Current FDA-Cleared TMS Systems and Future Innovations in TMS Therapy


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Current FDA-Cleared
TMS Systems and
Future Innovations
in TMS Therapy


Ian A. Cook, M.D., DFAPA


Treating patients with transcranial magnetic stimulation (TMS) demands the use of a system that is capable of generating magnetic fields with the desired spatial and temporal characteristics to stimulate the intended brain structures. There are many ways to construct a TMS system that can meet those requirements, and in this chapter, I review some technologies that have been developed into clinically available products. Before I delve into these specifics, however, some consideration of the bigger picture is in order.



In the United States, TMS systems are among the medical devices regulated by the U.S. Food and Drug Administration (FDA), specifically by the Center for Devices and Radiological Health. The FDA reviews information provided by manufacturers of therapeutic medical products to assess their safety and efficacy in treating specific medical conditions. At the present time, there are five manufacturers with FDA clearance to market therapeutic TMS systems in the United States, all for use in treating depression. Patients and physicians in other countries may be able to use different TMS systems because each jurisdiction has its own rules and regulations regarding legal access to these medical devices.


Although the FDA may regulate how manufacturers make their products available in the United States, licensed physicians may practice medicine by using a product as intended (“on-label”) or in alternative ways (“off-label”) that are consistent with their understanding of the best ways to treat their own patients (i.e., the FDA “does not regulate the practice of medicine,” per Wittich et al. [2012, p. 982]). A physician uses a product on-label by adhering to the written information regarding use, relying on instructions that the manufacturer has developed and the FDA has reviewed. Normally, this may include use for a specified clinical condition or indication and adhering to the specified dosing, as detailed in the “package insert” document that accompanies medications or the “instructions for use” manual that accompanies devices. Examples of an off-label use include prescribing a product to treat a different condition (e.g., using TMS to treat bipolar depression or tinnitus) and using different parameters (e.g., prescribing a medication dose that is outside the range in the package insert, providing TMS treatment at a frequency not in the “instructions for use” manual). The FDA bases its labeling decisions on the data that are provided for review. Therefore, the boundary between on-label and off-label use could reflect an absence of data (e.g., if no manufacturer has submitted studies using a 1-Hz repetition rate), or there could be data indicating the absence of a demonstrated effect (e.g., failed trials for treating some clinical condition, which would not be submitted for review).


The biomedical literature may describe findings of safety and effectiveness from encouraging research trials of TMS devices used in ways outside current labeling, but practitioners should remember that health care payers may have coverage policies that limit access for off-label TMS treatment. This is often a “moving target,” with policies and restrictions that change, and inquiry ahead of treatment is important to determine what coverage policy may apply to a given patient at a given time.



This emphasis on dry regulatory considerations is relevant at the outset of this chapter for two reasons: First, it is important for clinicians to understand the tools they use (i.e., the tools’ capabilities and where use crosses from on-label to off-label parameters). Second, to present reliable facts about the devices, I have derived much of the information on specific products from the legally reviewed documents the manufacturers submitted to the FDA, supplemented by information from the peer-reviewed medical literature. Some information in the remainder of this chapter concerns principles that are common to all the legally marketed devices, whereas other information may be unique to a particular system.


Contextual Notes From Foundational Biophysics


Regardless of manufacturer, all five current TMS systems rely on the principle of magnetic induction, first described by Michael Faraday in 1831 and independently (re)discovered by Joseph Henry in 1832. A common representation of Faraday’s law, as part of the Maxwell-Faraday equation, states that a time-varying magnetic field will always accompany a spatially varying electrical field, and vice versa, expressed mathematically as


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where E is the electrical field, B is the magnetic field (both fields being functions of both position and time), and ×E denotes the curl vector field operator. In the context of clinical TMS systems, what this means is that a changing magnetic field will generate an electrical field and a current in a conductive medium, such as brain structures or scalp tissue.


When the electrical field and current are of sufficient magnitude, a neuron in the field will become depolarized and an action potential will propagate along its axon. Once a neuron has become depolarized and has “fired” with an action potential, it cannot fire again until its refractory period is over. Thus, there is a physiological limit to how fast the magnetic field can change to produce a series of distinct nerve impulses. Because the neuronal depolarization phenomenon is nonlinear, a neuron does not fire more intensely if the stimulation is markedly larger than that needed to produce a depolarization rather than just minimally above threshold. Pragmatically, stimulating at levels in excess of the motor threshold does not make the specific neurons in the target region fire “harder,” but it does serve to increase the volume in space in which the depolarization threshold is met or exceeded (and thus may cause additional, unintended brain circuits to be stimulated).


Design of TMS Systems


All the devices that have FDA clearance as TMS systems (as of February 2017) share at least two common elements:




  • A coil to generate the time-varying magnetic field



  • A microprocessor-controlled source of electrical energy


There are numerous approaches to coil design, such as variations in the size and shape of the coil and use of ferromagnetic materials (to alter the field properties) versus an air core design. The following coils are commercially available for clinical use as part of the cleared TMS systems:




  • Figure-eight coil with a ferromagnetic core (Neuronetics)



  • H coil (Hesed coil) with an air core (Brainsway)



  • Figure-eight coil with an air core (Magstim, MagVenture, and Neurosoft)


Other coils, such as circular coils, are also available for research or other purposes. Coils can differ considerably in the electrical fields they induce. For example, a circular coil has maximum intensity in the tissue directly under the coil windings, whereas a figure-eight coil can be configured so that magnetic fields add at the crossing point of the “8,” yielding a focal area of high intensity that can be “aimed” at specific neuroanatomical targets (Figure 10–1).


A comprehensive examination of the surface electrical field patterns with 50 coil designs was conducted by Deng et al. (2013) at Duke University. A comparison of the fields from an air core figure-eight coil, a ferromagnetic core figure-eight coil, and an H1 coil can be seen in Figure 10–2. Although visual inspection illustrates how different the patterns may be, the clinical relevance of these differences can best be assessed only through head-to-head trials, but such work has not yet been conducted.


It is noteworthy that heat is generated in the coils, in proportion to the resistance of the conductor and to the square of the current (i.e., I2R heating losses). Dissipation of the heat produced in the coil is addressed in current products by passive air cooling, by forcing air to flow over the coil assembly, or by circulating a liquid coolant. Tales from the early days of TMS describe cooling the coils in buckets of ice water (M. George, personal communication, 2016).


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Figure 10–1. Fields induced by circular versus figure-eight coils.


See Plate 6 to view this figure in color.
Electrical field intensity is displayed by both height and color.
Source. Based on Cohen et al. 1990 and Thielscher and Kammer 2002.


The first report of a clinically useful TMS system is generally recognized as that by Anthony Barker and colleagues from the University of Sheffield in the United Kingdom (Barker et al. 1985). That device was initially developed as a diagnostic tool for performing neurological evaluations. Stimulation of the motor cortex with single magnetic pulses could elicit motor activity in terms of involuntary muscle contractions, and this system could also be used to interrogate the integrity of motor outflow tracts. Other uses soon followed, such as applying single pulses to produce a transient disruption in normal neuronal activity (a “virtual lesion”) in order to study the physiology of normal and pathological brain function (see Pascual-Leone et al. 2000). Therapeutic use depended on the development of systems that could safely produce sustained trains of repetitive pulses, and the first case of psychiatric treatment with repetitive TMS (rTMS) was reported by Mark George and colleagues at the National Institute of Mental Health (George et al. 1995).


Although the sophistication of TMS systems has since evolved considerably, the fundamental elements of the electronics continued to consist of a means to store a large amount of electrical energy (e.g., a capacitor); a means to charge it; a means to discharge the energy rapidly through the coil; and a means to produce these pulses in a controlled, regular pattern (Cowey 2005). Contemporary designs employ microprocessor circuits to control the system and provide other useful features (e.g., for monitoring progress during a treatment session, for monitoring the temperature of the coil) instead of the analog circuits used initially.


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Figure 10–2. Electrical fields from three example coil designs.


See Plate 7 to view this figure in color.
(A) Figure-eight coil, air core; (B) figure-eight coil, ferromagnetic core; and (C) H1 coil, air core.
Source. Adapted from Deng et al. 2013.



TMS Devices With FDA Permission to Market in the United States


The FDA provides the following definition of an rTMS system:


A repetitive transcranial magnetic stimulation system is an external device that delivers transcranial repetitive pulsed magnetic fields of sufficient magnitude to induce neural action potentials in the prefrontal cortex to treat the symptoms of major depressive disorder without inducing seizure in patients who have failed at least one antidepressant medication and are currently not on any antidepressant therapy (21 CFR 882.5805 [Code of Federal Regulations]).


This definition applies to all currently marketed rTMS products, categorized as Class II—special controls. By this definition, an rTMS system is not implanted; it induces action potentials without inducing a seizure, so it is distinct from devices for electroconvulsive therapy (ECT; covered in 21 CFR 882.5940); it targets the prefrontal cortex; it is intended for use in patients with major depressive disorder with at least one treatment failure; and it is intended to be used as stand-alone or monotherapy, as opposed to a treatment added onto pharmacotherapy. However, clinicians commonly use TMS as an adjunct for patients already prescribed psychotropic medication(s) (e.g., Carpenter et al. 2012).


Therapeutic TMS devices have been cleared for marketing in the United States via a so-called “510(k)” regulatory pathway. The regular 510(k) pathway allows for clearance for a low- to moderate-risk device for which there is “substantial equivalence” in safety and effectiveness to another lawfully marketed device (a “predicate” device); the de novo 510(k) pathway allows for approval of low- to moderate-risk devices for which general controls or general and special controls provide reasonable assurance of safety and effectiveness but for which there is no legally marketed predicate device.


NEURONETICS: NEUROSTAR TMS THERAPY SYSTEM


In late 2008, Neuronetics, Inc. (Malvern, Pennsylvania) was the first company to receive FDA clearance for a therapeutic TMS device, the NeuroStar TMS Therapy System. Table 10–1 summarizes the key parameters of the device, which is depicted in Figure 10–3. This system was approved in part on the basis of a pivotal trial, in which 301 adults who had not benefited from prior antidepressant medications were randomly assigned to active or sham treatment (Avery et al. 2008; Janicak et al. 2008; O’Reardon et al. 2007). Sessions were conducted five times/week with TMS at 10 pulses/second, 120% of motor threshold, and 3,000 pulses/session for 4–6 weeks. The primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Åsberg Depression Rating Scale (MADRS); secondary outcomes included changes on the Hamilton Depression Rating Scale (HDRS) and response and remission rates with both scales.





































































Table 10–1. Description of the Neuronetics NeuroStar TMS Therapy System


Product name


NeuroStar TMS Therapy System


FDA status


510(k) de novo clearance K061053, October 2008


Related FDA actions


DEN070003, October 7, 2008



K083538, December 16, 2008



K130233, April 30, 2013



K133408, March 28, 2014;



K160703, June 10, 2016



K161519, September 11, 2016


Coil


Biphasic figure-eight coil with ferromagnetic core


Pulse parameters approved


185-microsecond pulse width



10-Hz repetition rate



4-second train duration



26-second intertrain interval



3,000 pulses/session, over 37.5 minutes


Device capabilities


Repetition rate 0.1–30 Hz



Magnetic field intensity 0.22–1.6 standard motor threshold units



Train duration 1–20 seconds



Intertrain interval 10–60 seconds


Elements of system, as described in FDA 510(k) filing


Mobile console with electronics


Treatment coil


Gantry that supports treatment coil


Head support system with laser guidance


SenStar Treatment link for contact sensing and monitoring magnetic field and surface field cancellation


Source. Information derived from U.S. Food and Drug Administration (FDA) filings (www.accessdata.fda.gov/cdrh_docs/pdf6/K061053.pdf).



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Figure 10–3. NeuroStar TMS Therapy System.


Source. Image courtesy of Neuronetics, Inc.


The NeuroStar TMS Therapy System contains a number of patented features related to system design and user interface. A patented figure-eight coil with a ferromagnetic core is encased in a housing shaped to fit over the prefrontal area of the head—that is, over the target used in the pivotal trial—and is attached to a movable gantry with a gravity compensation mechanism. The use of an iron core promotes heat dissipation and eliminates the need for an external cooling system. It also increases the energy efficiency of magnetic field generation, with implications for the engineering design of the electronics that drives the coil. The shape of the coil housing may limit ease of use in stimulating brain regions other than the prefrontal cortex. The included treatment chair allows for multiple preprogrammed configurations related to height, degree of recline, and lumbar/leg support. The attached head support system can be adjusted for patient comfort and helps to prevent inadvertent head movement during treatment. Coil position is replicated from one treatment session to another using a built-in system of coordinates. The SenStar Treatment Link serves as a patient interface and performs several functions, including contact sensing and magnetic field detection. The MT Assist proprietary clinical software implements an algorithm to assist the operator in determining the motor threshold. The touch screen monitor allows entry of individual patient treatment parameters, coil position, and chair settings for future recall. The monitor also provides visual feedback to the operator regarding coil contact and alignment as well as real-time reporting of each treatment session, including elapsed time and number of pulses delivered.


The introduction of this system in 2008 was followed by critical work securing appropriate Current Procedural Terminology codes from the American Medical Association for demonstrating use of TMS procedures, which then facilitated the writing of coverage policies for TMS treatment by health care payers.


In a subsequent FDA 510(k) approval action, the stimulation parameters for on-label use were modified to allow for an intertrain interval (ITI) of between 11 and 26 seconds. Using the standard pulse train duration of 4 seconds, the new ITI changes the minimum cycle time from 30 seconds to 15 seconds, and thus the time for a 3,000-pulse treatment changes from 37.5 minutes to 18.75 minutes. It appears likely that other manufacturers may also seek 510(k) approvals for this change in ITI.


BRAINSWAY: DEEP TMS SYSTEM


The second product to receive FDA clearance as a therapeutic TMS device was the Deep TMS System from Brainsway, Inc. (Jerusalem, Israel, and Hackensack, New Jersey), cleared in early 2013. Table 10–2 summarizes the key parameters of the Brainsway Deep TMS System, depicted in Figure 10–4. This device uses a different coil design intended to produce deeper stimulation (see below) and also different stimulation parameters from the Neuronetics device; it was approved in part on the basis of a pivotal randomized clinical trial (Levkovitz et al. 2015) that recruited 212 adults with major depression. Twenty sessions of deep TMS at 18 Hz over the prefrontal cortex were administered for 4 weeks, and then sessions continued biweekly for 12 weeks. The primary outcome measure was the change in the HDRS score, and the secondary outcome measures were response and remission rates at week 5.



















































Table 10–2. Description of the Brainsway Deep TMS System


Product name


Brainsway Deep TMS System


FDA status


510(k) clearance K122288, January 7, 2013


Coil


H coil with air core, air cooling


Pulse parameters approved


370-microsecond pulse width



18-Hz repetition rate



2-second train duration



20-second intertrain interval



1,980 pulses/session, over 20.1 minutes


Device capabilities


Repetition rate 0.02–30 Hz



Magnetic field intensity 0.6–1.4 standard motor threshold units



Train duration 1–20 seconds



Intertrain interval 10–60 seconds


Elements of system, as described in FDA 510(k) filing


TMS neurostimulator


Electromagnetic coil (H1)


Cooling system


Positioning system


Source. Information derived from U.S. Food and Drug Administration (FDA) filings (www.fda.gov/cdrh/510k/K122288.pdf)).


The Deep TMS System also has a uniquely designed treatment coil. The Hesed H1 coil is contained within a helmet-like housing that fits over the patient’s head. Coil windings run tangential to the head in a unique pattern and provide convergent electrical fields from various directions (Roth et al. 2002). This coil design is intended to produce an electrical field that can depolarize neurons at a greater depth but with a more diffuse field than is possible with devices using the figure-eight coil. With this system, treatment parameters are entered using a dial and touch screen. A monitor provides real-time reporting of each treatment session, including elapsed time and number of pulses delivered. The patient sits in an upright position, and any comfortable chair may be used.


Brainsway has developed a series of unique coil designs, each intended to concentrate the magnetic field toward particular anatomical targets (e.g., bilateral prefrontal cortices, primary motor cortex) (Advanced Mental Health Care 2012). At present, only the H1 coil is cleared by the FDA for clinical use, and other designs are investigational products at this time. This system is also unique in receiving FDA clearance based on a trial that used 18-Hz stimulation and treatment sessions comprising 1,980 pulses in 20.1 minutes; in contrast, the other four TMS systems detailed in this chapter were initially cleared based on data with 10-Hz stimulation and 3,000 pulses in 37.5 minutes, as in the original pivotal trial by Neuronetics (O’Reardon et al. 2007). The FDA’s recent revisions to allow 3,000 pulses at 10 Hz to be delivered in 18.75 minutes (ITI=11 seconds) has reduced this differentiation.



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Figure 10–4. Brainsway Deep TMS System.


Source. Image courtesy of Brainsway, Inc.



MAGSTIM: RAPID2 THERAPY SYSTEM


In 2015, the third rTMS therapeutic system to receive FDA clearance was the Rapid2 Therapy System from the Magstim Company, Ltd. (Whitland, United Kingdom, and Morrisville, North Carolina). Of note, this company received clearance for a single-pulse TMS stimulator device for peripheral nerve stimulation use in 2000 (K992911) and historically traces its corporate lineage to Novametrix Medical Systems, the company that sought to commercialize the original work by A. Barker, I.L.Freeston, R. Jalinous, and M. Polson at the University of Sheffield in the 1980s (see www.magstim.com/heritage); many of the clinical studies prior to the NeuroStar system’s clearance were done using Magstim equipment. Table 10–3 summarizes the key parameters of this device, which is shown in Figure 10–5. This device was cleared on the basis of substantial equivalency to the NeuroStar system without an additional clinical trial.


A figure-eight coil with an air-cooled system is used for treatment and is attached to an articulated stand without gravity compensation. Multiple pulse frequencies are possible. An optional lightweight, handheld coil is available for use in motor threshold determination; pulses can be triggered by a push-button switch on the coil unit. Coil position is replicated from one treatment to another by using a cap marked to show coil location or some other method such as an electroencephalographic montage net placed on the patient’s head. An optional adjustable chair with headrest is available. Treatment parameters are entered using a dial and touch screen; storage of individual patient treatment parameters is not possible with current software (as of early 2017). The computer display provides real-time reporting of the parameters of each treatment session, including elapsed time and number of pulses delivered. Contact sensing is not available. In addition to the standard figure-eight coil that was cleared by the FDA for therapeutic use, other coil designs are available to allow flexibility for research purposes.


MAGVENTURE: MAGVITA TMS THERAPY SYSTEM


The fourth TMS system with FDA clearance (awarded July 2015) is the MagVita TMS Therapy System from MagVenture A/S (Farum, Denmark, and Alpharetta, Georgia). MagVenture’s sibling company, Tonica Elektronik A/S, received FDA clearance for peripheral nerve magnetic stimulators in 1993 (K926516, to Dantec Medical, their U.S. affiliate), but this was for use as a diagnostic tool only. Table 10–4 summarizes the key parameters of this device, which is shown in Figure 10–6. This device was cleared on the basis of substantial equivalency to the NeuroStar system without an additional clinical trial.






















































Table 10–3. Description of the Magstim Rapid2 Therapy System


Product name


Rapid2 Therapy System


FDA status Related FDA actions


510(k) clearance K143531, May 8, 2015


Related FDA actions


K162935, March 10, 2017


Coil


Biphasic figure-eight coil, air core, air cooling


Pulse parameters approved


300-microsecond pulse width



10-Hz repetition rate



4-second train duration



26-second intertrain interval



3,000 pulses/session, over 37.5 minutes


Device capabilities


Repetition rate 0.1–30 Hz



Magnetic field intensity 0.28–1.9 standard motor threshold units



Train duration 1–20 seconds



Intertrain interval 10–60 seconds


Elements of system, as described in FDA 510(k) filing


User interface


Mainframe


Power supply


Air film coil


Coil stand


Accessory foot switch


Source. Information derived from U.S. Food and Drug Administration (FDA) filings (www.accessdata.fda.gov/cdrh_docs/pdf14/K143531.pdf).


The MagVita system employs a liquid cooling system to ensure operation within expected parameters during prolonged usage. The coil is attached to an articulated arm without gravity compensation, and a handheld coil is available for use in determining the motor threshold. An optional adjustable chair is available; it employs a special pillow designed to limit head movement. Coil position is replicated from one treatment session to another by using a cap marked to show coil location or some other method such as an electroencephalographic montage net placed on the patient’s head; contact sensing is not available. Treatment parameters are entered using a dial and touch screen; storage of individual patient parameters is not possible. In addition to the figure-eight coil that was cleared by the FDA as part of the therapeutic system, other coils are available to provide flexibility in the research setting.



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Figure 10–5. Magstim Rapid2 Therapy System.


Source. Image courtesy of Magstim Company, Ltd.


NEUROSOFT: NEUROSOFT TMS SYSTEM


The fifth TMS system with FDA clearance (awarded December 2016) is the Neurosoft TMS System from Neurosoft (Ivanovo, Russia; distributed in the United States by Caputron Medical, New York, New York). Table 10–5 summarizes the key parameters of this device, which is shown in Figure 10–7. This device was cleared on the basis of substantial equivalency to the Magstim and MagVenture systems as predicate devices, without an additional clinical trial. The system employs a liquid cooling system to ensure operation within expected parameters during prolonged usage. The coil is attached to an articulated arm without gravity compensation.
















































Table 10–4. Description of the MagVenture MagVita TMS Therapy System


Product name


MagVita TMS Therapy System


FDA status


510(k) clearance K150641, July 31, 2015


Related FDA actions


K170114, May 1, 2017


Coil


Figure-eight coil, air core, liquid cooling


Pulse parameters approved


290-microsecond pulse width



10-Hz repetition rate



4-second train duration



26-second intertrain interval



3,000 pulses/session, over 37.5 minutes


Device capabilities


Repetition rate 0.1–30 Hz (0.1–100 Hz depending on model)



Magnetic field intensity 0–1.7 standard motor threshold units


Elements of system, as described in FDA 510(k) filing


MagPro stimulator and trolley


Coil C-B60 for motor threshold determination


Coil Cool-B65 for treatment with coil cooler unit


Treatment chair


Vacuum pump with vacuum pillow


Flexible arm mounted on trolley


Source. Information derived from U.S. Food and Drug Administration (FDA) filings (www.accessdata.fda.gov/cdrh_docs/pdf15/k150641.pdf).


Vignettes


Three anecdotal vignettes are provided to illustrate the clinical use of these TMS systems. It must be emphasized that there are no published comparative head-to-head effectiveness studies to provide systematic evidence comparing and contrasting treatment with the different systems. Some of the details of the following case vignettes have been altered to respect patient confidentiality and privacy.



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Figure 10–6. MagVita TMS Therapy System.


Source. Image courtesy of MagVenture A/S.



Clinical Vignette


The patient is a 48-year-old woman who had tried over five different antidepressant treatment regimens (monotherapies and combinations) at adequate doses and durations, as well as a course of cognitive-behavioral therapy, all in the current episode. The patient took medical leave from her employer—because of her depression, she was unable to perform her usual job responsibilities—and she was nearing the end of her paid leave period. TMS was a covered benefit under her health insurance policy, and she was referred by her treating psychiatrist to a TMS program. She was evaluated and found to be an appropriate candidate for treatment; she had no prior TMS experience. After discussion with her treating psychiatrist, she began TMS while continuing to take a selective serotonin reuptake inhibitor antidepressant augmented with a second-generation antipsychotic, having voiced a strong preference to continue these agents while receiving TMS “just in case they were helping me more than was apparent.” Treatment was initiated using 3,000 pulses/session at 10 Hz, administered over the dorsolateral prefrontal cortex (DLPFC) target assessed at the F3 electrode site with a system employing a figure-eight coil. Symptoms were monitored weekly with the 30-item Inventory of Depressive Symptomatology—Self-Report (IDS-SR30) and the 9-item Patient Health Questionnaire (PHQ-9). The patient noted symptom improvement in several domains after 10 sessions and further improvement after 20 sessions, and she was in remission around treatment 30. She then received six more tapering treatments, as had been done in the O’Reardon et al. (2007) trial, and was returned to the care of her treating psychiatrist. She was given copies of the IDS-SR30 and PHQ-9 for continued self-monitoring. For continuity of care, the TMS physician contacted the patient’s treating psychiatrist by telephone to clarify the psychiatrist’s understanding of TMS, discuss the empiric desirability of not eliminating pharmacotherapy right after ending TMS (although the patient was eager to stop her medications now that she was well), and discuss the possibility of retreatment in the event of another episode.

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Mar 17, 2020 | Posted by in PSYCHIATRY | Comments Off on Current FDA-Cleared TMS Systems and Future Innovations in TMS Therapy
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