Risk Management Issues in Transcranial Magnetic Stimulation for Treatment of Major Depression


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Risk Management Issues
in Transcranial Magnetic
Stimulation for Treatment
of Major Depression


Philip G. Janicak, M.D.


A determination about the overall effectiveness of any therapy should take into account the therapy’s efficacy, safety, and tolerability and a patient’s willingness to accept and adhere to it. In this chapter, I review the safety and tolerability of repetitive transcranial magnetic stimulation (TMS), focusing on its use for the treatment of depression. In these respects, TMS compares favorably with alternative therapies for major depression, including medications and other neuromodulation approaches such as electroconvulsive therapy (ECT) and vagus nerve stimulation. This low-risk profile is supported by results from numerous preclinical and clinical studies, as well as increasing practical experience since the first TMS device was cleared by the U.S. Food and Drug Administration (FDA) for treatment of depression in 2008 (Rossi et al. 2009). One caveat in interpreting data generated from controlled clinical trials is that the researchers have typically used TMS as a monotherapy. By contrast, clinicians typically use TMS as an adjunct to various medications, potentially altering the risk of certain adverse events (AEs). Overall, TMS has a very favorable safety and tolerability profile when compared with medications (e.g., TMS has minimal systemic effects) and other neuromodulation therapies (e.g., TMS is noninvasive and nonconvulsive). As a result, the retention rates in clinical trials were much better than with standard therapies, further improving the chances of a favorable outcome (see Chapter 4, “Combining Pharmacotherapy With Transcranial Magnetic Stimulation in the Treatment of Major Depression”).


This chapter begins with a description of the initial evaluation process, which should include an appropriate informed consent to facilitate the patient’s decision making regarding TMS. Next, the most common AEs associated with TMS; the uncommon but more serious potential for an inadvertent seizure; specific risks across the life cycle (i.e., TMS during the perinatal period, in children and adolescents, in the elderly); other potential safety and tolerability issues (e.g., auditory changes, potential for tissue injury, cognitive effects); and alternative approaches are discussed.


TMS Evaluation Process


The TMS evaluation process begins with the determination of a patient’s eligibility for TMS. Two crucial components of this process are confirming diagnostic criteria and assessing the patient’s ability to understand and accept the risk/benefit aspects of TMS.


To ensure informed consent after the diagnostic review, adequate time is needed for the professional to describe the components of a TMS device; the motor threshold (MT) determination procedure; a typical treatment session; a typical treatment course; the chances of response and remission; the most common AEs; the potential for a seizure; and other possible risks specific to an individual’s circumstances (e.g., medication regimen, medical history).


To minimize the potential risks associated with TMS, its prescription should be written by a licensed physician or other professional (e.g., an advanced practice nurse) with prescriptive authority. At a minimum, the treating professional and staff should be adequately trained and certified by the TMS device manufacturer. Recent professional consensus guidelines also recommend initial peer-to-peer direct supervision and ongoing, documented educational experiences (e.g., continuing medical education [CME] programs) to maintain and enhance competency (Perera et al. 2016).



























Table 3–1. Transcranial magnetic stimulation: guidelines for safe administration


Guideline


Action


Adequate risk/benefit assessment


Screen for contraindications/warnings


Informed consent


Discuss thoroughly what to expect


No routine labs or imaging required unless indicated


NA


Prescription for TMS


Obtain written prescription from licensed physician or another professional with prescriptive authority



Table 3–1 summarizes the guidelines for safe administration of TMS. These include assessing the risk-benefit ratio for TMS in each patient; securing informed consent; considering the need for laboratory assessments as dictated by a patient’s history (e.g., thyroid function tests, sleep study); and obtaining a specific prescription for the TMS procedure.


Common Adverse Events


The most common AEs associated with TMS include application site discomfort (e.g., scalp pain under the area where the coil is placed) and events due to direct stimulation of neural tissue. Some common examples of the latter events include trigeminal nerve–related pain, contraction of muscles around the eye, lachrymation, and toothaches, all of which occur primarily during delivery of the stimulation train. Tension-like headaches may also occur after a treatment session because of contraction of muscle tissue near the coil (Janicak et al. 2008). See Table 3–2.


Although a majority of patients experience these events, usually they are tolerable and/or progressively subside in intensity during the treatment course because of rapid accommodation and the ability of the technician to alter various treatment parameters (usually temporarily) or to change coil positioning to enhance comfort. As a result, discontinuation due to AEs associated with TMS therapy is relatively low (e.g., ~5% in sham-controlled trials).





































































Table 3–2. Adverse events associated with two transcranial magnetic stimulation (TMS) systems: results from three studies



NeuroStar TMS Therapy System


Brainsway Deep TMS System


Description


Biphasic figure eight with ferromagnetic core


H coil with air core, air cooling


Study participants


N=491 (studies 1 and 2)


N=181


FDA clearance


2008


2013


Deaths/suicides or suicide attempts


Study 1: 1 apparent suicidal gesture (sham patient)


None


Suicide ideation


Study 1: worsening suicidality (1 active patient; 10 sham patients)


Not reported


Common adverse events


Headache and application site pain


Headache and application site pain




15% of the ITT sample were excluded because they were treated at a lower intensity because of presumed intolerability at full intensity


Significant adverse events


Study 1: 16 SAEs (9 active patients; 7 sham patients; primarily symptom worsening)


8 SAEs (4 sham patients; 3 active patients; 1 patient prior to randomization)



Study 2: 3 SAEs (1 patient prior to randomization; 1 active patient with syncope; 1 sham patient with paranoia)


1 SAE considered device related (i.e., a seizure in an active patient)


Cognition


No effects


No effects


Discontinuation rate due to adverse events


~5%


1%


References


Study 1: Janicak et al. 2008


Levkovitz et al. 2015



Study 2: George et al. 2010



Note. FDA=U.S. Food and Drug Administration; ITT=intent-to-treat; SAE=significant adverse event.



Specific strategies to improve tolerability of the TMS procedure include 1) rotating the coil angle, 2) moving the coil slightly more anteriorly or laterally, 3) temporarily lowering the stimulus intensity, and 4) applying lidocaine anesthetic cream to the skin under the coil. Headaches are usually controlled by over-the-counter analgesics, which are taken at the onset of symptoms or before a treatment session to prevent the repeated occurrence of headaches. Occasionally, for patients who continue to experience intolerable AEs, switching to a low-frequency (i.e., 1 Hz or less) stimulation protocol over the right dorsolateral prefrontal cortex (DLPFC) has led to a successfully completed course of TMS (Brunelin et al. 2014).



CLINICAL VIGNETTE


The patient is a 33-year-old man experiencing his second episode of major depression. During his previous episode, at age 22, he had difficulty tolerating several trials of medication, which contributed to a worsening of his symptoms, particularly more severe suicidality. He then had a course of ECT, to which he responded, but he also experienced significant memory loss that took several months to clear. He now requests a trial of TMS in the hope that it will resolve this episode without his having to undergo poorly tolerated medication trials or another course of ECT and the resultant memory problems. Of note, the patient is presently experiencing only passive suicidality and has no psychotic symptoms. He initiates a course of TMS but experiences substantial application site pain, which is ameliorated with a reduction in his MT level to 100%. Over the next five sessions, the level is gradually increased as tolerated to the targeted 120% of MT. After a successful course of acute TMS, based on improvement in his scores on the 9-item Patient Health Questionnaire (PHQ-9), the patient’s clinician prescribes maintenance cognitive-behavioral therapy as well as TMS sessions at a frequency determined by a gradual reduction protocol over several weeks.


Seizure Risk With TMS


Although seizure risk is the most serious potential TMS-related AE, seizures are uncommon. The most recent data indicate an estimated risk of less than 0.1% over an entire treatment course (typically 20–30 sessions) (Dobek et al. 2015).


Of note, all documented TMS-induced seizures have occurred during treatment sessions. The risk of seizures during TMS compares favorably with risks from various psychotropic medications (e.g., antipsychotics, tricyclic antidepressants, bupropion) used to treat depression. Paradoxically, a recent systematic review indicates that TMS may suppress episodes in patients with epilepsy (Pereira et al. 2016). Although a patient’s history of seizures or a seizure disorder does not pose an absolute contraindication to TMS, this issue should be carefully explored with the patient and appropriately addressed. Safeguards may include discontinuation of medications, which can lower the seizure threshold; adjustment in anticonvulsant medications to ensure adequate control; and consultation with a neurologist.


Minimizing the risk of seizures begins with a careful assessment of factors that can increase seizure potential. These include a history of prior head injuries, stroke, brain lesions (e.g., vascular, traumatic, infectious), and/or seizure events; recent sleep deprivation; and the use of medications, alcohol, or other substances that may lower the seizure threshold. Administering TMS treatments within the recommended parameters (e.g., frequency, intensity, coil location, train duration, intertrain interval) is a crucial step in minimizing seizure risk. Because adhering to the suggested parameters may not always be possible, when parameters go beyond standard settings, patients should be informed of a potentially higher risk for a seizure.


After the initial assessment and appropriate modification of risk factors, it is important that staff frequently re-inquire about any changes in the patient’s status during the course of treatment. A corollary to such monitoring is the need for ongoing communication with the patient’s support system and primary treatment team. Table 3–3 includes a list of issues to be assessed prior to initiating TMS.


If confronted with a possible event, the treatment staff should clarify whether it is a vasovagal syncope, which may be more common than and can mimic some aspects of a seizure. Because of the possibilities of seizures and syncopal events, it is important that a licensed provider always be available on site for consultation when treatments are being provided. Furthermore, first-response training to manage a seizure episode is mandatory for all treating staff. Additionally, it is critical that the technician who typically administers the treatments has the appropriate background and training and is present throughout a session to monitor the patient. Although technicians’ backgrounds may vary, many are medically trained (e.g., registered nurses, licensed practical nurses, emergency medical technicians) and adept in techniques to maintain airway, breathing, and circulation. Because some sites use technicians with no formal credentials or licensure, however, additional training may be necessary.


Reports of TMS-related seizure events indicate that a relatively short time passes before spontaneous resolution (e.g., ~60 seconds) with no residual neurological or medical sequelae. Therefore, there is some debate about the need for on-site emergency equipment (e.g., oxygen, suction, intravenous medications). Regardless, the most important protective steps to prevent complications when a syncopal or seizure event occurs include stopping the TMS session; positioning the chair and the patient to prevent falls, asphyxiation, and aspiration; and calling for emergency personnel. Venous access and anticonvulsants may also be available but are not typically needed.





































Table 3–3. Issues to address prior to transcranial magnetic stimulation (TMS)


Patient’s history


 Epilepsy or seizure


 Fainting spell(s) or syncope


 Head trauma, concussion, or loss of consciousness


 Hearing problems, ringing in the ears


 Prior TMS treatment and any associated problems


 Prior magnetic resonance imaging and any associated problems


Patient’s current conditions


 Presence and type of metal substance in the brain, skull, or elsewhere in the body


 Presence of implanted device (e.g., cochlear implant, direct brain stimulation device, vagus nerve stimulation device)


 Presence of cardiac pacemaker or intracardiac lines


 Presence of medication infusion device


 Current medications


 Pregnancy


Source. Adapted from Rossi et al. 2011.


Finally, all TMS centers should have an approved seizure policy and procedure that has been thoroughly reviewed by treating personnel and is kept in a readily accessible location.



CLINICAL VIGNETTE


The patient is a 45-year-old woman with a 20-year history of recurrent major depression. Her present episode has lasted 2 years and, unlike her previous episodes, has not adequately responded to standard medication and cognitive-behavioral therapy trials. She has no psychotic symptoms and only passive thoughts of suicide with no intent or plan. A course of TMS is deemed appropriate, but her present medication regimen includes nortriptyline (150 mg/day) plus aripiprazole (5 mg/day) for augmentation, and the patient has increased her daily alcohol use to manage her mood symptoms and medication-related AEs. Her medications, as well as her increased alcohol consumption and possible related withdrawal phenomena, can lower the seizure threshold. Because the patient reports anxiety/akathisia but no benefit from aripiprazole, the medication is stopped for 2 weeks prior to assessment of the patient’s MT. She is also started on lorazepam (1 mg twice daily) and naltrexone (50 mg/day) to control her anxiety/akathisia, to counteract any symptoms associated with her agreed-on cessation of alcohol, and to decrease cravings. While continuing her nortriptyline, lorazepam, and naltrexone, the patient successfully completes her course of TMS without incident.

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Mar 17, 2020 | Posted by in PSYCHIATRY | Comments Off on Risk Management Issues in Transcranial Magnetic Stimulation for Treatment of Major Depression
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