Transcranial Magnetic Stimulation: Scientific Underpinnings and Practical Applications

Transcranial Magnetic Stimulation: Scientific Underpinnings and Practical Applications Jon Draud, MS, MD Clinical Professor of Psychiatry University of Tennessee College of Medicine Memphis, Tennessee Medical Director of Psychiatry Pain Management Group Trust Point Psychiatric Hospital St. Thomas Rutherford Hospital Medical Director and Principal Draud Sudbury Psychiatric Solutions Private Practice Adult and Adolescent Psychiatry Nashville, Tennessee

Disclosure The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance.

Developed in collaboration with the Clinical TMS Society.

The Biology of Depression

The Brain as an Electrochemical Organ Despite the predominance of pharmaceutical agents for the treatment of depression, the monoamine transmitters are only part of the picture of dysfunction when there is Depression Sophisticated forms of brain imaging such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fmri) are permitting scientists to understand the working brain This technology is leading towards understanding which brain regions regulate mood. Areas such as the prefrontal cortex, cingulate cortex, amygdala, the thalamus, and the hippocampus are important in the brain illness that is depression

Major Depression is a Brain Disease PFC = prefrontal cortex. Mark S. George, MD. Images acquired at the National Institute of Mental Health (NIMH, Bethesda, MD), 1994.

Higgins ES, George MS. The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness. Philadelphia, PA: Lippincott; 2007: Chapter 18

STAR*D Study Demonstrated Decreased Remission with Each Treatment Failure STAR*D = Sequenced Treatment Alternatives to Relieve Depression; HAM-D = Hamilton Rating Scale for Depression. Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40. Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917. Fava M, et al. Am J Psychiatry. 2006;163(7):1161-1172. McGrath PJ, et al. Am J Psychiatry. 2006;163(9):1531-1541.

STAR*D Study Demonstrated Decreased Remission with Each Treatment Failure TMS Indicated Here TMS = transcranial magnetic stimulation. Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40. Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917. Fava M, et al. Am J Psychiatry. 2006;163(7):1161-1172. McGrath PJ, et al. Am J Psychiatry. 2006;163(9):1531-1541.

Antidepressant Medications Antidepressants get patients to remission about one-third of the time Most recent meta-analysis shows that antidepressants have an Effect Size approximately 0.311 We understand that different medications have different mechanisms of actions that can be beneficial for some patients With medication combinations and the development of pharmacogenomic testing, we are likely improving these outcomes Unfortunately, many patients still do not respond to medications or do not tolerate the side effects associated with the medications Cipriani A, et al. Lancet. 2018;391(10128):1357-1366.

Typical Medication Side Effects Increased or decreased sleep Changes in energy and fatigue Blurred vision Dry mouth Weight changes Appetite changes Sexual dysfunction Vital sign changes: Blood pressure and pulse Gastrointestinal distress: Nausea, vomiting, diarrhea, constipation Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Third Edition. New York, NY: Cambridge University Press; 2008.

STAR*D Data Support Need for Other Treatment Options Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40. Fava M, et al. Am J Psychiatry. 2006;163(7):1161-1172.

TMS is NOT ECT TMS is not a replacement for ECT, but is a different modality and should likely be used earlier in the course of care ECT is still best for MDD with psychotic features, acute suicidality, or catatonia Some patients who fail ECT respond to TMS and vice versa Head-to-head trials comparing ECT and TMS have not been completed with double-blind due to the challenge of creating double-dummy sham design It is well established that, regardless of continuation treatment, relapse following ECT concentrates heavily in the weeks immediately following ECT termination, indicating that ECT has little intrinsic durability of benefit. ECT = electroconvulsive therapy; MDD = major depressive disorder. Sackeim HA. Brain Stimul. 2016;9(3):313-319.

Transcranial Magnetic Stimulation: Mechanism of Action

Science Behind TMS: 1831 Michael Faraday The physical principles of electromagnetism were discovered in 1831 by Michael Faraday, who observed that a pulse of electric current passing through wire coil generates a magnetic field The rate of change (flux) of this magnetic field determines the induction of a secondary current in a nearby conductor that is placed in a perpendicular plane Faraday M. Experimental Research in Electricity. Volume 1. London: Quaritch; 1839:1-15. Barker AT. J Clin Neurophysiol. 1991;8(1):26-37. Barker AT, et al. Lancet. 1985;11(8437):1106-1107.

TMS Physics: Faraday s Law Magnetic Field Passes through Scalp and Skull Unimpeded Cortical Neurons Act as Conductors, Like Copper Wire Pulsed Magnetic Field Induces Current in Neurons Faraday M. Experimental Research in Electricity. Volume 1. London: Quaritch; 1839:1-15. Barker AT. J Clin Neurophysiol. 1991;8(1):26-37. Barker AT, et al. Lancet. 1985;11(8437):1106-1107.

TMS Directly Depolarizes Cortical Neurons to Produce an Action Potential Sequence of Effects of TMS Pulsed Magnetic Fields: Induces a local electric current in the superficial cortex Depolarizes neurons (change in charge differential across the membrane) Elicits an action potential (neuron fires) Release of chemical neurotransmitters at synapse Propagation of signal to other brain regions and structures Neuron Post A, et al. J Psychiatr Res. 2001;35(4):193-215.

Anderson RJ, et al. Clin Neurophysiol. 2016;127(11):3394-3405. TMS Coil

Targeted Effects on Mood Circuits in the Brain L R Dorsolateral prefrontal cortex L TMS Coil R Anterior cingulate cortex Activation of fronto-cingulate brain circuit following a course of TMS applied to the left dorsolateral prefrontal cortex in patients with MDD Kito S, et al. J Neuropsychiatry Clin Neurosci. 2008;20(1):74-80.

Biological and Behavioral Effects of TMS Effects Seen after Chronic Exposure (Repeated TMS Applications): Specific outcome is dependent upon stimulation parameters Changes in blood flow and metabolism at the stimulation site Alteration of monoamine concentrations β-receptor, serotonin-receptor modulation Evidence of induction of neurogenesis genes (eg, BDNF upregulation) Plasticity-like actions (ie, LTD/LTP-like effects) Local GABA and glutamate effects Increase in gray matter volume and hippocampal volume Changes in connectivity/activity of neural circuitry, eg, DLPFC-anterior cingulate cortex BDNF = brain-derived neurotrophic factor; LTD = long-term depression; LTP = long-term potentiation; GABA = gamma-aminobutyric acid. Lisanby SH, et al. Depress Anxiety. 2000;12(3):178-187. Kim EJ, et al. Neurosci Lett. 2006;405(1-2):79-83. Shajahan PM, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(5):945-954. Teneback CC, et al. J Neuropsychiatry Clin Neurosci. 1999;11(4):426-435. Epstein CM, et al. Neurology. 1990;40(4):666-670. George MS, et al. Neuroreport. 1995;6(14):1853-1856.

Other Theory of TMS Mechanism of Action MDD is marked by disturbances in brain functional connectivity, thalamocortical dysrhythmia. This connectivity is modulated by rhythmic oscillations of brain electrical activity. A recent study confirmed and measured the dysrhythmias by computer models TMS entrains and resets thalamocortical oscillators, normalizes regulation, and facilitates re-emergence of intrinsic cerebral rhythms, and through this mechanism of action restores normal brain function Vanneste S, et al. Nat Commun. 2018;9(1):1103. Leuchter AF, et al. Front Hum Neurosci. 2013;7:37.

Transcranial Magnetic Stimulation: what to expect from treatment

NeuroStar TMS Therapy System Nexstim TMS Device Brainsway TMS Device Magstim TMS System Cloud TMS NeuoSoft System Magventure MagVita TMS Therapy System Brand names are included in this slide for participant clarification purposes only. No product promotion should be inferred.

TMS Therapy Session Patient is awake and alert No anesthesia or sedation needed No negative effects on thinking and memory After treatment, patients can drive or return to work Some patients experience headache or mild to moderate pain or discomfort at or near the treatment area None of the side effects typical with antidepressant medications TMS Coil

TMS: Contraindications Only absolute contraindication is non-removable metallic objects in or around the head Conductive, ferromagnetic, or other magnetic sensitive metals that are implanted or are non-removable within 30 cm of figure-8 treatment coil Other concerns Implanted electrodes/stimulators Deep brain stimulator Aneurysm clips or coils Cochlear implants Intracranial stents Bullet or other metal fragments Vagus nerve stimulators (per package insert vs practical implementation) Hadley D, et al. J ECT. 2011;27(1):18-25. Philip NS, et al. Brain Stimul. 2014;7(4):608-612. Schrader LM, et al. Clin Neurophysiol. 2005;116(10):2501-2504.

TMS Therapy is a Well-Tolerated Antidepressant: list of most common adverse events with all coils (incidence > 5%) No Systemic Side Effects: TMS Side Effects: Scalp/head pain at treatment site Headache Weight gain Nausea Dry mouth Weight loss Nervousness/anxiety Sweating Appetite changes Sexual side effects Tremor Constipation Impotence Fatigue Diarrhea Weakness Treatment discontinuation symptoms 510(k) applications for Neuronetics and Brainsway devices.

Time Course for Most Common Adverse Events with Figure-8 TMS Coil Janicak PG, et al. J Clin Psychiatry. 2008;69(2):222-232.

Serious Adverse Events That Have Been Studied

Hearing Loss Small proportion of adult humans have experienced transient increases in auditory thresholds Permanent threshold shift in single patient who did not wear ear plugs and stimulated with H-coil Majority of studies where hearing protection was used report no change in hearing after TMS Recommendations: Patients and TMS technicians are required to use ear plugs that meet a minimum standard of 30 db protection Loo C, et al. Biol Psychiatry. 2001;49(7):615-623. Zangen A, et al. Clin Neurophysiol. 2005;116(4):775-9. Folmer RL, et al. Acta Otolaryngol Suppl. 2006;(556):96-101. Rossi S, et al. J Neurol Neurosurg Psychiatry. 2007;78(8):857-863. Janicak PG, et al. J Clin Psychiatry. 2008;69(2):222-232.

Treatment-Emergent Mania Study reviewed 10 of 53 TMS studies involving both patients with depression and bipolar disorder Early pooled data reported treatment-emergent mania was 0.84% for active treatment group and 0.73% for sham group This difference was not statistically different The switch rate for unipolar patients was 0.34% The switch rate for bipolar patients was 3.1% Xia G, et al. Int J Neuropsychopharmacol. 2008;11(1):119-130.

Emergence of Suicidal Ideation: Multicenter Study Treatment-emergent disease exacerbation Population with increased severity of clinical condition Most commonly reported event 1.9% with sham; 0.6% active TMS One non-lethal overdose in sham treatment group Janicak PG, et al. J Clin Psychiatry. 2008;69(2):222-232.

TMS and Seizures Seizure is the most serious side effect associated with TMS. The risk of seizures is 0.1% per treatment course. Sack AT, et al. Brain Res Brain Res Rev. 2003;43(1):41-56. Dumontheil I. Dev Cogn Neurosci. 2014;10:57-76.

TMS and Seizures (cont d) Most cases associated with TMS were prior to the publication of the TMS safety guidelines in 1998 Considering the large number of healthy individuals and patients who have undergone TMS sessions since 1998 and the small number of seizures reported, the risk of TMS to induce seizures could be considered very low The risk is less than or comparable to risk of seizure associated with antidepressant medications Wassermann EM. Electroencephalogr Clin Neurophysiol. 1998;108(1):1-16. George MS, et al. Curr Opin Psychiatry. 2013;26(1):13-18.

Transcranial Magnetic Stimulation: what to expect from treatment

Large-Scale Randomized Controlled Trials 4 large-scale studies (sample sizes > 100); 3 studies patients off medications and 1 study patients on medications concurrently 2 large multicenter industry supported trials that lead to FDA approval for 2 devices NIH-funded study with dosage parameters similar to those in the industry-sponsored study, but with sham design enhancements European study of the augmentation effects of TMS when used in combination with pharmacotherapy O Reardon JP, et al. Biol Psychiatry. 2007;62(11):1208-1216. Levkovitz Y, et al. World Psychiatry. 2015;14(1):64-73. George MS, et al. Arch Gen Psychiatry. 2010;67(5):507-516. Herwig U, et al. Br J Psychiatry. 2007;191:441-448.

Evidence for Efficacy of TMS for MDD 30+ clinical trials in adults Numerous meta-analyses Greater effects in more recent studies Longer duration of treatment Increase intensity Increase pulse number Most recent 34 individual trials 1383 patients TMS more effective than sham TMS Large effect size = 0.55. Slotema CW, et al. J Clin Psychiatry. 2010;71(7):873-884.

Multisite Naturalistic Observational Study of TMS for MDD: Acute Treatment Outcomes and 1-Year Follow-Up Study Goal: Define real world outcomes associated with TMS Therapy across a broad spectrum of patients and practitioners 42 Sites: Comprised of institutions and private practice 307 Patients: Unipolar, nonpsychotic MDD patients in acute phase Acute Phase Treatment course driven by patient clinical response Long-term Outcomes Measured at 3, 6, 9, and 12 months Carpenter LL, et al. Depress Anxiety. 2012;29(7):587-596. Dunner DL, et al. J Clin Psychiatry. 2014;75(12):1394-1401.

Study Patients Had Significant Morbidity Carpenter LL, et al. Depress Anxiety. 2012;29(7):587-596.

Comparison of End of Acute Treatment Clinical Status: Clinician- and Patient-Assessed Outcomes 80 70 60 50 40 30 20 10 0 Clinician Rating (CGI-Severity of Illness) Baseline 58.0% End of Treatment 80 70 60 50 40 30 20 10 0 Patient Rating (PHQ-9 Scale) Baseline 56.4% End of Treatment LOCF Analysis of intent-to-treat population Markedly ill or worse Moderately ill Mildly ill or better CGI = Clinical Global Impressions; PHQ-9 = 9-Item Patient Health Questionnaire; LOCF = last observation carried forward. Carpenter LL, et al. Depress Anxiety. 2012;29(7):587-596.

Remission is Possible with TMS Therapy: 1 in 2 Patients Respond, 1 in 3 Achieve Remission Percent of Patients (N=307) 70 60 50 40 30 20 10 0 Clinician Rating (CGI-Severity of Illness) 58.0% 56.4% 37.1% Patient Rating (PHQ-9 Scale) 28.7% Responders (CGI-S 3, PHQ-9 < 10) Remitters (CGI-S 2, PHQ-9 < 5) LOCF Analysis of Intention-to-Treat Population Carpenter LL, et al. Depress Anxiety. 2012;29(7):587-596. Avery DH, et al. J Clin Psychiatry. 2008;69(3):441-451. George MS, et al. Arch Gen Psychiatry. 2010;67(5):507-516.

Long-Term Phase Results (12 Months) 70 Clinician Rating (CGI-Severity of Illness) Patient Rating (PHQ-9 Scale) Outcomes measured 1 year following acute treatment Percent of Patients N=257 60 50 40 30 20 44% Physician directed standard of care 36.2% of patients received TMS reintroduction Average # of TMS treatment days during year = 16 10 0 Responders (CGI-S 3, PHQ-9 <10) Remitters (CGI-S 2, PHQ-9 <5) Dunner DL, et al. J Clin Psychiatry. 2014;75(12):1394-1401.

Why are Real World Results Better than Clinical Trial Results? Combination Strategies Well-tolerated with many medications Psychotherapy Engagement in Life Intensive Outpatient Program Routine Interaction Engaging with People who Care Psychological Bio Social Rossi S, et al. J Neurol Neurosurg Psychiatry. 2007;78(8):857-863. Arns M, et al. Brain Stimul. 2012;5(4):569-576.

Maintenance TMS No approved maintenance protocol TMS is consistently effective for recapturing prior level of response when introduced in the face of symptom relapse It is notable that TMS reintroduction was successful in rescuing most patients with threshold deterioration and returning them to their prior level of depressive symptom relief. Important observation given: There s a chronic and relapsing nature of pharmacoresistant major depression Absence of definitive data suggesting that retreatment with previously effective medications is capable of doing the same The results provide support for long-term treatment strategy that incorporates retreatment with TMS for patients who showed positive response to an initial acute course. Philip NS, et al. Brain Stimul. 2016;9(2):251-257.

Who may be candidates for TMS?

Why Do We Need to Consider TMS as a Treatment Option? Depression is a common mental disorder. Globally, more than 300 million people of all ages suffer from depression Depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease Approximately 50% of individuals diagnosed, seek help More than 30% do NOT receive adequate treatment from medication or psychotherapy; they need options! World Health Organization. March 22, 2018. www.who.int/news-room/fact-sheets/detail/depression. Accessed June 15, 2018.

Who is Right for TMS? Indicated for: TMS is indicated for the treatment of MDD in adult patients who have failed to receive satisfactory improvement from prior antidepressant medications at or above the minimal effective dose and duration in the current episode Best Practices: In recurrent episode Multiple medication attempts, yet still symptomatic Prescribed a complex drug regimen Experience frequent side effects from medication McIntyre RS, et al. J Clin Psychiatry. 2017;78(6):703-713.

TMS Insurance Coverage TMS has coverage in every state for MDD Covered by all major private insurance companies Covered by Medicare in every state Over 300 Million Covered Lives Coverage policies vary, but most typically require a failure of 3 to 6 antidepressant medications from different classes and Psychotherapy

Conclusion TMS is a focal non-invasive form of brain stimulation based on principles of electromagnetic induction of current that has been well-established for nearly 200 years TMS is a safe and effective treatment of moderate to severe MDD and research supporting its efficacy in treatment of other mental and neurological disorders TMS is well-tolerated and without risks of systemic side effects TMS should be considered a treatment option for patients with MDD who do not benefit sufficiently from antidepressant medications

Where to Learn More Textbooks George MS, Belmaker RH. Transcranial Magnetic Stimulation in Clinical Psychiatry. Arlington, VA: American Psychiatric Publishing, Inc.; 2007. Bermudes RA, et al (Eds). Transcranial Magnetic Stimulation: Clinical Applications for Psychiatric Practice. Arlington, VA: American Psychiatric Publishing, Inc.; 2018. Consensus Statements McClintock SM, et al. Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rtms) in the Treatment of Depression. J Clin Psychiatry. 2018 Jan/Feb;79(1). Perera T, et al. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9(3):336-346. Lefaucheur JP, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rtms). Clin Neurophysiol. 2014;125(11):2150-2206.

Educational Courses University-based training courses Medical University of South Carolina Berenson-Allen Center for Noninvasive Stimulation Duke University Medical Center