Louis B. Cady, MD – CEO & Founder – Cady Wellness Institute
Adjunct Clinical Lecturer – Indiana University School of Medicine
Department of Psychiatry
Child, Adolescent, Adult & Forensic Psychiatry – Evansville, Indiana
Grand Rounds – Saint Mary’s Hospital April 2, 2014
TMS: The 21st Century Treatment for Depression

Continuing Medical Education Commercial Disclosure Requirement
for Louis B. Cady, M.D.
I, Louis B. Cady, MD, have the following commercial relationships to
disclose:
•Speaker honoraria received from:
• Immunolaboratories, Great Plains Diagnostic Labs, LABRIX
•Speaker’s bureaus (active) for:
• Forest Pharmaceuticals, Sunovion
•Historical data – speaker’s bureau for Bristol-Myers Squibb,
Celltech, Cephalon, Eli Lilly, Glaxo-Smith Kline, Janssen, McNeil,
Pfizer-Roerig, Sanofi!~aventis, Sepracor, Shire, McNeil, Takeda,
Janssen, Searle, Shire, Takeda, Wyeth-Ayerst
This CME presentation is not being underwritten by any
pharmaceutical or medical device company, and Dr. Cady is not
receiving a fee or honorarium for presenting it.

“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
DEPRESSION
SIG: 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.
Boerner and Möller, 1999.
of all
psychological
disorders
of all
psychological
disorders
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 Outcomes
vs. Pharmacotherapy (STAR*D)
%
of
Patients
Relapsing
During
Long
Term
Follow
Up
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)

Question 1
• Based on the STAR*D Trial, it appears that
there is a “law of diminishing returns” for
every antidepressant after the first one
employed.
– TRUE
– FALSE

Best Practices Treatment Guideline for Depression
Based on 2010 APA guidelines and NeuroStar TMS Therapy® indication for use.
Adapted from: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd Edition, APA (2010)
Unmet
Medical
Needs

TMS is Included in Practice Guidelines
Following 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 1935
Prozac - 1987

Shrinking
Shocking
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.”

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 are
associated with
improvements in
depressive
symptoms

• TMS uses Faraday’s principle of magnetic
induction to:
– Induce a current flow and depolarization in
“local” neurons close to the TMS Coil, and
– It also induces, by additional synaptic pathways,
release of neurotransmitters diffusely in the
brain from deep brain nuclei
• Choose one:
– TRUE
– FALSE
Question 2

ECT vs. TMS
ECT 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

Identify which of these statements are true:
a)ECT induces seizures; TMS does not.
b) There is systemic exposure to drugs with ECT;
there is none for TMS.
c)ECT causes memory loss/confusion; TMS does
not
d)ECT is well reimbursed by insurance; TMS is not
yet well reimbursed.
ANSWERS:
1)All are true
2)Not all of these statements are true.
Question 3

• Outpatient 37-minute daily
procedure (3000 pulses)
• 4-6 week treatment course
• “Antidepressant medication
monotherapy” may be used for
maintenance – we use multiple
both during and after.
• At CWI – multiple medications
thyroid balancing, NT balancing,
and psychotherapy (during
treatment)
• “Hot-rodding” the TMS machine
– ( 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
42

• In the original registration study for TMS:
– There were multiple failed medications trials in
these patients (average of four)
– 1 out of 2 patients responded
– 1 out of 3 patients remitted
– The effect size of the treatment was roughly 0.5
• Choose one:
– All of the previous statements are TRUE
– Not all of the previous statements are true
Question 4

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%)
47
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
49
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 01114477
50

%
of
Patients
(N=307)
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 Summary
Long Term Follow Up Phase (N=257)
#
of
Patients
Treated
with
TMS
Date Following Completion of Acute Treatment Phase
Month 1
(Taper)
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
Outcome
TMS
(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
Completion
73.2%
% 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 Outcomes
vs. Pharmacotherapy (STAR*D)
%
of
Patients
Relapsing
During
Long
Term
Follow
Up
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
56

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.
HAMD
Item
3
Suicidal
Ideation
Shift
Score
(%)*
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.

• Appropriate patients for TMS might include
the following:
– Failed one antidepressant at appropriate dose
and duration of treatment
– Desire for no seizures, memory loss, or
systemic exposure to drugs (e.g. pregnancy,
breast feeding)
– Appropriate if patient MUST keep working.
• Choose one:
– All of the previous statements are TRUE
– Not all of the previous statements are true
Question 5

“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 opening
into another hallway,
again lined with doors.
Medicine is always
wonderful and never will
be finished.”
- Charles H. Mayo, M.D.