Transcranial magnetic stimulation (TMS) is a noninvasive method of brain
stimulation. The technique involves placement of a small coil over the scalp
and passing a rapidly alternating current through the coil wire which produces
a magnetic field that passes unimpeded through the brain. Depending on
stimulation parameters (frequency, intensity, pulse duration, stimulation
site), repetitive TMS (rTMS) to specific cortical regions can either increase
or decrease the excitability of the affected brain structures. The procedure
is usually carried out in an outpatient setting and does not require
anesthesia or analgesia.  
  
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**  
  
TMS may be covered if prescribed and administered by a licensed physician who
is knowledgeable in the use of repetitive transcranial magnetic stimulation.
Outpatient rTMS may be indicated for patients with DSM-IV defined Major
Depressive Disorder who have failed to benefit from initial treatment of their
depression.  
  
Initial Treatment  
  
Left Prefrontal rTMS of the brain is considered medically necessary for use in
an adult who has a confirmed diagnosis of severe major depressive disorder
(MDD) single or recurrent episode; and  
  
 **One or more of the following:**

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

**AND**  
A trial of an evidence-based psychotherapy known to be effective in the
treatment of MDD of an adequate frequency and duration without significant
improvement in depressive symptoms as documented by standardized rating scales
that reliably measure depressive symptoms.  
  
**AND**  
The order for treatment (or retreatment) is written by a psychiatrist (MD or
DO) who has examined the patient and reviewed the record. The physician will
have experience in administering TMS therapy. The treatment shall be given
under direct supervision of this physician (physician present in the area but
does not necessarily personally provide the treatment).  
  
 **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).

All other uses of Transcranial Magnetic are experimental and are not covered.  
  
 **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.

**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/MA2-16 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 rTMS 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 preclude
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. study.12 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 al17 performed a systematic review on the effect of rTMS and dTMS
on different brain targets in OCD. Twenty studies met inclusion criteria with
19 using rTMS and one dTMS. All but one of the rTMS trials are included in the
meta-analyses described above. Included brain areas were the dorsolateral
prefrontal cortex (DLPFC), supplementary motor area (SMA),
orbitofrontal/medial prefrontal cortex (OFC), and anterior cingulate cortex
(ACC). Frequency stimulation was low (1 Hz) or high (>/=5 Hz). Treatment
duration varied from two to six weeks with follow-up ranging from none to
three months. 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 at 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 mPFC and ACC was not performed. A
different mechanism for dTMS compared to pharmaceuticals and CBT was suggested
as well as the need to determine which patients might respond to dTMS. Further
studies were recommended. Twelve of the fourteen authors reported some
financial relationship with Brainsway.

Elbeh et al20 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 al21 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, CGI-S scores were assessed at baseline, after last session and at 2
weeks post-rTMS. They reportedd 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 al22 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.

**Society Guidance/Technology Analysis**

  * NICE Guidance23-Transcranial magnetic stimulation for obsessive-compulsive disorder. 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.
  * UpToDate24 \- Technique for performing transcranial magnetic stimulation (TMS) mentions for use in patients with major depression. There was no mention of TMS for OCD.
  * ECRI25\- Transcranial Magnetic Stimulation for Treating Adults with Obsessive-compulsive Disorder executive summary evidence was inconclusive based on too few data on outcomes of interest.

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

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

The 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.
WPS 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. WPS will continue to monitor scientific developments
and may adjust this coverage policy in accordance.