1. Tariq J. Faridi, B. Sc, M. Ed. Director of Education and Research, Visual Odyssey Temple Georgia Transcranial Magnetic Stimulation  Neurostar Treatment Device  Patient Introduction

2. Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry 2

3. Systemic Drug Side Effects  Weight Gain  Constipation  Diarrhea  Nausea  Drowsiness  Insomnia  Decreased Libido  Nervous Anxiety  Increased Appetite  Decreased Appetite  Fatigue  Headache/ Migraine  Abnormal Ejaculation  Impotence  Sweating  Tremor  Treatment Discontinuation Side Effects  Weakness  Dry Mouth  Dizziness Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry; Neuronetics, Inc. (data on file) 3

4. Demitrack & Thase. (2009) Psychopharm Bull “The NeuroStar TMS System is indicated for the treatment of adult patients with Major Depressive Disorder (MDD) who have failed to receive satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode…” Nearly all patients received multiple ineffective treatment attempts in current episode (range: 1 to 23 attempts, avg: 4)

5. Adapted from: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3 rd Edition, APA (2010) 5

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7. prefrontal cortex In MDD, some areas of the brain are hypoactive and others are hyperactive. amygdala brainstem neurotransmitter centers thalamus striatu m anterior cingulate cortex hippocampus hypothalamus LOW HIGH Neural Activity

8. When there is an appropriate amount of monoamine neurotransmitter activity, neuronal activity throughout the brain functions normally. Monoamine dysfunction is linked to MDD Malfunctioning circuits lead to specific symptoms Serotonin (5-HT)Dopamine (DA)Norepinephrine (NE) Monoamine Neurotransmitters monoamine neurotransmitter projections concentration pleasure/ interests guilt suicidality worthlessness mood sleep appetite psychomotor fatigue (physical) pleasure/interests psychomotor fatigue (mental) guilt suicidality worthlessness mood Regions implicated in MDD are connected to the brainstem via monoaminergic circuits

9. The treatment coil produces MRI- strength magnetic field pulses. Magnetic field pulses pass unimpeded through the cranium for 2-3 cm. and induce a small electric current. Induced electric currents stimulate the firing of nearby neurons, causing the release of neurotransmitters and clinical effects. Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet 9

10. Depolarization of neurons in the DLPFC causes local neurotransmitter release Depolarization of pyramidal neurons in the DLPFC also causes neurotransmitter release in deeper brain neurons Activation of deeper brain neurons then exerts secondary effects on remaining portions of targeted mood circuits Dorsolateral prefrontal cortex Anterior cingulate cortex Kito (2008) J Neuropsychiatry Clin Neurosci These effects are associated with improvements in depressive symptoms

11. Activation of fronto-cingulate brain circuit following a course of TMS applied to the left dorsolateral prefrontal cortex in patients with Major Depression Kito (2008) J Neuropsychiatry Clin Neurosci TMS Coil L L R R

13.  Only TMS device FDA-cleared for the treatment of depression  Non-invasive and non-systemic  The most common side effect associated with treatment is scalp pain or discomfort – generally mild to moderate  Outpatient procedure, can be performed in a psychiatrist’s office; no anesthesia or sedation  37 minute treatment, administered daily for 4-6 weeks  Observed therapy facilitates adherence with treatment  Available by prescription only 13

14.  No systemic side effects  No adverse effect on cognition  Most common adverse event associated with treatment was scalp pain or discomfort  < 5% of patients discontinued due to adverse events  No seizures with TMS during clinical studies (over 10,000 treatments)  Six seizures reported with TMS in post-marketing period (estimated risk of seizure < 0.1% per acute treatment course)  Long term safety demonstrated in 6 months follow-up Janicak, et al. J Clin Psychiatry, 2008; Janicak, et al. Brain Stimulation, 2010.

16. John P. O’Reardon, H. Brent Sovason, Philip G. Janicak, Shirlene Sampson, Keith E. Isenberg, Ziad Nahas, William M. McDonald, David Avery, Paul B. Fitzgerald, Colleen Loo, Mark A. Demitrack, Mark S. George, and Harold A. Sackeim BIOL PSYCHIATRY 2007;62:1208-1216 ©2007 Society of Biological Psychiatry N=301 patients (ATHF 1 thru 4), 23 sites 22.1% reduction in MADRS total score with active NeuroStar TMS vs 9.1% on sham at 4 weeks (in ATHF = 1 population) Conclusion: “Transcranial Magnetic Stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.” Clinically meaningful effect size = 0.52 (in ATHF = 1 population) In open label extension study, 1 in 2 patients responded, 1 in 3 patients achieved remission at 6 weeks Safety confirmed in 6 month follow-up Major Findings: Demitrack & Thase (2009) Psychopharm Bulletin

17. NIMH-funded, independent of industry N=190 patients, 4 premier academic sites Primary outcome measure: % Remission - Active 15% vs Sham 4% (P = 0.015); Odds Ratio of achieving remission: 4.2 (95%CI, 1.3-13.2) Major Findings: 30% of patients achieved remission in open-label extension phase Excellent safety, nearly 90% of patients adherent to acute phase treatment course Conclusion: “Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham.” Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD; Martina Pavlicova, Phd; Berry Anderson, Phd, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD; Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PHD

18.  The evidence for the clinical efficacy of TMS in the treatment of depression is considerable, spanning more than 30 controlled clinical research studies  Most recent meta-analysis (Slotema, et al, 2010):  Included analysis of 34 studies involving 1,383 patients  Estimated standardized effect size = 0.55 (P < 0.001) Conclusion: “…rTMS deserves a place in the standard toolbox of psychiatric treatment methods, as it is effective for depression …and has a mild side effect profile….” Slotema, et al. J Clin Psych (2010)

19. Janicak, et al. Brain Stimulation, 2010. Safety confirmed during long term, open-label 6 month follow up period –During open-label follow up on antidepressant medication monotherapy, ~37% of patients required TMS reintroduction – ~85% of patients who received TMS reintroduction benefited Net incidence of illness relapse under these open-label follow up conditions: 11% –Six-month relapse with antidepressant treatment alone in STAR*D study was 35-50% (Level 2 and 3 range)