Depression?There is something new under the sun…

TheraMind Services, Inc.Energizing brains…Healing Minds TM

Transcranial Magnetic Stimulation (“TMS”)

Major Depressive Disorder (“MDD”): Circuits and Neurotransmitters

• Monoamine dysfunction is linked to MDD

• Malfunctioning circuits lead to specific symptoms

Monoamine Neurotransmitters: Serotonin (5-HT); Dopamine (DA); and, Norepinephrine (NE).

monoamine neurotransmitter

projections

concentrationpleasure/interests

guiltsuicidalityworthlessnessmood

sleepappetite

psychomotor fatigue (physical)pleasure/interests

psychomotor fatigue (mental)

mood

Regions implicated in MDD are connected to

the brainstem via monoaminergic circuits

When there is an appropriate amount

of monoamine neurotransmitter activity, neuronal

activity throughout the brain functions

normally.

Chemical Antidepressants

improved mood

weight gain

sexual dysfunction

insomnia

nausea

GI distress

Blood pressure changes

blurred vision

reduced feelings of guilt, suicidality, and worthlessness

weight gain

insomnia

agitation

dry mouth

fatigue

Neuron

Rapidly pulsed magnetic fields from TMS : • induce a local

electric current in the cortex which depolarizes neurons

• elicit action potentials

• cause the release of chemical neurotransmitters

Neurons are electrochemical cells that

respond to either electrical or chemical stimulation

TMS Directly Depolarizes Cortical Neurons, causing them to fire

Depolarization leads to action potentials in local neurons and

thereby releases neurotransmitters

Depolarization of neurons in the Dorsolateral Prefrontal Cortex causes local neurotransmitter

release

Depolarization of pyramidal neurons in the DLPFC

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

Cingulate cortex

Kito (2008) J Neuropsychiatry Clin Neurosci

These effects are associated with improvements in

depressive symptoms

TMS Releases Neurotransmitters in the Brain

Brain SPECT

TheraMind Patient 101 TheraMind Patient 102

Week 1 Week 2 Week 3 Week 4 Week 50

10

20

30

40

Beck score measured during acute phase of

treatment

Week 1 Week 2 Week 3 Week 4 Week 50

10

20

30

40

50

60

Beck score measured during acute phase of

treatment

Classification Total Score Level of Depression

Low 0-10 Normal

11-16 Mild Mood Disturbance

Moderate 17-20 Borderline clinical depression

21-30 Moderate Depression

Significant 31-40Over 40

Severe DepressionExtreme Depression

Optimization of TMS (‘OPT-TMS’) Study

• 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

10

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. SackeimBIOL 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

11

Randomized Controlled Trials

In a controlled clinical study, 1 in 2 patients suffering from clinical depression improved significantly, and 1 in 3 patients were completely free of depression symptoms after six weeks of treatment.

Other TMS providers are reporting 80% of their patients treated have significantly improved in their mood, energy and motivation.

1. Demitrack, MA, Thase ME. “Clinical significance of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant depression: synthesis of recent data.” Psychopharm Bull, 2009, 42(2): 5-38. 2. Premier Psych TMS, Walter Duffy, MD. Lincoln, Nebraska.

EFFECTIVENESS

TheraMind Services TMS Therapy…

Specifically targets the brain circuits involved in mood regulation

Directly depolarizes cortical neurons and modulates neurotransmitter release in the brain

Effects involve both the cortical and deep neural circuits in the brain

Accomplishes these effects without unwanted systemic adverse effects

Summary

Prospective, naturalistic study confirms prior trial results for both clinician- and patient-reported outcomes in real-world practice settings

Some TMS providers are reporting 80% of their patients treated have significant improvement in their mood, energy and motivation. Premier Psych TMS, Walter Duffy, M.D., Lincoln, Nebraska

Patient-reported outcomes showed improvements both in quality of life and functional status

High level of treatment adherence, >80% of patients completed acute treatment

TMS Benefits Patients in Real World Settings

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

Rare risk of seizure with TMS in post-market use (0.003% per treatment, <0.1% per patient)

- (~100,000 treatments in post-marketing experience to date)

Long term safety demonstrated in 6 months follow-up

TheraMind TMS Systems: Safety Overview

Janicak, et al J Clin Psychiatry, 2008; Janicak, et al. Brain Stimulation, 2010

Energizing brains...Healing minds.™