Summary Of Evidence

Two articles regarding meta-analyses of studies pertaining to the use of rTMS for maintenance therapy in treatment resistant MDD in the absence of relapse or recurrence of symptoms were presented in support of a request for Medicare coverage for the use of rTMS in patients who have responded to a previous course(s) of rTMS as ongoing maintenance therapy without recurrence of symptoms of depression.

Review of the first meta-analysis “Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systemic review and meta-analysis”¹ reveals a number of weaknesses that would bring into question the results of a comparison of the data that this article includes. Those weaknesses include:

• Maintenance rTMS was defined as any rTMS session delivered after the induction cycle. There is no differentiation of maintenance in the asymptomatic patient versus a patient in relapse of major depression.
• The few randomized controlled clinical trials (RCT) included in the meta-analysis had either very small numbers of enrolled subjects or had serious design flaws.
• Several of the studies analyzed included a large percentage or were composed entirely of patients with bipolar disorder.
• The demographic for age listed for each of the studies is younger than the Medicare population. There does not appear to be any information on the age range on those studies in this publication.
• The parameters for the rTMS administered varied greatly from study to study. There was no standardized treatment protocol across studies.
• There were no standardized response criteria across studies.
• The studies did not address the outcome of any treatments for a course of treatment longer than 12 months.

The authors conclude that “While this meta-analysis suggests that there is value in maintenance rTMS, it provides limited insight regarding the protocol that should be used, specifically the duration and frequency of the treatments, as well as optimal stimulation parameters. The methods for symptomatic re-introduction of rTMS were also not fully described namely with regard to exact the criteria for reintroduction of rTMS. Ultimately, there was too much variability, and insufficient replication for clear meta-analytic conclusions.”

Review of the second meta-analysis “Maintenance repetitive transcranial magnetic stimulation (rTMS) for relapse prevention in depression: A review”² also revealed a number of weaknesses. Those weaknesses include:

• The studies included in this meta-analysis were primarily single case reports, retrospective analyses, open label studies, or naturalistic studies.
• This meta-analysis shares many of the same issues as the previous meta-analysis (i.e., lack of RCT, small sample size, inclusion of patients with bipolar disorder, lack of standardization of inclusion criteria and treatment protocol).
• The patients described in the case reports were all significantly younger than the Medicare population. There was no information given regarding the age of the subjects of the other studies included in this meta-analysis with the exception of Connolly, et al. (2012) where it was noted that the mean age in years was 48.6 with a standard deviation of 14.2.

The authors conclude that, “Further sham-controlled studies with increased statistical power, rigorous standards of randomization, blinding procedures, optimal stimulus parameters, and clinical outcome as well as global functioning measures are needed to confirm the long term safety and efficacy of maintenance rTMS in the treatment of such conditions.”

Level of evidence:

There is no current treatment recommendation or guideline published by the American Psychiatric Association (APA) in reference to maintenance rTMS.

At this time there is insufficient published evidence to evaluate the safety and efficacy of this treatment in the context of maintenance therapy to prevent relapse in a patient who had a major depressive episode that remitted with prior treatment. Therefore, maintenance rTMS for the prevention of relapse of recurrent treatment resistant depression in the Medicare population is not considered to be reasonable and necessary.

OCD is a chronic and debilitating neuropsychiatric disorder with a lifetime prevalence of 2.5%. It is characterized by a cycle of persistent thoughts, images or urges that cause anxiety or distress. Compulsions are the behaviors the individual engages in to attempt to decrease this distress. OCD is severely incapacitating due to its intensity and continuous or deteriorative course and is associated with impaired social and occupational functioning, and reduced quality of life.¹³

Many patients with OCD respond to traditional treatments, including high dose serotonin reuptake inhibitors (SSRIs), cognitive behavioral therapy (CBT), or a combination of both. This satisfactory response is typically measured by a reduction in Y-BOCS score ≥ 25% with respect to baseline. However, as many as 40- 60% remain symptomatic with minimal benefit or are unable to tolerate medication side effects. These patients are therefore considered to have “treatment-resistant” OCD.

The etiology and pathophysiology of OCD is not completely understood. It is thought to be associated with dysfunction of the orbitofronto-striato-pallido-thalamic circuitry. As rTMS can modulate cortical activity, it has been utilized in the treatment of OCD.¹⁴ In August of 2018, the FDA approved rTMS by Brainsway for use in treatment resistant OCD.¹⁵

Berlim, et al. conducted 1 of the first meta-analyses of RCTs on rTMS for OCD. Data was obtained from 10 RCTs, totaling 282 subjects with OCD. The pooled Hedges’ g for pre and post Y-BOCS scores was 0.59 (z = 2.73, p = 0.006), indicating a significant and medium-sized difference in outcome favoring active rTMS. Furthermore, response rates were 35% and 13% for patients receiving active and sham rTMS, respectively (OR = 3.4, p = 0.002). Sub-group analyses indicated that low frequency rTMS (LF-rTMS) and rTMS protocols targeting orbitofrontal cortex or supplementary motor area seem to be the most promising for reducing OCD-related symptoms. No differences on baseline depression scores or dropout rates at study end were observed between active and sham rTMS groups, although OCD severity at baseline was higher in the active group. The conclusion was that active rTMS seems to be efficacious for treating OCD. Moreover, LF-rTMS and protocols targeting the orbitofrontal cortex, or the supplementary motor area seem to be the most promising. The authors also opined that future RCTs on rTMS for OCD should include larger sample sizes and be more homogeneous in terms of demographic/clinical variables as well as stimulation parameters and brain targets.¹⁶

Subsequently, Rhen, et al. performed an updated systematic review and meta-analysis on the effectiveness of 18 RCTs of rTMS for the treatment of OCD. Studies included 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 5 OCD subjects per arm. To determine whether rTMS parameters may have influenced treatment effectiveness, studies were further analyzed according to cortical target, stimulation frequency, and length of follow-up. Total number of subjects was 484 with 262 receiving active rTMS and 222 sham rTMS. Study size ranged from 18 to 46 subjects. Overall, rTMS yielded a modest effect in reducing Y-BOCS scores with Hedge’s g of 0.79 (95% CI = 0.43–1.15, p < 0.001). Stimulation of the supplementary motor area yielded the greatest reductions in Y-BOCS scores relative to other cortical targets. Subgroup analyses suggested that low frequency rTMS was more effective than high frequency rTMS. Six trials had Y-BOCS scores at 4 weeks or less post-treatment and 3 had scores 12 weeks post-treatment. Improvements in scores were maintained. The effectiveness of rTMS was also greater at 12 weeks follow-up than at 4 weeks follow-up.¹⁷

This meta-analysis was the first to assess whether improvements in OCD symptoms persisted post-rTMS. Their findings revealed that active rTMS was superior to sham rTMS in improving OCD symptoms at 4 weeks or less and at 12 weeks post-treatment. The authors suggested that future large-scale studies focus on the supplementary motor area and include follow-up periods of 12 weeks or more.

Ma and Shi analyzed 9 RCTs consisting of 290 subjects with SSRI resistant OCD randomly assigned to either active rTMS or sham rTMS, as augmentation or monotherapy. Study size ranged from 18-65 patients. Active rTMS was an effective augmentation strategy in treating SSRI-resistant OCD with a pooled weighted mean difference (WMD) of 3.89 (95% CI = [1.27, 6.50]) for reducing Y-BOCS score and a pooled odds ratio (OR) of 2.65 (95% CI = [1.36, 5.17] for response rates. This response was seen following a mean of 3.8 weeks of treatment. The pooled examination demonstrated that this strategy seems to be efficacious and acceptable for treating SSRI-resistant OCD. The limitations of the studies led the authors to conclude that the optimum stimulus parameters of rTMS as augmentation for SSRI-resistant OCD remain unclear. They also cited the limitation of study treatment duration of 2-6 weeks; thus, long-term effects could not be assessed.¹⁸

A pilot study by Carmi, et al. studied 41 OCD patients who had failed 2 SSRI trials plus CBT. Baseline clinical and electrophysiological measurements, a 5-week treatment, and a 1-month follow-up were performed. The medial prefrontal cortex (mPFC) and the anterior cruciate cortex (ACC) were targeted. Entrance criteria included an age range of 18-65 years old; a DSM-IV diagnosis of OCD; a score of >/=20 on the Y-BOCS; stable SSRI medications for 8 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 low frequency (LF), 20 Hz high frequency (HF) or sham occurred using a computer program. Treatment occurred 5 times per week for 5 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 2 to 4, prior to the last treatment session (post-treatment) and at 1 week and 1 month follow-up beginning with an exposure to personalized obsessive-compulsive cues. Interim analysis revealed that Y-BOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Completion by 16 HF and 14 sham participants occurred. The percent change in Y-BOCS scores was significant at weeks 4 and 5 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 5 weeks. Using the more restrictive criterion of 35%, 5/16 HF and 1/14 sham individuals achieved the higher rate. Significant differences at 1 week occurred but not at 1 month follow-up.¹⁹

This pilot study led to a prospective multicenter randomized double-blind placebo-controlled trial by Carmi, et al. One hundred patients with OCD and Y-BOCS score >/= 20 between the ages of 22 and 68 receiving treatment in an outpatient setting were recruited. Inclusion criteria were a limited response to previous treatments and maintenance treatment with a therapeutic dosage of a serotonin uptake inhibitor (SRI) for least 2 months before randomization; or if not on a SSRI, in CBT maintenance therapy with failure to respond adequately to a SSRI and other antidepressants. SSRIs and other antidepressants and D2 or D2/5-HT2 antagonist medications were allowed but could not be changed for at least 2 months before enrollment. Exclusion criteria were any primary axis I disorder other than OCD, severe neurological impairment, and any condition associated with an increased risk for seizures. Patients were randomized 1:1 into an active dTMS or sham group. A 3 – 5-minute individualized symptom provocation occurred before each treatment session. The medial prefrontal cortex and anterior cingulate cortex were targeted with 20 Hz dTMS. Patients, operators, and raters were blinded to treatment group. Subjects were queried regarding the group to which they had been assigned after the first treatment with 66% of the active and 69% of the sham group giving an incorrect answer. The treatment phase lasted 6 weeks with 1 day for assessment and had 3 phases – a 3 week screening phase, a 6 week treatment of 5 treatments per week, and a 4 week follow-up phase.²⁰

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 6 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 4 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 CGI-S scores also showed a significant difference in the treatment group post-treatment. The drop-out rate was around 12% for each group (6/48 and 6/51). Adverse event rates did not differ between groups.

Limitations noted by the authors were that the provocations were uncontrolled and functional brain imaging of the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) was not performed. A further limitation was that 12 of the 14 authors reported some financial relationship with Brainsway.

There have been concerns that outcomes in sham-controlled studies do not accurately represent outcomes in community practice. A post marketing study of 219 OCD patients looked at efficacy in real world practice. The primary outcome measure was response, defined by at least a 30% reduction in the Y-BOCS score from baseline to endpoint. Secondary outcome measures included first response, defined as the first time the Y-BOCS score has met response criteria, and at least 1 month sustained response. Twenty-two clinical sites found a response rate of 72.6% and a sustained > 1 month response of 52.4% after 29 sessions. Extending the treatment course beyond 29 sessions resulted in continued reduction of OCD symptoms, raising the prospect of value for extended treatment protocols in non-responders. From this study it appeared that response rates are even higher in a real-world clinical setting than was seen in the multicenter clinical trial. A possible reason for the higher response rate noticed in the real-world clinical practice is the clinicians’ option to increase frequency of exposure therapy or use augmentation medications, neither of which were allowed in the rigorous sham-controlled study.²¹

Analysis of Evidence

There exists a body of moderate quality evidence supporting the use of high-frequency left repetitive transcranial magnetic stimulation (HFL-rTMS) as a monotherapy or an add-on therapy for treatment of moderate to severe MDD in adult patients with a prior failure of ≥ 1 antidepressant trials and who do not have contraindications to HFL-rTMS suggesting some positive benefit demonstrated by improved depression symptoms and better rates of response and remission than sham stimulation. Within this body of evidence, the findings are somewhat inconsistent likely due to small group sizes, lack of sufficient statistical power, limited follow-up, and substantial heterogeneity in treatment regimens. While existing evidence supports a modest benefit from initial treatment with HFL-rTMS there is very little evidence to support the use of HFL-rTMS as a maintenance therapy to prevent relapse in patients who had a major depressive episode that remitted with treatment.

There exists a body of moderate quality evidence supporting the use of rTMS as a monotherapy or an add-on therapy for treatment of adult patients with treatment resistant OCD and who do not have contraindications. This positive benefit is demonstrated by improved OCD symptoms and better rates of response and remission than sham stimulation. Within this body of evidence, the findings are somewhat inconsistent, likely due to small group sizes, limited follow-up, and substantial heterogeneity in treatment regimens. The lack of standardization in these studies makes comparisons somewhat difficult. Additionally, most of the authors have some financial relationship with industry. Greater definition of these parameters as well as looking at secondary outcomes of functionality will be helpful in defining future care. However, given the superiority over sham treatments, the safety of the procedure and the lack of other effective treatments, rTMS will be covered as outlined above.

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

TMS may be covered if prescribed and administered by a licensed physician who is knowledgeable in the use of rTMS. Outpatient rTMS may be indicated for patients with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined Major Depressive Disorder (MDD) 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 meets #1 and #2 of the following criteria:

1. Has a confirmed diagnosis of severe 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 2 trials of psychopharmacologic agents in the current depressive episode from at least 2 different agent classes. At least 1 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 2 trials of psychopharmacologic agents from at least 2 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

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 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).

TMS for Obsessive Compulsive Disorder (OCD) may be covered if prescribed and administered by a licensed physician who is knowledgeable in the use of rTMS. Outpatient rTMS may be indicated for patients with DSM-5 defined OCD who have failed to benefit from initial treatment of their OCD.

Initial Treatment:

rTMS of the brain is considered medically necessary for use in an adult who meets #1 and #2 of the following criteria:

1. Has a confirmed diagnosis of OCD as per DSM-5 criteria; 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 a trial of 2 distinct psychopharmacologic agents, administered for a minimum of 8 weeks; or
• Inability to tolerate psychopharmacologic agents as evidenced by trials of psychopharmacologic agents from 2 distinct psychopharmacologic agents; or
• History of response to TMS for OCD in the past that was clinically meaningful; or
• If patient is currently receiving antipsychotics, opioids, benzodiazepines, glutamatergic agents or other agents which could be considered investigational or risky treatments, TMS may be considered reasonable and necessary as a safer treatment option.

AND

3. A trial of an evidence-based psychotherapy known to be effective in the treatment of OCD for a minimum of 8 weeks duration without significant improvement in OCD symptoms as documented by standardized rating scales that reliably measure OCD 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 physician will have experience in administering TMS therapy and will prescribe an evidence-based OCD TMS protocol. The treatment shall be given under direct supervision of this physician (physician present in the area but does not necessarily personally provide the treatment).

The Brainsway Deep TMS System is 1 TMS System for OCD, however any TMS system that has received FDA clearance for treatment of OCD may be utilized.

 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 for MDD 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., Geriatric Depression Scale (GDS), Patient Health Questionnaire Depression Scale (PHQ-9), Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology (QIDS) or Inventory of Depressive Symptomatology-Systems Review (IDS-SR).

Retreatment for OCD may be considered for patients who met the guidelines for initial treatment and experienced at least a 30% reduction in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score, as long as the improvement persisted for at least 1 month after the prior treatments ended.

All other uses of TMS are experimental and are not covered.