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
f P
atie
nts
Rel
apsi
ng
Du
rin
g L
ong
Ter
m F
ollo
w U
p
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
atie
nts
(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
f P
atie
nts
Rel
apsi
ng
Du
rin
g L
ong
Ter
m F
ollo
w U
p
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
tio
nS
hif
t S
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: [email protected]
4727 Rosebud Lane – Suite FInterstate Office Park
Newburgh, IN 47630 (USA)
Top Related