|Subject:||Transcranial Magnetic Stimulation for Depression and Other Neuropsychiatric Disorders|
|Policy #:||BEH.00002||Current Effective Date:||04/16/2013|
|Status:||Revised||Last Review Date:||02/14/2013|
Transcranial magnetic stimulation (TMS) involves placement of a small coil over the scalp through which a rapidly alternating current is passed. This produces a magnetic field which affects electrical activity in the brain. This document addresses TMS as a treatment of behavioral health indications including depression and other neuropsychiatric disorders.
Note: Please see the following related documents for additional information:
Transcranial magnetic stimulation (TMS) of the brain is considered medically necessary for use in an adult who meets the following criteria:
Investigational and Not Medically Necessary:
Transcranial magnetic stimulation of the brain is considered investigational and not medically necessary for MDD when the above criteria are not met, and for all other behavioral health indications and neuropsychiatric disorders (e.g., anxiety disorders, mood disorders, schizophrenia).
TMS for Treatment-Resistant Depression (TRD)
According to Gaynes and colleagues (2011), MDD is a common condition experienced by more than 13 million people over the course of a year. Treatment choices are wide ranging, including both pharmacologic and nonpharmacologic therapies. Each of the numerous antidepressant drugs available are categorized by class according to the neurotransmitter system with which it mostly interacts. If an antidepressant drug in one class does not relieve symptoms or causes intolerable side effects, an antidepressant drug in another class may be prescribed. The rate of remission, or complete symptom relief, has been reported to be approximately 33% for monotherapy with the first prescribed antidepressant drug and lessens with each successive antidepressant drug trial. Individuals with two or more prior treatment failures are considered to have TRD. These individuals represent a complex population with a disease that is difficult to manage. This data and the increasing prevalence of MDD and drug-resistant MDD suggest a need for alternative treatments for TRD.
Repetitive transcranial magnetic stimulation (rTMS) has been studied as a nonpharmacologic treatment option for individuals with TRD. The peer-reviewed medical literature focusing on the use of rTMS for TRD (variably defined), includes a number of double-blind randomized sham-controlled short-term trials. Trial results show statistically significant improvement with active treatment, suggesting a response rate two to three times that of sham controls. Approximately 15% to 25% of the active treatment population in these trials showed a clinical response to rTMS despite the existence of differences in study definitions for trial inclusion and prior treatment heterogeneity within each study.
O'Reardon and colleagues (2007) conducted an industry-sponsored study under an Investigational Device Exemption (IDE) to determine whether rTMS over the left dorsolateral prefrontal cortex (DLPFC) was effective and safe. The trial findings resulted in the FDA clearance of the NeuroStar® TMS Therapy System (Neuronetics, Malvern, PA), for the treatment of adults with MDD without psychosis who "have not adequately responded to appropriate pharmacological treatment intervention" (FDA, 2008). A total of 301 participants enrolled at 23 study sites with antidepressant medication-free major depression were randomly assigned to active (n=155) or sham (n=146) rTMS. Participants were required to have failed at least one, but no more than four adequate antidepressant treatments in the current or most recent episode of depression. Treatment and rating personnel were blinded to participant assignments. Repetitive TMS occurred daily, five days a week for six weeks, followed by a tapering period of three additional weeks during which time antidepressant drug therapy was initiated. Participants achieving less than a 25% reduction on the Hamilton Depression Rating Scale-17 (HAMD-17) at four weeks could crossover to an open-label, acute treatment extension study. The primary outcome was the difference between active and sham rTMS using the last visit Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item HAMD and response and remission rates using the MADRS and HAMD. At the primary efficacy point of four weeks, the baseline to endpoint change on both the HAMD-17 and the HAMD-24 but not the MADRS showed a significant improvement for the active rTMS group. The result was sustained at six weeks. Significant response rates (greater than 50% improvement from baseline) were present at four and six weeks for the active treatment group using each of the three scales (HAMD-17, HAMD-24, and MADRS). A significant difference in remission rates did not occur at four weeks but was higher for the active group at six weeks for the MADRS and HAMD-24. A significant number of participants, 74 (47.7%) in the active group and 92 (63.0%) in the sham group, dropped out after four weeks to enter the open-label trial (Avery, 2008), thus, many of the six-week observation values in the trial reflected four-week values.
Avery and colleagues (2008) reported on the results of the open-label, crossover extension of participants from the O'Reardon trial (2007) who failed to receive benefit from at least four weeks of randomized treatment assignment, either active or sham rTMS, in the controlled trial. The first six-week phase of the study was antidepressant-free followed by a three-week rTMS taper phase with initiation of one of 15 different antidepressants. During the taper phase, rTMS was delivered three times in the first week, two times in the second week and one time in third week. As noted above, 166 participants entered the study but only 158 were present for at least one post-baseline observation, 73 of whom had been in the active arm and 85 in the sham. The primary efficacy outcome was the change in total score on the MADRS from the start of the open-label phase to six weeks or study endpoint. Secondary outcome measures included the HAMD-17 and HAMD-24. Remission was defined as a score of less than 10 on the MADRS, less than 8 on the HAMD-17, or less than 11 on the HAMD-24. Improvement was noted in both groups over the six-week active and the three-week taper periods. At the conclusion of the taper phase, in the sham-to-rTMS group, 44.7% of participants achieved response criteria on the MADRS, and 30.6% achieved remission. In the same group, 45.9% achieved response on the HAMD-24 and 36.5% achieved remission. Similar observations were noted in the extended rTMS group; at the end of the taper phase, 34.2% of participants achieved response criteria on the MADRS, and 17.8% achieved remission. In the same group, 31.5% achieved response on the HAMD-24 and 19.2% achieved remission.
George and colleagues (2010) published a prospective, multicenter, randomized, sham-controlled trial reporting results using daily DLPFC rTMS on 199 participants with a moderate level of antidepressant drug-free, unipolar MDD (i.e., single episode or recurrent with less than five years from onset). The study participants were required to be stable during a two-week medication-free lead-in period and have a moderate level of treatment resistance defined as insufficient clinical benefit from one to four adequate medication trials or intolerant to three medication trials. The trial used the FDA-cleared NeuroStar TMS device. Magnetic resonance imaging was used to refine the location of the magnetic coil; relocation of the coil occurred in 33.2% of participants. Subjects received treatment for three to six weeks. Lack of improvement in the first three weeks (classified as treatment failures) led to discontinuation from Phase 1 of the clinical trial and crossover to open treatment in Phase 2 of the trial. Partial responders in the first three weeks continued with sham or rTMS. At the end point of the study, the response rate using an intention-to-treat (ITT) analysis for remitters (n=18) was 14.1% in the active rTMS group and 5.1% in the sham group (p=0.02). Most remitters had low antidepressant treatment resistance. Results were similar for response to treatment outcomes, 15.5% in the active rTMS group versus 5% in the sham group. Comparing participants receiving active rTMS to sham rTMS, active rTMS participants demonstrated significantly greater improvement in mean scores for the MADRS, Clinical Global Impression Improvement Scale (CGI-S), and the Inventory of Depressive Symptomatology-Symptoms Review/Self Rated (IDS-SR) but not the HAMD-24. A limitation of this trial was the failure to enroll the projected 240 participants as suggested by the initial power analysis, due in part to the delayed start of the trial as a result of extensive work in designing a sham system. It was also unclear how long participants required treatment. Those who met the 30% improvement criteria continued randomized treatment for an additional three weeks or until cessation of meaningful response to treatment; as such, no participant received treatment for a full six weeks. Despite more rigorous requirements for progression (30% improvement at three weeks compared to 25% improvement at four weeks), this study showed a significant improvement in remission at three to five weeks. The treatment was relatively well tolerated, with no difference in the adverse events between the sham and the active rTMS treatment arms. Adverse events included headache (active 29% versus sham 23%), discomfort at the stimulation site (active 17% versus sham 10%), insomnia (active 10% versus sham 7%) and worsening of depression or anxiety (active 6% versus sham 8%). No seizure activity was reported in any of the study participants. The investigators concluded that daily DLPFC rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.21-13.24).
TMS for Maintenance of Remission for TRD
While the antidepressant effects of rTMS for individuals with TRD have been demonstrated, a limited number of studies have examined the efficacy of rTMS for maintaining response or remission (e.g., preventing relapse or recurrence) after treatment. The majority of the research focuses on the acute short-term efficacy of rTMS treatment, and there is considerable risk of relapse and variable rates reported post rTMS in these early published studies. For example, Dannon and colleagues (2002) reported a 20% six-month relapse rate in a group of individuals with major depression treated with either ECT (n = 20) or rTMS (n = 21). In another small study of reintroduction of rTMS treatment for refractory MDD, the mean duration of rTMS benefit was reported as five months (Demirtas-Tatlidede, 2008).
Janicak and colleagues (2010) reported that rTMS can be an effective acute antidepressant treatment, but noted that few studies systematically examine the persistence of benefit. The investigators assessed the durability of antidepressant treatment after acute response to rTMS in individuals with MDD during a longer term observational study of responders in the two trials described in an FDA Executive Summary concerning the NeuroStar TMS Therapy System (FDA, 2007). Participants that ultimately responded to active rTMS or sham in the original randomized controlled trial, or responded to active rTMS in the open label extension were followed for recurrence of depression and/or need for reintroduction of active rTMS over a 24-week treatment period. The participants who met criteria for partial response (i.e., greater than 25% decrease from the baseline HAMD-17) (n=142) were tapered off rTMS over three weeks, while simultaneously starting maintenance antidepressant monotherapy. During this durability study, rTMS was readministered if participants met pre-specified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for two consecutive weeks). Relapse was the primary outcome measure, defined as a recurrence of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depression or failure to achieve symptom improvement upon reintroduction of rTMS. Ten of 99 (10%) participants relapsed, 38 (38.4%) participants had worsening symptoms, and 32 of the 38 participants (84%) achieved symptomatic benefit with adjunctive rTMS. Safety and tolerability were similar to acute rTMS monotherapy. It is difficult to draw conclusions from this data regarding the treatment effect of rTMS. All the study participants had initiated antidepressants, making it difficult to attribute the duration of response to rTMS alone. The control group only received sham rTMS. Although participants who initially responded to sham had higher relapse and rTMS re-treatment rates, the numbers are too small for statistically meaningful comparisons, and the groups may not be comparable. Additional data are needed to determine the durability of the treatment effect, particularly in maintenance phases.
Fitzgerald and colleagues (2012) reported on a large prospective open-label trial of clustered maintenance rTMS that included 35 individuals with refractory depression. Participants with TRD received a second successful course of rTMS following relapse and were subsequently treated with monthly maintenance therapy consisting of five rTMS treatments over a 2.5-day period (Friday evening, Saturday and Sunday). Participants were treated with maintenance therapy of the same type that they had initially received (i.e., 14 high frequency to the left DLPFC, 12 low frequency to the right DLPFC, and 9 bilateral rTMS). The primary outcome was the mean duration until clinical relapse, addition or change of antidepressant medication, or withdrawal from maintenance treatment to pursue other treatment options. Twenty-five of the 35 participants (71%) relapsed at a mean of 10.2 months (range, 2 to 48 months), which was substantially shorter than the interval (less than three months) for relapse from the initial treatment. The other 10 participants either withdrew while still in remission or remained well and in maintenance treatment at the end of the study (n=6, mean 12.0 plus/minus 9.7 months, range 1-24 months). In terms of prediction of time to relapse, there was no effect of any of the analyzed clinical or demographic variables on duration of time (in months) until relapse. Limitations of this study include the inability to compare the results to other rTMS follow-up or maintenance studies employing a more standardized approach, due to the unique form of the applied maintenance treatment and characteristics of the sample of participants. The overall relapse rate was fairly high when compared to the earlier study by Janicak (38% rTMS reinduction rate) (2010), although not greater than the results of a study by Cohen and colleagues (2009) that reported a 77% rate of relapse at six months. In addition, there was no form of placebo control in the trial and changes in medication treatment across the duration of maintenance therapy were not accurately documented.
Mantovani and colleagues (2012) examined the persistence of benefit of rTMS during a three-month follow-up of individuals after acute treatment with rTMS for MDD. Participants were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension trial of those who did not respond to the acute trial (n = 43). The primary outcome was relapse, defined as a HAMD-24 score of greater than or equal to 20. Of the 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the rTMS taper. Thirty-two participants completed rTMS taper and one-, two-, and three-month follow-up. At the three-month visit, 29 of 50 participants (58%) were classified as in remission (HAMD-24 score: less than or equal to 10), two of 50 participants (4%) as partial responders (30% less than or equal to HAMD-24 reduction, less than 50% from baseline), and one of 50 participants (2%) met criteria for relapse. During the entire three-month follow-up, five of the 37 participants relapsed (relapse rate = 13.5%; average time to relapse 7.2 plus/minus 3.3 weeks), but four of them regained remission by the end of the study. Participants who relapsed had higher depression scores at one month. Limitations of this study include the small number of participants who completed the three-month follow-up (one third of the sample were lost to follow-up), and the nonrandomized study design.
Connolly and colleagues (2012) reported on a retrospective cohort study of 100 consecutive individuals treated with rTMS for depression in an outpatient treatment program. Out of the first 100 cases treated at the institution, 42 received maintenance rTMS. Most of the individuals had failed more than one adequate antidepressant trial and were treated with high-frequency rTMS over the DLPFC. Low-frequency rTMS to the right DLPFC was given in individuals with a family or personal history of seizures and in some who were also receiving high-frequency rTMS. The primary outcomes for the acute sample were the response and remission rates at treatment end point as measured by the CGI-S scale. At the end point of up to 30 adjunctive TMS sessions, the CGI-S response rate was 50.6% of the first 100 cases and the remission rate was 24.7%. Maintenance treatment (n = 42 individuals) was tapered gradually from two sessions per week for the first three weeks to monthly. At six months after the initial rTMS treatment, 26 of the 42 individuals (62%) maintained their response. Overall, 40 individuals discontinued treatment for reasons including adverse events (n = 3), logistical difficulties (n = 10), or stopped treatment for lack of efficacy or were lost to follow-up (n = 27). Additional limitations of this open-label study are inclusion of individuals with bipolar disorder in addition to those with MDD and reported differences in the treatment parameters and methods of targeting rTMS to the DLPFC. The absence of a control group and the sample of records reviewed from a single treatment center limit generalizing the results to other clinical rTMS treatment.
Additional research is needed to determine the durability of remission produced by rTMS. This includes identification of which of the locations and treatment parameters are most effective to guide the number of sessions needed to elicit a clinically significant response, to determine whether the response is durable with or without antidepressant medications, and to provide some information about whether maintenance treatments are needed and which types of maintenance treatment are most effective.
Slotema and colleagues (2010) conducted a meta-analysis evaluating the efficacy of rTMS for various psychiatric disorders. Data were obtained from randomized, double-blind, sham-controlled trials of rTMS treatment for depression (34 studies, 1383 participants). Studies of rTMS versus ECT (six studies) for depression were meta-analyzed. The 2007 clinical trial by O'Reardon and colleagues is included in this meta-analysis. The analysis had very broad selection criteria for inclusion, allowing any type of rTMS treatment and any type of depression experienced by the study participants. Participants were free of antidepressant agents (i.e., rTMS monotherapy) in seven studies, antidepressants were continued in 17 studies, and antidepressants were initiated along with rTMS in five studies. The mean weighted effect size of rTMS versus sham for depression was 0.55 (p<0.001). ECT therapy was superior to rTMS in the treatment of depression (mean weighted effect size of 0.54 (p<0.001). Subgroup analyses comparing rTMS as a monotherapy versus continuation or initiation of antidepressants showed that the mean weighted effect size for rTMS monotherapy (effect size 0.96, p<0.001), trended toward having a stronger treatment effect than for rTMS with continuation of antidepressants (effect size 0.51, p<0.001) or rTMS with initiation of antidepressants (effect size 0.37, p=0.03). This analysis, however, should not be interpreted to mean that rTMS monotherapy is possibly more effective than as used with antidepressants, but that the treatment difference between rTMS and the corresponding control group for each type of study is larger for rTMS monotherapy versus a no-treatment sham-only control group. According to the authors, "[a]lthough the efficacy of rTMS in the treatment of depression…may be considered proven, the duration of the effect is as yet unknown. Effect sizes were measured immediately after the cessation of rTMS treatment. There are indications that the effects of rTMS may last for several weeks to months. Further studies should assess symptom relief with longer follow-up periods to assess the cost-effectiveness of rTMS treatment, and to indicate its economic advantages and disadvantages." "Although rTMS cannot replace ECT in depressive patients, there may be subgroups in which rTMS can replace antidepressant medication."
A work group of the American Psychiatric Association (APA) published the third edition of the Practice Guideline for the Treatment of Patients with Major Depressive Disorder (Gelenberg/APA, 2010). According to the work group, "A substantial number of studies of TMS have been conducted, but most have had small sample sizes, and the studies overall have yielded heterogeneous results. Further complicating the interpretation of the TMS literature is the variability in stimulation intensities (relative to the motor threshold), stimulus parameters (e.g., pulses/second, pulses/session), anatomical localization of stimulation, and number of TMS sessions in the treatment course." As an initial treatment modality, the guideline recommends:
Treatment in the acute phase should be aimed at inducing remission of the major depressive episode and achieving a full return to the patient's baseline level of functioning. Acute phase treatment may include pharmacotherapy, depression-focused psychotherapy, the combination of medications and psychotherapy, or other somatic therapies such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or light therapy. In comparisons of actual TMS versus sham TMS, most but not all recent meta-analyses have found relatively small to moderate benefits of TMS in terms of clinical response. Although the primary studies used in these meta-analyses are highly overlapping and the variability in TMS stimulus parameters and treatment paradigms complicates the interpretation of research findings, these meta-analyses also support the use of high-frequency TMS over the left dorsolateral prefrontal cortex. Lesser degrees of treatment resistance may be associated with a better acute response to TMS (Lisanby, 2009). In comparison with ECT, TMS has been found in randomized studies to be either less effective than ECT (Eranti, 2007) or comparable in efficacy to ECT (Grunhaus, 2003; Janicak, 2002; Rosa, 2006), but in the latter studies TMS was more effective and ECT was less effective than is typically seen in clinical trials.
For individuals who do not respond adequately to pharmacotherapy, the guideline states (Level II: Recommended with moderate clinical confidence): "TMS could also be an option, as it appears to be safe and well tolerated. In addition, it has shown small to moderate benefits in most but not all (Couturier, 2005; Herwig, 2007) clinical trials and recent meta-analyses." However, when comparing rTMS to other somatic therapies such as ECT and VNS, the guideline states, "ECT is recommended as a treatment of choice for patients with severe major depressive disorder that is not responsive to psychotherapeutic and/or pharmacological interventions, particularly in those who have significant functional impairment or have not responded to numerous medication trials" (Level I: Recommended with substantial clinical confidence) (Gelenberg/APA, 2010).
The Institute for Clinical Systems Improvement's (ICSI, 2012) health care guideline titled Major Depression in Adults in Primary Care discusses rTMS as a treatment for MDD that fails to respond to at least one antidepressant trial during the current illness episode. In addition, the guideline states "While many studies have been conducted, results are heterogeneous, likely due to small sample sizes and significant variability of anatomical localizations and stimulation intensities and parameters. Compared to early rTMS studies, more recent studies improve upon methodological limitations including active sham treatment mimicking the somatosenory experience of rTMS, masking rTMS administrators and patients to acoustic signals produced by stimulation, and competency certification for outcome evaluators." The guideline goes on to summarize, "At this time, a number of treatment and protocol variations for rTMS remain, and the optimum treatment protocol and patient characteristics may not yet be identified (Allan, 2011). Nonetheless, rTMS is a low-risk and appealing treatment for treatment-refractory depressed patients for whom it is practical and cost-effective."
The Agency for Healthcare Research and Quality (AHRQ) recently published a comparative effectiveness review of nonpharmacologic interventions for TRD in adults (Gaynes, 2011). Treatment modalities reviewed included ECT, rTMS, VNS and psychotherapy. The review focused on randomized controlled trials comparing one intervention with another for efficacy and effectiveness. The authors also evaluated trials using nonpharmacologic interventions versus placebo- or sham-controlled evidence or "treatment as usual" controls. The quality of individual studies was categorized as "good, fair, or poor," with only good or fair studies included in the analyses. The strength of the various bodies of evidence used principles in the AHRQ's method guide, grading strength of evidence as "high, moderate, low, or insufficient." The greatest volume of evidence found for TRD intervention was for ECT and rTMS; however, the direct comparative evidence about these treatments was limited. The available head-to-head literature concerning the efficacy of these interventions for TRD was limited to two trials (both rated as fair) in MDD-only populations. One trial compared ECT and rTMS, and the other compared ECT and ECT plus rTMS. They showed no differences between treatment options for depressive severity, response rates, and remission rates. Indirect evidence that was available to assess the potential benefits of nonpharmacologic interventions versus controls was also measured by calculating mean changes in depressive severity, relative risks of response, and relative risks of remission. Repetitive TMS was beneficial relative to controls receiving a sham procedure for all three outcomes and produced a greater decrease in depressive severity (high strength of evidence). Specifically, rTMS averaged a decrease in depressive severity measured by the HAMD of more than five points relative to sham control (a three point HAMD difference is considered clinically meaningful). Response rates were greater with rTMS than sham (also high strength of evidence); those receiving rTMS were more than three times as likely to achieve a depressive response as persons receiving a sham procedure. Finally, rTMS was also more likely to produce remission than the control procedure (moderate strength of evidence); persons receiving rTMS were more than six times as likely to achieve remission as those receiving the sham procedure. With respect to maintaining remission (or preventing relapse) for TRD, the authors found no direct comparisons involving ECT, rTMS, VNS, or cognitive behavioral therapy (CBT). Indirect evidence in three fair trials compared rTMS with a sham procedure and found no significant differences. However, too few participants were followed during the relapse prevention phases in two of the three studies, and participants in the third received a co-intervention providing insufficient evidence for a conclusion. In the final analysis, the report concludes that when used as an antidepressant therapy, rTMS appears to produce a clinical benefit without the systemic side effects typical with oral medications, has no adverse effects on cognition, and unlike ECT, does not induce amnesia or seizures. Repetitive TMS offers a well-tolerated, nonpharmacologic alternative that does not require attendant anesthesia services and can be administered in an outpatient setting for individuals with MDD who have failed to benefit from initial treatment of their depression. The report suggests that when effective, rTMS may prevent the need to utilize more complex pharmaceutical augmentation strategies (e.g., atypical antipsychotic medication), ECT, and inpatient hospitalization at later stages of the illness.
In December 2011, the New England Comparative Effectiveness Public Advisory Council (CEPAC), an AHRQ funded, independent body composed of clinician and public representatives and led by a research team at the Institute for Clinical and Economic Review (ICER) at the Massachusetts General Hospital, reviewed the AHRQ comparative effective analysis on rTMS along with consideration of supplemental information. A majority of CEPAC members determined that for individuals with TRD, the evidence is adequate to demonstrate that rTMS provides a net health benefit equivalent or superior to usual care (i.e., general supportive psychotherapy with or without continued use of antidepressant medication) and a net health benefit equivalent to ECT. In a subsequent coverage policy analysis of the CEPAC report, the ICER (2012) recommended the need to further identify: 1) the appropriate subpopulations of individuals with TRD to receive treatment with rTMS and ECT; 2) treatment duration and frequency for rTMS; 3) maintenance therapy requirements for rTMS; and 4) threshold for previously failed treatments required before considering rTMS (i.e., equal to or greater than two failed drug treatments during the most recent episode of depression, a higher threshold than that included in the FDA license).
In summary, the studies of rTMS in the peer-reviewed medical literature show a short-term benefit for individuals with treatment resistant MDD who received active versus sham rTMS. Treatment benefit has been defined by response or remission rates using depression rating scales. Most studies have short treatment periods, varying from one to six weeks and few studies have included long term outcomes. Durability of rTMS response at this time is unclear and the optimal approach to sustaining any benefit achieved is unknown. In addition, the use of rTMS as a maintenance therapy is not supported by a controlled clinical trial. A search of the Clinical Trials.gov database revealed an industry-sponsored clinical trial (NCT01415154) without results posted for a randomized, open-label 12-month maintenance treatment study to evaluate individuals who have responded to a six week course of acute rTMS treatment for MDD. The study will assess the change in depressive symptoms across the duration of maintenance treatment using observer and self-administered efficacy measures, describe the efficacy of rTMS re-introduction in individuals not receiving maintenance pharmacotherapy who show a recurrence of depressive symptoms, and assess the safety and durability of acute rTMS therapy followed by maintenance rTMS treatment for up to 12 months (NIH, 2013). The primary outcome measure will examine the proportion of individuals maintaining a sustained response throughout a 12-month maintenance treatment phase, with sustained response defined as not requiring rTMS reintroduction at every observation point during the maintenance phase. A secondary outcome measure plans to compare the average time to first reintroduction of rTMS between the two maintenance treatment arms. The treatment arms are defined as: 1) scheduled treatment arm - a three week rTMS taper, clinical assessments and one TMS session every fourth week and rTMS reintroduction as needed for clinical deterioration, and 2) monthly observational follow-up arm - a three week rTMS taper, clinical assessments and office follow- up every fourth week and rTMS reintroduction "as needed" for clinical deterioration. The estimated date for the final data collection for the primary outcome measure was October 2012.
Published evidence is limited and further investigation in large randomized controlled clinical trials is needed to assess the safety and durability of acute rTMS therapy followed by maintenance rTMS treatment for individuals with treatment resistant MDD. Despite questions that remain about stimulation parameters and the length of optimal treatment, rTMS is well-tolerated without significant adverse events and clinically significant results. Repetitive TMS is a safe and less invasive alternative treatment option for individuals with TRD.
Repetitive TMS as Treatment for Other Neuropsychiatric Disorders
A number of studies and meta-analyses explore the efficacy of rTMS for the treatment of auditory verbal hallucinations (AVH) in schizophrenia and other conditions (Blumberger, 2010; Burt, 2002; Cordes, 2010; Dlabac-de, 2010; Freitas, 2009; Hoffman, 2000; Hoffman, 2002; Hoffman, 2003; Klein, 1999; Loo, 2010; Matheson, 2010; Rollnik, 2000; Slotema, 2010; Slotema, 2011; Tranulis, 2008), bulimic eating disorders and addictions (Van den Eynde, 2010; Walpoth, 2008), cravings in alcohol dependence syndrome (Mishra, 2010), mood status post stroke (Kim, 2010), obsessive-compulsive disorder (OCD) (Alonso, 2001; Greenberg, 1997; Kang, 2009; Mantovani, 2006; Mantovani, 2010; Martin, 2003; Sachdev, 2007; Slotema, 2011), panic disorders (Prasko, 2007), and post-traumatic stress disorder (PTSD) (Boggio, 2010; Cohen, 2004; Osuch, 2009). Methodological limitations of these studies include small sample size, absence of a placebo control group, presence of concurrent pharmacotherapy, and lack of long-term outcomes. The durability of this treatment and its role in the treatment of other neuropsychiatric disorders is unknown.
The American Academy of Neurology (AAN) (Miyasaki, 2006) evidence-based practice parameter for the evaluation and treatment of depression, psychosis, and dementia has concluded there is insufficient evidence to support or refute the efficacy of rTMS or ECT in the treatment of depression associated with Parkinson disease.
The APA has practice guidelines that address the use of rTMS in individuals with auditory hallucinations in schizophrenia and OCD. For individuals with hallucinations in schizophrenia, the practice guideline states "although it has been suggested that repetitive transcranial magnetic stimulation (rTMS) may share beneficial features of ECT and several studies with rTMS have shown promising results in decreasing auditory hallucinations, rTMS does not have an FDA indication for the treatment of psychosis, and additional research is needed before recommending its use in clinical practice" (Lehman/APA, 2004). A subsequent Guideline Watch issued in September 2009 offers no updated recommendations to the 2004 guideline. The APA practice guideline for treatment of OCD evaluated four trials of rTMS, reporting results as "inconsistent, perhaps because the studies differed in design, stimulation sites, duration, and stimulation parameters. The available results and the technique's non-invasiveness and good tolerability should encourage future research, but the need for daily treatment may limit the use of TMS in practice" (Koran/APA, 2007).
According to the National Institute of Mental Health (NIMH, 2010) an estimated 26.2 percent of Americans ages 18 and older - about one in four adults - suffer from a diagnosable mental disorder in a given year. The occurrence of mood disorders, including major depressive disorder, dysthymic disorder, and bipolar disorder, affects approximately 20.9 million American adults, or about 9.5 percent of the U.S. population age 18 and older in a given year. Other conditions such as anxiety disorders, including generalized anxiety disorder, OCD, panic disorder, phobias, and PTSD affect approximately 40 million U.S. adults ages 18 and older, or about 18% in this age group in a given year. Individuals who suffer from depression may experience functional impairment, increased risk of suicide, higher health care expenses and losses in productivity. Complaints of sleep disturbance, fatigue and pain are the most common presentations of depression. Treatment in the acute phase of a major depressive episode may include pharmacotherapy, depression-focused psychotherapy (i.e. "talk therapy"), and the combination of medications and psychotherapy, or other somatic therapies such as ECT, recommended as the treatment of choice for individuals with severe major depression not responsive to psychotherapeutic and/or pharmacological interventions.
Repetitive TMS was first introduced in 1985 as a method of noninvasive stimulation of the brain. The technique involves placement of a small coil over the scalp; a rapidly alternating current is passed through the coil wire, producing a magnetic field that passes unimpeded through the cranium and scalp. Repetitive TMS was initially used to investigate nerve conduction. For example, rTMS over the motor cortex of the brain produced a muscle-evoked response on the opposite side. Interest in the use of rTMS as a treatment for depression was prompted by the development of a device that could deliver rapid, repetitive stimulation.
In contrast to ECT, rTMS does not require anesthesia, and does not induce a convulsion. Early studies suggested that rTMS of the left prefrontal cortex was associated with antidepressant properties. The device utilized for this procedure has been studied as a treatment for other behavioral health and neuropsychiatric disorders including auditory hallucinations in schizophrenia, OCD, and PTSD.
The NeuroStar TMS Therapy System (Neuronetics, Malvern, PA) received clearance for marketing as a Class II rTMS device in December, 2008. NeuroStar TMS Therapy is indicated for the treatment of adults with "major depressive disorder who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the episode" (FDA, October 2008). The Brainsway H-Coil Deep TMS (DTMS) device (Brainsway Ltd., Jerusalem, Israel) received FDA clearance in January 2013 as substantially equivalent to the predicate rTMS device (NeuroStar TMS System). According to the FDA 510(k) summary, the Brainsway Deep TMS System is indicated for the treatment of depressive episodes in adults with MDD who failed to achieve satisfactory improvement from previous antidepressant medication treatment in the current episode (FDA, 2013).
Repetitive TMS may be performed on an outpatient procedure but must be repeated several times per week over the course of four to six weeks to achieve maximum response. Repetitive TMS may be used alone or as an adjunct to antidepressant medication. An acute treatment course of rTMS consists of 30 treatments for 30 minute to 60 minute sessions, usually delivered daily for 5 days a week with treatment taper of three weeks duration. Each session consists of rTMS to the left DLPFC area at around 120% of the individual's observed motor threshold (10Hz, 4-second train duration, 26 second inter-train interval, at 3000 pulses per session), using a figure-eight solid core coil.
According to the prescribing information, the NeuroStar TMS System is contraindicated for use in some individuals. These individuals should not be treated with the system or will need to take special precautions before treatment, including those having conductive, ferromagnetic, or other magnetic-sensitive metals in the head or within 30 centimeters (cm) of the treatment coil. Examples include cochlear implants, ocular implants, implanted electrodes and stimulators such as deep brain stimulation devices, pacemakers, ICDs, or VNS devices, and aneurysm clips or coils, stents, and bullet fragments. Failure to follow this restriction could result in serious injury or death. The TMS System is also contraindicated for use in an individual with a wearable cardioverter defibrillator (WCD), even if the device is removed, due to the potentially unstable cardiac condition of such a person. Caution should be used in individuals with other implanted devices or metallic objects that are not controlled by physiologic signals including sutures and implanted insulin pumps located in areas outside the 30cm distance from the coil during rTMS therapy, otherwise serious injury could result.
The safety and effectiveness of NeuroStar TMS Therapy has not been established in the following special populations or clinical conditions through a controlled clinical trial (NeuroStar TMS User Manual):
Safe operation of the NeuroStar TMS System is based on treatment parameters to reduce the potential risk of seizure. These treatment parameters observe the 1998 National Institute of Neurological Disorders and Stroke (NINDS) Workshop report guidelines and are outlined in the NeuroStar TMS System User Manual available on the FDA Advisory Committee web site. Treatment outside of these guidelines is not recommended. Additional warnings and precautions associated with the operation of the NeuroStar TMS System are also included in the User Manual (FDA, 2007).The major adverse effects of rTMS therapy are headache and pain or discomfort at the site of application of the device. In a study reported by Janicak and colleagues (2008), aggregate safety data were obtained from a comprehensive clinical development program examining the use of rTMS in the treatment of MDD. There were three separate clinical protocols, including 325 individuals from 23 clinical sites in the United States, Australia, and Canada. The authors reported that rTMS was associated with a low incidence of adverse events that were mild to moderate in intensity and demonstrated a largely predictable time course of resolution.
Augmentation therapy: A drug regimen consisting of one or more drugs, which are not antidepressant drugs, added to increase the efficacy of an antidepressant drug in an adult with MDD. An example would be to add pindolol to fluoxetine.
Depression: A state of depressed mood characterized by feelings of sadness, despair and discouragement.
Depression Rating Scales: Standardized rating scales to reliably assess the range of symptoms that are most frequently observed in adults with major depression. The following rating scales comprehensively survey the type and magnitude of symptom burden present, and are therefore considered to be measures of illness severity:
Adequate trial of an antidepressant drug: The therapeutic dose range of a drug for a duration of at least 6 weeks at the maximum dose for the specific antidepressant as approved by the FDA, or, documentation exists that higher doses were not tolerated when the dose is less than the FDA-approved maximum.
Dysthymia: A type of depression involving long-term, chronic symptoms that does not disable a person but inhibits their ability to function at a high level or to feel well.
Major depression: A combination of symptoms (e.g., overwhelming sadness, anxiety, or "empty" feelings, hopelessness and pessimism, trouble making decisions, remembering, and concentrating) that are disabling and makes daily functioning extremely difficult if not impossible.
Schizophrenia: A disorder or group of disorders characterized by disturbances in form and content of thought, mood, sense of self, and relationship to the external world.
Transcranial magnetic stimulation (TMS): Involves placement of a small coil over the scalp through which a rapidly alternating current, producing a magnetic field, is passed unimpeded through the cranium and scalp.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
|90867||Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management|
|90868||Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent delivery and management, per session|
|90869||Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent motor threshold re-determination with delivery and management|
|296.23||Major depressive disorder, single episode, severe, without mention of psychotic behavior|
|296.33||Major depressive disorder, recurrent episode, severe, without mention of psychotic behavior|
|ICD-10 Diagnosis||ICD-10-CM draft codes; effective 10/01/2014:|
|F32.2||Major depressive disorder, single episode, severe, without psychotic features|
|F33.2||Major depressive disorder, recurrent, severe, without psychotic features|
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other behavioral health and neuropsychiatric disorders, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Web Sites for Additional Information|
Brainsway Deep TMS System
NeuroStar TMS Therapy System
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Revised||02/14/2013||Medical Policy & Technology Assessment Committee (MPTAC) review|
|Revised||02/08/2013||Behavioral Health Subcommittee review. Clarified medically necessary criteria (4). Added bullet that individuals with specified neurological disorders do not meet the medically necessary criteria for rTMS (e.g. cerebrovascular disease, dementia). Updated Rationale, Background, References, and Web Sites for Additional Information.|
|Revised||08/03/2012||Behavioral Health Subcommittee review. Added medically necessary indications for the treatment of major depressive disorder (MDD) when criteria are met. Revised investigational and not medically necessary statement. Updated the Description, Rationale, Background, Definitions, Coding, References and Index.|
|01/01/2012||Updated Coding section with 01/01/2012 CPT changes.|
|Behavioral Health Subcommittee review. Updated Rationale and References. Updated Coding section; removed CPT 0160T, 0161T deleted 12/31/2010.|
|MPTAC review. Revised the Subject of document to: Transcranial Magnetic Stimulation for Depression and Other Neuropsychiatric Disorders. Revised investigational and not medically necessary statement, adding …for all "behavioral health" indications to the Position Statement. Rationale updated to address rTMS for an individual with antidepressant medication treatment failure, including discussion of recently updated practice guidelines. Updated Description and References. Added section: Web Sites for Additional Information. Updated Coding section to include 01/01/2011 CPT changes.|
|MPTAC review. Updated Rationale, Background, and References.|
|MPTAC review. Rationale, Background, Index, and References updated to address the FDA 510(k) determination for the NeuroStar TMS Therapy device for treatment of major depressive disorder.|
|MPTAC review. Title changed to: Transcranial Magnetic Stimulation as a Treatment of Depression and Other Neuropsychiatric Disorders. Updated Rationale and References.|
|The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.|
|MPTAC review. Rationale, Definitions, and References updated.|
|MPTAC review. References and Coding updated.|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
Last Review Date
|BEH.00002||Transcranial Magnetic Stimulation as a Treatment of Depression and Other Psychiatric Disorders|
|WellPoint Health Networks, Inc.|
|6.01.03||Transcranial Magnetic Stimulation as a Treatment of Depression and Other Neuropsychiatric Disorders|