Louis B. Cady, MD, CEO & FounderLouis B. Cady, MD, CEO & Founder Cady Wellness Institute Cady Wellness Institute

Adjunct Clinical Lecturer – Indiana University School of Medicine Department of Psychiatry

Child, Adolescent, Adult & Functional Neuropsychiatry – Evansville, Indiana

IMMH – San Antonio, TexasSaturday, September 20, 2014

Magnets, Not Drugs:Transcranial Magnetic Stimulation (TMS)

for Depression

Continuing Medical Education Commercial Disclosure Requirement

I, Louis B. Cady, M.D., have the following commercial relationships to disclose:

• Speaker faculties: Forest Pharmaceuticals, Sunovion, Shionogi, Takeda-Lundbeck

•Testing laboratories: Immunolaboratories, Great Plains Diagnostic Labs, LABRIX•Commercial endeavors: Pharmanex distributor•Historical honoraria, speaking: Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo Smith Kline, Janssen, McNeil, Pfizer-Roerig, Sanofi~aventis, Searle, Sepracor, Shire, Takeda, WorldLink Medical, Wyeth-Ayerst

www.slideshare.net/lcadymd

This is where to follow along on your tablets and smart

phones, or access the presentation slides later…

“Slumber not in the tents of your fathers. The world is advancing. Advance with it.”

- Giuseppe Mazzine

– How it works– Safety and tolerability– Where it fits in the “Treatment

Algorithm” for Major Depression

Topics we will cover in this talk

– Diagnosis– Unmet medical needs

Major Depression

TMS

Major Depression

Unmet Medical Needs

Depression & Anxiety & a malpractice suit in 1 Easy Lesson

DEPRESSIONSIG: E- CAPS!

• Sleep• Sadness • Interest loss• Guilt• *Energy• Concentration• Appetite• Psychomotor Sx• Suicidal thinking

Gen. ANXIETY D.O.•Somatic Sx (“energy”,etc.)•WORRY•Irritability•Concentration•Keyed up•Insomnia (“sleep”)•Restlessness

SWICKIR is Quicker:

Worry + 3 = GAD (Baughman)5of 9 with 1 of 2 x 2 weeks

*ACCURATE MEDICAL diagnosis “mood disorder due to a general medical condition” AND r/o bipolar disorder

BEWARE BEWARE – “too much” energy

Lifetime Prevalence of Common Psychiatric Disorders

Kessler 1994; Kessler 1995; DSM-IV-TR™ 2000.*In menstruating women.

Lifetime prevalence (%)0 2 4 6 8 10 12 14

7.8%PTSD

5.1%Generalized anxiety d.o

3.5%Panic disorder

2.5%OCD

16 18

Alcohol dependence 14.1%

Major depressive disorder 17.1%

13.3%Social anxiety disorder

5%*PMDD

Conceptual Evolution of Depression/Anxiety Comorbidity

67.8% of patients diagnosed with depression also fulfill the criteria for an anxiety disorder.

67.8% of patients diagnosed with depression also fulfill the criteria for an anxiety disorder.

Boerner and Möller, 1999.Boerner and Möller, 1999.

of all of all psychological psychological

disordersdisorders

of all of all psychological psychological

disordersdisorders

67.8% 10.4%10.5%

Depression—Impact on the Healthcare System

• Compared with those without depression, depressed individuals: – Utilize all types of healthcare services more

often

– Incur 1½ to 2 times greater healthcare costs

– increased length of hospital stay

– significant worsening of physical, social, and role functioning

Simon 1995; Luber 2000; Verbosky 1993; Wells 1989.

STAR*D Study demonstrates that current treatments have limited effectiveness

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

TMS* Therapy Outcomesvs. Pharmacotherapy (STAR*D)

% o

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Relapse Rate among those patients in remission at entry into long term follow up

rTMS

*Using Neurostar TMS device

Likelihood of discontinuing treatment increases with each new medication attempt

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)

Best Practices Treatment Guideline for DepressionBased on 2010 APA guidelines and NeuroStar TMS Therapy® indication for use.

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

Unmet Medical Needs

TMS is Included in Practice GuidelinesFollowing Failure of Initial Treatment

Schlaepfer, et al. World J Biol Psychiatry (2009); Kennedy, et al J Aff Disorders (2009); American Psychiatric Association (2010)

Canadian Network for Mood and Anxiety Treatments

(2009)

Guideline Sources

American Psychiatric Association (2010)“…Acute phase treatment may include pharmacotherapy, depression-focused psychotherapy, the combination of medications and psychotherapy, or other somatic therapies such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or light therapy…”

World Federation of Societies for Biological Psychiatry

(2009)

A quick look back in history

The Interpretation of Dreams – 1885 - 1890

Ugo Cerletti 1935Prozac - 1987

ShrinkingShocking

or Drugging

[Supposedly] the only three things you could do to a patient’s

brain…]

The Therapeutic Trifecta of Psychiatry:

ECT – origins• Origin in 1700’s – Middlesex Hospital

– machine with weak electrical current used for range of illnesses.– John Birch, English neurosurgeon, used it to shock the brains of

depressed patients– Benjamin Franklin, after shocked, recommended electric shock for

tx of mental illness

• Ugo Cerletti – 1935 – noted (incorrectly) that epilepsy and schizophrenia didn’t occur in same patient

• Problems with ECT – memory loss, anesthesia risk• Cost of $6400 for eight treatments• 80% improvement • 33,000 hospitalized Americans – ECT in 1980, last year for

NIMH figures– http://www.faqs.org/health/topics/19/Electroconvulsive-therapy.html

"The Shock Shop, Mr. McMurphy, might be said to do the work of the sleeping pill, the electric chair and the torture rack. It's a clever little procedure, simple, quick, nearly painless it happens so fast, but no one ever wants another one. Ever.”

But even before these guys…

• Electromagnetic induction – 1831 (Faraday & Joseph Henry)

• 1st demonstrated by Faraday August 29, 1831

Faraday’s law• “The induced electromotive force (EMF) in

any closed circuit is equal to the time rate of change of the magnetic flux through the circuit.”

• Discovered by Michael Faraday and Joseph Henry in 1831 – Faraday first to publish.

Faraday’s Law of Induction

TMS Magnetic

field

Induced neuronal current

From electricity to magnetism

• Bartholow, R (1874)– Stimulation of human brain

(exposed cortex) of patient with cranial defect.

• d’Arsonval – “Phosphenes and vertigo” induced inside powerful magnetic coil

• Silvanus P. Thomson, Ph.D. – new type of magnetic stimulation (1910)

Thompson, SP. “A Physiological Effect of an Alternating Magnetic Field.” Proceedings of the Royal Society of London B82:396-399, 1910

First patent application for magnetic therapy:

• 1902 Adrian Pollacsek and Berthold Beer – Vienna, Austria for a “therapeutical apparatus”

• Electromagnetic coil, placed over the skull was noted to “pass vibrations into the skull” and “treat depression and neuroses.”

First modern TMS:

• Barker AT, et al. “Non-invasive magnetic stimulation of the human motor cortex. The Lancet 1:1106-1107, 1985.

• 1st device – designed by Barker – Univ. of Sheffield, England.– 100 microsecond, 2 T

pulse

Coil types and rationale

From Matt Edwardson, MD – Research Fellow and Acting Instructor, Dept. of Neurology, Univ. of WA 10/16/2011

TMS Targeted Effects on Local and Distant Regional Blood Flow

Nahas Z et al. Brain Effects of TMS Delivered Over Prefrontal Cortex in Depressed Adults. Journal of Neuropsychiatry and Clinical Neurosciences 2001:13:459-460.

Nahas Z et al. Brain Effects of TMS Delivered Over Prefrontal Cortex in Depressed Adults. Journal of Neuropsychiatry and Clinical Neurosciences 2001:13:459-460.

An unusual side effect of imaging (2004)…

• CONCLUSIONS: “These preliminary data suggest that the EP-MRSI scan induces electric field that are associated with reported mood improvement in subjects with bipolar disorder.”

Brainsway deep TMS device

Application of Brainsway helmet

Neuron

TMS Directly Depolarizes Cortical Neurons

Pulsed magnetic fields from TMS: •induce a local electric current in the cortex which depolarizes neurons •eliciting action potentials•causing the release of chemical neurotransmitters

Neurons are “electrochemical

cells” and respond to either electrical or

chemical stimulation

TMS Releases Neurotransmitters in the Brain

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 These effects are associated are associated

with with improvements in improvements in

depressive depressive symptomssymptoms

ECT vs. TMSECT TMS

Anesthesia, LOC Yes No

Induction of seizure Yes No

Systemic effects Anesthetic drugs, increase HR

none

Treatment schedule 3X/ week (8 -15 tx) Daily, M-F, six weeks (30 tx)

Rapidity of onset 2 – 3 treatments 2 – 3 weeks

Mechanism of action SEIZURE. Massive NT release; rise in sz threshold

Reactivation of neural circuits. Precise, LOCAL release of NT’s.

Side effects Memory loss, confusion Essentially none (mild HA 1st week)

Psychosocial impact can’t work Drive to and from tx’s, work improved

After-effects Mild (usually transient) memory loss

None. Pro-cognitive

Insurance coverage Almost always Rare. Improving

• Outpatient 37-minute daily procedure (3000 pulses) = on label

• 4-6 week treatment course• “Antidepressant medication

monotherapy” may be used for maintenance – we use multiple both during and after.

• At CWI – multiple medicationsthyroid balancing, NT balancing,and psychotherapy (during treatment)

• “Hot-rodding” the TMS machine– Alternatively – 3000 – 5000 pulses, R & L– ( www.cwiyoutube.com )

TMS in Clinical Practice at CWI

O’Reardon, JP, et al. (2007) Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multi-Site Randomized Controlled Trial. Biol Psychiatry 62:1208-1216.

Who Was Studied?• Primary diagnosis: DSM-IV Major Depressive

Disorder– Unipolar type, non-psychotic– Moderate to severe symptoms at baseline– Approximately one-third of patients had a co-morbid anxiety

disorder (OCD excluded)

• Antidepressant Treatment History:– Average number of antidepressant medication trials in current

episode = 4 (range: 1 to 23 attempts)• Majority of treatment attempts were unable to achieve adequate

dose and duration of treatment due to intolerance

– all patients had failed to achieve satisfactory benefit from one antidepressant medication at an adequate dose and duration in current episode

Demitrack and Thase (2009) Psychopharm Bulletin

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:• MADRS total score decreased:16.6%

(Active) vs 6.9% (Sham) p=0.01 (Effect size: 0.51)

• 30% of patients achieved remission in open-label extension phase

• Excellent safety and adherence

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

Recent TMS Literature Review• Roughly 30 controlled clinical research studies to date• 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….”

1.Slotema, CW, Blom, JD, Hoek, HW, Sommer, IEC. (2010) Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)J Clin Psych 71(7):873-84.

2.Schutter, DJLG. (2009) Antidepressant Efficacy of High-Frequency Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex in Double-Blind Sham-Controlled Designs: A Meta-Analysis. Psychol Medicine, 39:65-75.

• Independent, Peer-reviewed• 15 TMS clinical trials involving nearly 500 patients

– Average HAM-D decrease in depressive symptoms >5 points vs. sham control

• Meets clinical significance threshold of 3 points on the HAM-D scale

– Response rate with active TMS was >3x higher than sham treatment

– Remission rate with active TMS was >6x higher than sham treatment

• “High strength of evidence” for efficacy from well-controlled RCTs

Independent U.S. Agency for Healthcare Research and Quality (AHRQ) Confirms Evidence for Efficacy of TMS

Agency for Healthcare Research and Quality: Comparative Effectiveness Report on Non-Pharmacologic Treatments for Depression , October 2011

• Pharmacologic “switch” to next best medication:

• 22.3% (95% CI: 16.2%-28.4%)

• Augmentation: • 27.2% (95% CI: 20.4%-34.0%)

• TMS (Neuronetics) Outcomes Study: • 37.2% (95% CI: 31.9%-42.7%)

45

AHRQ – the “betting odds” on remission in the next step in treatment

Agency for Healthcare Research and Quality: Comparative Effectiveness Report on Non-Pharmacologic Treatments for Depression , October 2011

NeuroStar TMS Therapy:

Acute Efficacy Outcomes in Real-World Clinical

Practice

• Goal– Define real world outcomes associated with NeuroStar TMS

Therapy across a broad spectrum of patients and practitioners

• Patient Population & Sites– 307 evaluable unipolar, non-psychotic MDD patients in acute

phase– 42 sites comprised of institutions and private practice

• Study Design Phases– Acute phase (clinician determined care based on clinical

progress)– Long-term outcomes at 12 months (ongoing)

• Patient Treatment– Clinical care initiated per current labeled guidelines

47

Treatment Utilization and Outcomes Study ( Protocol No. 19-50001-000)

Neuronetics, Inc. (data on file) ; clinicaltrials.gov listing number NCT 01114477

Patient and Treatment Characteristics (N=307)

N (%) Female 205 (66.8)

Age in years, mean (SD) 48.6 (14.2)

Disease and Treatment History N(%)- Recurrent Major Depression- Comorbid Anxiety Disorder

285 (92.8)46 (15.0)

Psychiatric Treatment History N(%)- History of Inpatient Hospitalization- History of ECT Treatment

133 (43.3)15 (4.9)

Prior Antidepressant Medication Treatment mean(SD)- Avg # of Adequate Treatments in Current Episode

2.5 (2.3)

Mean (SD) Number of TMS Sessions During Acute Treatment 28 (10.1)

Neuronetics, Inc. (data on file) ; clinicaltrials.gov listing number NCT 0111447748

% o

f P

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(N

=3

07

)

LOCF Analysis of intent-to-treat population

Comparison of End of Acute Treatment Clinical Status: Clinician- and Patient-Assessed Outcomes

Clinician Rating(CGI-Severity of Illness)

Patient Rating(PHQ-9 Scale)

Markedly ill or worse Moderately ill Mildly ill or better

TMS Reintroduction SummaryLong Term Follow Up Phase (N=257)

# of

Pati

ents

Tre

ated

with

TM

S

Date Following Completion of Acute Treatment Phase

Month 1(Taper)

Month 2

Month 3

Month 4

Month 5

Month 6

Month 7

Month 8

Month 9

Month 10

Month 11

Month 12

N=93 (36.2%) patients received at least 1 TMS treatment day during long term follow up after Taper Phase (i.e., from month 2 thru month 12)

Mean (SD) # of TMS treatment days among those patients receiving TMS = 16.2 days (21.1)

Long Term Follow Up After Acute Treatment

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)

TMS Open-Label Durability of Effect Study

OutcomeTMS

(in remission)

(N=56)Outcome

ECT - Combination Pharmacotherapy 1

(N=95)

ECT - Continuation ECT 1

(N=89)

% Early Discontinuation 16.1%

% Early Discontinuation 22.1% 16.8%

% Disease Recurrence 10.7%

% Disease Recurrence 31.6% 37.1%

% In Remission by Study

Completion73.2%

% In Remission by Study Completion 46.3% 46.1%

1 Kellner, CH, Knapp, RG, Petrides, G, et al. Continuation Electroconvulsive Therapy vs Pharmacotherapy for Relapse Prevention in Major Depression: A Multisite Study From the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry 2006, 63:1337-1344.

Janicak, et al., Brain Stimulation (2010)

NeuroStar TMS Therapy Outcomesvs. Pharmacotherapy (STAR*D)

% o

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Relapse Rate among those patients in remission at entry into long term follow up

• In research settings, two large, multisite, randomized controlled trials demonstrated clinically significant antidepressant effect of TMS

• Prospective, naturalistic study confirms these results in real-world practice settings

• Overall, 1 in 2 patients respond and 1 in 3 patients achieve remission

• Meta-analyses from multiple studies shows TMS effect size of >0.5

• High level of treatment adherence , >80% of patients completed acute treatment in both research setting and in clinical practice

• Appears to be at least as effective as ECT for treatment and relapse prevention

Summary of Clinical Outcomes

54

Safety and Tolerability of NeuroStar TMS

Therapy

• 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 NeuroStar device during clinical studies (over 10,000 treatments)

• Rare risk of seizure with NeuroStar TMS in post-market use (0.003% per treatment, <0.1% per acute treatment course) (>150,000 treatments in post-marketing experience to date)

• Long term safety demonstrated in 6 months follow-up

NeuroStar TMS Therapy: Safety Overview

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

No Evidence of Emergent Suicidal Ideation

* Shift Score indicates the percent of subjects who experienced a change in HAMD Item 3 score from 0 or 1 at baseline to 3 or 4 at later point in time.

HA

MD

Ite

m 3

Su

icid

al I

dea

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hif

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core

(%

)*

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Baseline Week 2 Week 4 Week 6

NeuroStar TMS Therapy (n=155)

Sham TMS (n=146)

Janicak (2008) J Clinical Psychiatry.

Current Research

rTMS - Current interesting findings

• rTMS upregulates BDNF in experimentally damaged area of brain in mouse model– Makowiecki K et al. J Neurosci. 2014 Aug6;34(32):10780-92

• 10Hz rTMS - improvement of freezing of gait in Parkinsonism with stimulation over M1-LL and DLPFC in single session. – Lee SY et al. Restor Neurol Neurosci. 2014 Jul 30.

• Use in treatment-resistant schizophrenia– Miyajmoto S. et al. J Psychiatr Res. 2014 Jul 8.

Transcranial magnetic stimulation in the treatment of substance additionGorelick DA et al. Ann NY Acad Sci. 2014 Jul 28

• 19 human studies reviewed, 316 adults– Tobacco (9 studies), alcohol (6), cocaine (3), and

methamphetamine (1)– Only FIVE studies were controlled tirals.

• 2 out of 45 nicotine trials = decreased smoking• Cocaine trial = decreased use.

• Actions – “may involved increased dopamine and glutamate function in corticomesolimbic brain circuits and modulation of neural activity in brain ircuits that mediate cognitive processes relevant to addiction.”

• Considered experimental at present

A double-blind, randomized trial of deep repetitive transcranial magnetic stimulation for autism

spectrum disorder. Enticott PG et al. Brain Stimul. 2014 Mar-Apr;7(2):206-11

• 28 adults with high-functioning Autism or Asperger’s– Double-blind, randomized, placebo controlled design– 2 weeks of daily weekday treatment – rTMS to bilateral dorsomedial PFC

• “Deep rTMS to bilateral dorsomedial PFC yielded a reduction in social relating impairment and socially-related anxiety.”

Entire article, free: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725288/Entire article, free: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725288/

Neuropharmacology. Jan 2013; 64: 566-578

Improvement in Alzheimer’sCotelli M et al. J Neurol Neurosurg Psychiatry. 2011 Jul;82(7):794-7

• 10 AD patients randomized– 4 weeks of rTMS vs. – 2 weeks of placebo followed by 2 weeks of real rTMS

• Protocol – 25 minute rTMS, DLPFC, weekdays.• Significant difference was found between groups

in terms of % of correct responses of auditory sentence comprehension.

• “…rTMS …may represent a novel approach to the treatment of language dysfunction in AD patients.”

Improvement in Alzheimer’s IIAhmed MA et al. J Neurol. 2012 Jan;259(1):83-92.

• Study of high vs. low frequency rTMS applied bilaterally over DLPFC on cognitive function and cortical excitability of AD patients.

• 45 patients studied. 3 groups:– Sham– High frequency – Low frequency

• “…five sessions of high frequency rTMS over the left and then the right DLPFC improves cognitive function in patients with mild to moderate degree of AD. This improvement was maintained for three months.”

Positive effects of rTMS on attention in ADHDBloch Y et al. World J Biol Psychiatry. 2010 Aug;11(5)755-8

• Known that rTMS affects dopaminergic secretion in PFC.

• Double blind crossover randomized, sham controlled study of 13 patients (7 male, 6 female) – who fulfilled DSM-IV criteria.

• “There was a specific beneficial effect on attention 10 minutes after a real rTMS course.”

“But my patients don’t know about this and aren’t asking for it….”

“It’s not the consumers’ job to know what they want.” - Steve Jobs

“For me, the practice of medicine has opened the door to the greatest adventure in life. Medicine is like a hallway lined with doors, each door opening into a different room, and each room openinginto another hallway, again lined with doors. Medicine is always wonderful and never will be finished.”- Charles H. Mayo, M.D.

Contact information:Louis B. Cady, M.D.

www.cadywellness.com

http://www.tms-relief.com

Office: 812-429-0772E-mail: lcady@cadywellness.com

4727 Rosebud Lane – Suite FInterstate Office Park

Newburgh, IN 47630 (USA)