Naturalistic outcomes study in community practices

Neuronetics sponsored a naturalistic, multisite, clinical outcomes study (Clinicaltrials.gov listing: NCT001114477) evaluating the effectiveness of the NeuroStar TMS Therapy System in routine clinical practice [13,14]. In these studies, 307 MDD patients undergoing open label TMS showed statistically significant improvement in functional status on a broad range of global, mental health and physical health domains.

Training

Peer-to-peer and graduate medical education have an important role in physician and staff training. In addition to industry-sponsored training that is device specific, we recommend that TMS providers complete additional training either through a university affiliated or industry independent Continuous Medical Education (CME) program or through additional peer-to-peer direct supervision. Providers with a strong foundation in TMS through their training or extensive TMS experience may be exempt from the above recommendation. It is also recommended that the attending physician and all staff who are members of the TMS treatment team receive appropriate product training on the use of the new technology. It is recommended that at a minimum, the TMS team receive the detailed product training offered by the device manufacturer and obtain written documentation of training.

We also advise that a TMS clinic establish formal standard operating procedures (SOPs) related to training and ongoing criteria to maintain procedural skills for all staff who are involved in the delivery of TMS in the office setting. Documentation of implementation and adherence to these procedures should be a routine part of office practice. The cTMSs can offer recommendations and support of specific examples of these practices among its members.

Establishing a treatment plan

The standard treatment regimen recommended in the TMS depression clinical development studies involved a specified parameter set of high frequency, left prefrontal rTMS that showed gradual and continued benefit after five daily treatments over 4–6 weeks. Some patients who respond slowly to TMS may benefit from 1–4 additional weeks of treatment [15,17]. The Brainsway study demonstrated that an additional 12 weeks of twice weekly continuation increased response rates by 8%. Therefore, patients should be advised of this likely pattern of outcome prior to initiating treatment, in order to set appropriate expectations of the time course of benefit and when and how assessment of efficacy should reasonably be estimated.

Informed consent

Once a decision has been made to prescribe the use of TMS as a treatment option, it is crucial that the patient has a thorough, accurate, and informative presentation of what a course of TMS will entail. During the treatment sessions, the patient will be unable to have free movement of their head and thus have a limited field of view of the operating aspects of the device. As such, reducing anxiety regarding the nature of the treatment process is essential prior to starting. A variety of visual aids should be provided with the product documentation, including brochures and videos, which can be used to instruct the patient on the treatment process. In many clinical situations, it is appropriate to invite family members into the consultation room to address any questions they may have. Only when the procedure is well understood and questions have been answered should written informed consent be obtained and documented in the medical record.

Safety considerations

A significant safety risk associated with TMS is the inadvertent induction of a seizure [51,52]. Therefore, it is essential that both the supervising physician and the TMS treatment staff are familiar with proper first responder capability for such an event.

The incidence of seizure with TMS is small and appears slightly lower than the incident risk reported for the use of current antidepressant medications [12]. Adherence to recommendations endorsed by International Federation for Clinical Neurophysiology can help minimize this risk [52,53]. In clinical practice, the use of an appropriately worded informed consent procedure (discussed in the preceding section) is recommended, as are adequate methods for pre-treatment clinical screening of potential seizure risk and continuous clinical monitoring of the TMS treatment session itself. All clinical personnel involved in the delivery of TMS must be trained as first responders to provide appropriate initial management of a seizure or other medical event. The overall risk of seizure is estimated to be less than 1 in 30,000 treatment sessions (<0.003%) or less than 1 in 1000 patient exposures (<0.1%) with the NeuroStar coil (NeuroStar TMS Therapy User Manual, Neuronetics, Inc., Malvern, PA, USA) and 6 in 5000 patients with the Brainsway coil (User Manual, Brainsway, Israel) [54]. All seizures to date have been self-limited and occurred only during the treatment session. We note that there are no specific labeling requirements that advanced resuscitative equipment be present in the TMS treatment room. It is the consensus of the cTMSs that IV access, cardiac defibrillators, suction, and oxygen are NOT necessary for the safe administration of TMS in an outpatient TMS office.

Vasovagal syncope has also occurred with TMS, particularly in initial sessions. Management here is largely reassurance to the patient, and protection from harm if they fall.

During a TMS session, the magnetic pulse produces an audible clicking sound, which varies with different coil designs and intensity [55,56]. Therefore, an additional standard safety precaution for all TMS treatments is the use of earplugs or other hearing protection capable of at least 30 dB sound reduction [57]. Such a precaution eliminates the risk of changes in auditory threshold with treatment for either the patient or the treatment provider. Of note, the Dhamne review concluded that for short exposure of a session, the sound pressure level does not exceed Occupational Safety Hazard permissible thresholds [35].

The TMS treatment can produce scalp discomfort [35,58,59]. This is location and intensity dependent, and patients generally develop tolerance to this over the first two weeks. As a result, in patients that are highly sensitive, many clinicians use a gradually escalating dose of TMS over the first week.

Outcome evaluation

We recommend that objective documentation of clinical benefit be obtained as a routine practice in a TMS service in order to document changes and provide data for making clinical decisions. This is important for ongoing clinical care and may be required by payers for insurance approval. Several validated patient-reported outcome measures of depression symptoms are available in the public domain, along with their methods of scoring. A majority of cTMSs members use either the Patient Health Questionnaire, 9-Item scale (PHQ-9; 49; http://www.depression-primarycare.org/clinicians/toolkits/materials/forms/phq9/), the Inventory of Depression Scale – Self Rated (IDS-SR) [60] or the Beck Depression Inventory [61].

Clinical recommendations

Indicated Patient Population: The labeled indication for use for the TMS therapy states that, “TMS therapy is indicated for the treatment of Major Depressive Disorder in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode.”

In clinical descriptive terms, patients for whom TMS therapy is indicated demonstrated the following demographic and clinical features in the three major published, randomized controlled trials:

Moderate to severe treatment resistance in the current treatment episode – Patients had received 1–4 adequate antidepressant medication attempts and a range of 1–23 total antidepressant attempts. Among all of these treatment attempts, a patient had received at least one antidepressant medication at a research-grade level of exposure adequacy (i.e. adequate dose and duration) in order to formally establish evidence of resistance to pharmacological interventions in the current illness episode. The majority of clinical TMS society members reported that a “sufficient trial” means one with adequate dose and duration of at least 6–8 weeks and antidepressant failure from an adequate trial or intolerance of antidepressants provided over a shorter duration.

The OPT-TMS trial and the Brainsway Deep TMS trial also included patients who were treatment intolerant (i.e. had tried antidepressant medications but were unable to receive a full dose due to emergent side effects). The total lifetime number of antidepressant medication treatment exposures was not limited in these clinical studies.

A recurrent course of illness – More than 95% of patients had experienced prior illness episodes. The average patient age was approximately 49 years, constituting an average age about a decade older than typical for a first-episode depression population.

Moderate to severe illness severity (symptoms and functional disability) at initial clinical evaluation where work productivity reflected significant functional morbidity. Nearly 50% of patients were currently unemployed due to their illness and about 30% were receiving disability due to their current illness.

Based on the published evidence summarized in this clinical guideline, the cTMSs affirms the following recommendations for the routine use of TMS in clinical practice. Each recommendation is graded in a manner that follows the format of the Grades of Recommendation framework published by the University of Oxford Centre for Evidence Based Medicine.

Recommendation 1: TMS therapy is recommended as an acute treatment for symptomatic relief of depression in the indicated patient population.

Statement of specific recommendation for use: TMS therapy should be considered in patients who present with a clinical diagnosis consistent with DSM-5 defined Major Depressive Disorder, single or recurrent episode, or equivalent nosology and for whom antidepressant medication has not provided a satisfactory clinical benefit, or for whom intolerance to medications precludes their use. TMS therapy should be administered in a standard protocol of high-frequency, left prefrontal treatment as specified in the product labeling, though other treatment parameters can be used based on clinical considerations for a specific patient and the judgment of the provider. The standard parameter set described in each product labeling was studied in three Level 1 randomized controlled trials and provided clinical benefit in treatment courses up to 6 weeks in duration. Controlled studies of longer duration, acute treatment courses or using alternative treatment parameters are not established.

Strength of the recommendation: A, consistent evidence from Level 1 studies

Principal Supporting Evidence: O’Reardon et al. [6] [Level 1b – Individual RCT]; George et al. [7] [Level 1b – Individual RCT]; Levkovitz et al. [8] [Level 1b – Individual RCT]

Additional Expert Consensus Comments: The cTMSs guideline committee considers the following comments to be appropriate considerations as additional guidance in the application of this recommendation. This is based on the consensus review of the committee members and input from members of the society with applied TMS clinical experience:

• Extended treatment course: While the peer-reviewed studies demonstrate that the majority of patients who receive acute benefit from TMS therapy do so within 4–6 weeks, it is reasonable to continue treatment beyond 6 weeks in specific circumstances. For example:

  • In patients who experience only partial improvement and the clinician believes that a clear plateau of benefit has not been obtained, it might be appropriate to extend the course of treatment for one or two weeks.

  • For patients who have had no meaningful benefit after 6 weeks, but who have a history of late response to antidepressant treatment in prior episodes, have a lengthy duration of the present episode, or are highly treatment resistant; clinical experience suggests that continuing the course of acute treatment beyond 6 weeks may be indicated, but with likely low probability of success.

• These considerations are further justified by the absence of any known cumulative toxicity with extended exposure to TMS [12,19,62,63] and because of open-label data supporting the potential for late response in some patients. In clinical TMS practice and in one case series [15], there is documented evidence of eventual remission at 10 weeks in patients who failed to show any clinical response at the end of 6 weeks.

Recommendation 2: TMS therapy is recommended for use as a subsequent option in patients who previously benefited from an acute treatment course and are experiencing a recurrence of their illness (continuation or maintenance).

Statement of specific recommendation for use: TMS therapy should be considered in patients who present with a clinical diagnosis consistent with DSM-5 defined Major Depressive Disorder, single or recurrent episode, or equivalent nosology and for whom a prior course of TMS therapy has provided satisfactory clinical benefit in an earlier episode of their illness. Evidence of satisfactory clinical benefit should have been verified with standardized, validated clinical depression rating scales. Examples of such scales include the Patient Health Questionnaire, 9-Item Scale or the Quick Inventory of Depressive Symptoms, Self Report version. The strongest evidence supports high-frequency treatment over the left DLPFC. Early studies used measurement based approaches to placing the coil relative to the motor cortex. These were found to miss the target in about 30% of patients. More recent studies use placement strategies that adjust for the patient’s skull size [64]. There are intriguing research leads but no strong clinical data to suggest that neuronavigation from MRI improves outcome [65–71]. The standard parameter set described in the product labeling was studied in three Level 1 randomized controlled trials and has demonstrated clinical benefit in treatment courses up to six weeks in duration. Controlled studies of longer duration or using alternative treatment parameters are not clearly established.

Strength of the recommendation: A, consistent evidence from Level 1 studies

Principal Supporting Evidence: Level 1b [6–8]

Additional Expert Consensus Comments: The cTMSs Guideline committee considers the following comments to be clinically appropriate considerations as additional guidance in the application of this recommendation, based on the consensus review of the Guideline committee members and input from members of the Society with applied clinical TMS therapy experience:

• Extended treatment course: (see above following recommendation #1)

Recommendation 3: TMS therapy can be administered with or without the concomitant administration of antidepressant or other psychotropic medications.

Statement of specific recommendation for use: TMS therapy should be considered in patients who present with a clinical diagnosis consistent with DSM-5 defined Major Depressive Disorder, single or recurrent episode, or equivalent nosology and for whom antidepressant medication treatment has provided an unsatisfactory clinical benefit. TMS therapy should be administered in a standard protocol of high frequency, left prefrontal treatment.

TMS therapy can be administered in the presence or absence of concurrent antidepressant or other psychotropic medications. There are currently no data from controlled trials supporting the use of medications with TMS, but there is currently no evidence of an increased risk of adverse events by combining medications with TMS. Any change in medications during the course of TMS therapy should prompt consideration for reassessment of the patient’s motor threshold to ensure that there are no significant changes in this parameter.

Strength of the recommendation: B, Extrapolation from Level 2 studies

Principal Supporting Evidence: Carpenter et al. [13] [Level 2b – individual cohort study]

Additional Expert Consensus Comments: The cTMSs guideline committee considers the following comments to be appropriate considerations as additional guidance in the application of this recommendation. A majority of members recommend continuing extant medications during TMS therapy. Most members refrained from medication taper during the acute TMS course.

Recommendation 4: TMS therapy can be used as a continuation or maintenance treatment for patients who benefit from an acute course.

Statement of specific recommendation for use: TMS therapy can be considered for intermittent use on an empirical basis as a continuation treatment for patients who responded to a prior standard acute course of treatment administered consistent with Recommendations 2 or 3. At the present time, the only controlled trial with TMS therapy that establishes a specific continuation regimen is the Brainsway multi-center trial, which included 12 weeks of biweekly Deep TMS treatment. A majority of cTMSs members use maintenance medications and psychotherapy, considering continuation or maintenance TMS therapy when other established methods of maintenance antidepressant therapy fail to provide a satisfactory sustained pattern of clinical benefit or a patient has a history of frequent relapse (two or more in one year). Further considerations in support of continuation or maintenance TMS therapy are based on current expert consensus opinion and are discussed below.

Strength of the recommendation: A, consistent evidence from Level 1 studies

Supporting Evidence: Levkovitz et al. [8] [Level 1b studies]

Additional Expert Consensus Comments: The cTMSs guideline committee considers the following comments clinically appropriate considerations as additional guidance in the application of this recommendation. In terms of avoiding relapse, the majority of cTMSs members use maintenance medications and psychotherapy. Some members consider continuation or maintenance TMS or both when a patient has a history of frequent relapse (two or more in one year). cTMSs members reported that they typically administer continuation or maintenance treatments, one session at a time either monthly, biweekly or weekly; or they titrate the frequency to the patient’s response.

Recommendation 5: TMS therapy can be reintroduced in patients who are relapsing into depression after initially responding to TMS treatment.

Statement of specific recommendation for use: Should relapse occur in patients who benefitted from an acute TMS course, it is recommended that TMS should be reintroduced until remission is re-achieved. The first study that assessed TMS reintroduction involved the 24-week naturalistic follow-up study [16] that recruited (n = 99) partial responders to acute TMS (i.e. 25% decrease from the baseline HAMD17) in the first Neuronetics-sponsored multicenter trial [6]. These patients were tapered off TMS, started on maintenance antidepressant monotherapy, and followed for a 6-month period. During this period, 10% (10/99) (Kaplan–Meier survival estimate = 12.9%) of patients relapsed (mean time ~23.5 weeks) and another 38.4% (38/99) (Kaplan–Meier survival estimate = 40%) patients met criteria for symptom worsening (at least 1-point decrease in Clinical Global Impression scale over 2 weeks). The latter group received adjunctive TMS and 32/38 (84.2%) re-achieved symptomatic benefits. The mean time for first TMS reintroduction was 109 (±5) days and the mean number of sessions was 14.3 (SD = 9.3). The more recent study by Phillips found high rates of response in previous TMS responders or remitters (78% in those getting scheduled TMS, and 63% in those in the watch and wait group) [37].

Strength of the recommendation: B, Extrapolation from Level 2 studies

Principal Supporting Evidence: Janicak et al. [12] [Level 2b – open label study]

Additional Expert Consensus Comments: Most (90%) of cTMSs members reintroduce TMS during early relapse when symptoms worsen beyond mild severity while only a few (10%) wait until full relapse occurs. Most cTMSs members provided 3–5 treatments per week until response or remission is reestablished. The length of TMS introduction was brief (1–3 weeks) if TMS was reintroduced early in relapse. Most cTMSs members rechecked the motor threshold and location prior to TMS reintroduction.

Partial and non-responders

In non-responders who have completed four to six weeks of treatment, most cTMSs members terminate treatment after extending treatment by one to two additional weeks of daily TMS. A smaller percentage of members ceased treatment immediately after six weeks. In partial responders who complete the acute phase of six weeks, most cTMSs members either extend the course but maintain the same protocol or extend the course after altering the protocol (i.e. changing dose and/or location or extending the number of days between treatments). Most cTMSs members do not extend the acute course beyond six weeks unless the patient is a partial responder who has not yet achieved maximum benefit.

Dr. Tarique Perera, Dr. Mark George, Dr. Geoffrey Grammer, Dr. Philip G. Janicak and Dr. Alvaro Pascual-Leone drafted a White Paper using published (and submitted) data and product labeling information gathered from the first two manufacturers with FDA approval in the USA (Neuronetics, Inc. and Brainsway Corp.), with newer information from MagStim. Additional contributors to this document were Dr. Aron Tendler, Dr. Richard Pitch, Dr. Kevin Kinback, Dr. James Barbee, Dr. Ian Cook, Dr. Mahmoud Okasha and others. Over 100 edits of the original draft were submitted by board members and incorporated into this document. Dr. Theodore Wirecki coordinated the incorporation of the board and manufacturer edits into the final document, with Dr. George acting as the corresponding author editing the White paper into a format suitable for publication in a journal.