Tariq J. Faridi, B. Sc, M. Ed.Director of Education and Research, Visual OdysseyTemple Georgia

Transcranial Magnetic Stimulation

Neurostar Treatment Device

Patient Introduction

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

2

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

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)

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

6

prefrontalcortex

In MDD, some areas of the

brain are hypoactive and

others are hyperactive.

amygdala

brainstem neurotransmitter centers

thalamus

striatum

anterior cingulate

cortex

hippocampus

hypothalamus

LOW

HIGH

Neural Activity

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

concentrationpleasure/interests

guiltsuicidalityworthlessnessmood

sleepappetite

psychomotor fatigue (physical)pleasure/interests

psychomotor fatigue (mental)

guiltsuicidalityworthlessness

mood

Regions implicated in MDD are connected to the brainstem via monoaminergic circuits

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) Lancet9

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 cortexAnterior

cingulate cortex

Kito (2008) J Neuropsychiatry Clin Neurosci

These effects These effects are associated are associated

with with improvements improvements in depressive in depressive

symptomssymptoms

Activation of fronto-cingulate brain circuit following a course of TMS applied to the left dorsolateral prefrontal cortex in patients with Major DepressionKito (2008) J Neuropsychiatry Clin Neurosci

TMS CoilL

L

R

R

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

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.

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

• 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

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)

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)