
short follow-up (4-5 weeks for most studies) with lack of longterm outcome
data, and lack of real-world application of the technology. There was a
discussion of risk of co-morbid depression and OCD and different coil
locations with some potential overlap so brought up the potential impact of
treatment for both conditions. One paper reviewed low vs. high frequency
showing improvement with high frequency but not low. Another challenge
addressed was which region of the brain should be targeted for OCD as the
studies varied in the location treated. The panelist felt that there was not
clarity regarding the degree of improvement in scores would result in
meaningful clinical improvement, but even small change would be significant in
refractory OCD. In the study on predictors to response the panel did consider
the secondary analysis that those with more severe disease had greater
response to treatment. Overall, the panel felt there was potential improvement
for OCD with TMS and it appears to be safe, but limitations in literature are
substantial as described.

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

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