Treatment of Depression in 21st Century
Ascent NBI and TMS Center
A. Sibel Yasar, MD
Overview
• Definition
• Subtypes of depression
• Incidence/Prevalence
• The burden of depression
• Pathogenesis
• Treatment options
2
Depression
3
Depression: Definition
• Depression is a condition characterized by
• Persistent low mood,
• Lack of positive affect,
• Loss of interest in usually pleasurable activities
• Neuro-vegetative symptoms:
changes in sleep, energy level, psychomotor
activity, appetite, concentration.
• Impairs persons’ daily functioning.
4
Subtypes of depression
•
•
psychotic depression - delusions or hallucinations, either may be congruent or incongruent with
depressed mood
catatonic depression - has at least 2 of
–
–
–
–
–
•
immobility (stupor or catalepsy)
extreme agitation
extreme negativism
odd voluntary movement (posturing, stereotyped movements, mannerism, grimacing)
echolalia or echopraxia
melancholic depression –
–
lack of interest or pleasure in most or all activities, or lack of reactivity to pleasurable stimuli, and ≥ 3 of
distinct quality of depressed mood (experienced differently from loss of a loved one)
–
–
–
–
–
•
symptoms regularly worse in morning
early morning awakening (at least 2 hours before usual time of awakening)
significant anorexia or weight loss
noticeable psychomotor retardation or agitation
excessive or inappropriate guilt
atypical depression –
–
mood reactivity and ≥ 2 of
•
•
•
•
•
•
leaden paralysis
lengthy pattern of interpersonal rejection sensitivity
significant weight gain or appetite increase
hypersomnia
seasonal pattern depression - regular temporal relationship between time of year and symptom
onset/remission
Post partum depression
5
Definitions
• "double depression" - major depression
superimposed on underlying dysthymic disorder
• chronic major depressive disorder - depression with
duration ≥ 2 years
6
Incidence/Prevalence
• 9% adults in United States meet criteria for current
depression
• 3.4% adults in US meet criteria for major depression
• Pregnant women and elderly have increased
prevalence of depression.
7
Depression common in many countries
• 121 million people globally have depression,
– based on World Health Organization report (Lancet 2001
Oct 27;358(9291):1469)
• estimated 34% prevalence of anxiety and depressive
disorders in Pakistan
• 8.5% lifetime prevalence of major depression in
Europe
8
Depression in Children and Adolescents
• overall prevalence of depression 2.8% in patients < 13 years old and 5.6% in
patients aged 13-18 years
– Reference - J Child Psychol Psychiatry 2006 Dec;47(12):1263
• 18% prevalence among young adolescents
– Reference - Arch Pediatr Adolesc Med 2004 Aug;158(8):760
• 15% lifetime prevalence of major depression in United States adolescents
and young adults
– Reference - Depress Anxiety 1998;7(1):3
• 20% of adolescents admitted to emergency department met criteria for
moderate-to-severe depression
– based on cross-sectional study of 967 patients aged 13-17 years admitted to
emergency department
– Reference - Arch Pediatr Adolesc Med 2008 Aug;162(8):769
9
The Burden of Depression
• Depression is an independent factor impacting a range
of medical conditions and increasing risk of death and
hospitalization:
– All cause mortality1
– Acute stroke2
– Diabetes3
– Myocardial infarction4
– Cardiovascular disease5
– Congestive heart failure6
– HIV7
1. Murphy, JM, et al Arch Gen Psychiatry. 1987. 44(5)473-480; 2. Everson, SA, et. al. Arch Intern Med. 1998; 158(10):
1133-1138; 3. Lustman, PT, et.al. Diabetes Care. 2000: 23(7): 934-942; 4. Frasure-Smith, N, et. al. JAMA. 1993;
270(15): 1819-1825; 5. Penninx, BW, et. al. Arch Gen Psych. 2001; 58(3): 221-227. 6. Vaccarino, V, et. al J. Am Coll
Cardiol. 2001; 38(1): 199-205. 7. Ickovics, JR, et. JAMA. 2001: 285(11): 1466-1474.
10
Mean Health Score in Depressed
People
• Amongst people with one chronic condition,
depressed respondents had lowest mean health
score (published in Lancet, in 2007).
• Conditions compared were:
Asthma, Angina, Arthritis, Diabetes, Depression.
• Depressed respondents with another chronic
condition had lower mean health scores than
respondents with the chronic condition alone.
11
Mean Health Score in Depressed
People
Depression Has an Impact on Mean Health Scores More
Than Other Chronic Conditions
“Depression had the largest effect on worsening mean health scores”
Mean Health Score (0-100)
100
†P<.01
*P<.0001
N=245,404
90.6 = No Chronic Condition
90
80
*
1
80
*2
*3
*4
80
79
79
70
60
*
73
Depression
Only
0
50
One Chronic Condition
†
1
†
2
†
3
67
66
65
†
4
59
Conditions
1. Asthma
2. Angina
3. Arthritis
4. Diabetes
Depression +
One Chronic Condition
* Depressed respondents had lowest mean score among all chronic conditions (P<.0001)
† Depressed respondents with another chronic condition had lower mean health scores than
respondents with the chronic condition alone (P<.01)
12
Depression and Stroke
• Depression increases risk of stroke in elderly
• Patients with depression have increased risk of
stroke mortality
• Stroke patients have increased risk of developing
depression
• Post stroke depression independently increases the
risk of death
13
Depression and Cardiovascular
Disease
• Prevalence of depression was increased in CAD,
Acute MI, Angina, CHF
• Patients with depressive symptoms had increased
risk of MI, cardiac death and mortality from all causes
• Depression doubled mortality rate after heart failure
• Post MI depression was associated with higher
mortality rate within 6 months following acute MI
14
The Impact of Depression
• Of the 30,000 people in the U.S. who commit suicide
each year, 60 percent have depression
• Increased risk of substance abuse/dependence
• Increased medical co-morbidities
• Strain on interpersonal relationships
• Estimated U.S. economic burden: $83.1 billion in
2000
• World Health Organization reported that MDD is
projected to become the second leading cause of
disability worldwide by 2020
Carney RM, Freedland KE. Biological Psychiatry. 2003;54(3):241-247.
15
Pathogenesis:
• Altered neurotransmitter levels : decreased
serotonin, decreased dopamine, and decreased
norepinephrine
• Biochemical changes: abnormal stress hormones,
decreased thyroid-stimulating hormone (TSH),
growth hormone, follicle-stimulating hormone,
luteinizing hormone, testosterone, immune function;
decreased TSH response to thyrotropin-releasing
hormone, decreased prolactin response to
tryptophan
• Depression is associated with lower occipital cortex
GABA levels and higher glutamate levels
16
Depression and Genetics
• A single gene has been shown to have high
correlation with depression
– Codes for serotonin transporter
17
Depression and Genetics
• Getting the short end of the gene:
• Why stressful experiences lead to depression in
some people but not in others?
• A functional polymorphism in the promoter region of
the serotonin transporter (5-HT T) gene was found to
moderate the influence of stressful life events on
depression.
• Individuals with one or two copies of the short allele
of the 5-HT T promoter polymorphism (SS or SL)
exhibited more depressive sxs, diagnosable
depression, and suicidality in relation to stressful life
events than individuals homozygous for the long
allele (LL).
18
Depression, Genetics and Coping
19
Interaction between stress and
genetic make up
20
Gender and Genetics Interaction
21
Mechanism of Atrophy 1
Dendrite Shrinkage
22
Mechanism of Atrophy 2
Neurogenesis: Control group of rats were allowed free life and other group was
restrained, causing stress and depression. They had less neurons being
formed; they had loss of neurogenesis.
23
Current Depression Treatment Options
• Pharmacologic
– Antidepressants and augmentation treatments
• Non-pharmacologic
– Psychotherapy
• Cognitive behavioral therapy
• Interpersonal therapy
• Psychodynamic therapy
– Life style changes and mindfulness
– Phototherapy
– Electroconvulsive therapy
– Deep Brain Stimulation (DBS)
– Vagus nerve stimulation
– Repetitive Transcranial Magnetic Stimulation (rTMS)
24
Role of Neurotrophic Factors
Antidepressants and Neurotrophic Factors
May Help Restore Communication in MDD
Micrograph
Micrograph
Hippocampal Pyramidal Neurons1,2
Reduced:
<
• Dendritic
arborization
Increased:
• Dendritic
arborization
>
• BDNF
expression
>
< • BDNF
expression
1. Adapted from: Nestler EJ, et al. Neuron. 2002;34:13-25.
2. Adapted from: Manji HK, et al. Biol Psychiatry. 2003;53:707-742.
Images reprinted with permission from Elsevier.
25
•
•
•
•
•
•
TCAs
MAOIs
SSRIs
SNRIs
Others
Augmentation
agents
26
Selective Antidepressants
Types
Generic BRAND
Serotonergic
•citalopram CELEXA
•escitalopram LEXAPRO
•fluvoxamine LUVOX
•fluoxetine PROZAC
•paroxetine PAXIL
•sertraline ZOLOFT
Catecholaminergic
• bupropion WELLBUTRIN SR,XL
Dual Mechanism
•venlafaxine EFFEXOR
mirtazapine REMERON
• duloxetine CYMBALTA
•desmethylvenlafaxine PRISTIQ
•Vilazodone VIIBRYD
Other (Serotonin+5HT1A)
27
Many Obstacles to Treatment of
Depression with Medications
Adequate Dosage
Adequate Duration
Factors contributing to inadequate treatment include:
Lack of
Efficacy
Poor
Tolerability
Nonadherence
Safety Issues
Comorbidities
Despite treatment ▬
4 million remain depressed4
.
1. Nemeroff CB. Depress Anxiety. 1996/1997;4(4):169-181; 2. Oquendo MA et al. J Clin Psychiatry. 2003;64(7):825-833; 3.
Oquendo MA et al. Am J Psychiatry. 1999;156(2):190-194. 4.Kessler RC, et al. JAMA. 2003;289(23):3095-3105.
28
STAR*D: Achieving Remission Is Difficult
Despite Adequate Treatment
Augmentation/Combination
Monotherapy
Mono
Level 11
(n=3671)
Aug
Mono
Level 22,3
(n=1439)
Aug
Mono
Level 34,5
(n=390)
Comb Mono
Level 46
(n=123)
Initial Treatment
Treatment-Resistance Continuum
1. Trivedi MH et al. Am J Psychiatry. 2006;163(1):28-40; 2. Trivedi MH et al. N Engl J Med. 2006;354(12):1243-1252;
3. Rush AJ et al. N Engl J Med. 2006;354(12):1231-1242; 4. Nierenberg AA et al. Am J Psychiatry. 2006;163(9):1519-1530;
5. Fava M et al. Am J Psychiatry. 2006;163(7):1161-1172; 6. McGrath PJ et al. Am J Psychiatry. 2006;163(9):1531-1541.
29
STAR*D: Discontinuation Rates Increase
With Increasing Treatment Resistance
Discontinuation Rate (%)
Augmentation/Combination
Monotherapy
Level 11
Level 22,3
Level 34,5
Level 46
Adverse events were the most common reason for treatment discontinuation
1. Trivedi MH et al. Am J Psychiatry. 2006;163(1):28-40; 2. Trivedi MH et al. N Engl J Med. 2006;354(12):1243-1252;
3. Rush AJ et al. N Engl J Med. 2006;354(12):1231-1242; 4. Nierenberg AA et al. Am J Psychiatry. 2006;163(9):1519-1530;
5. Fava M et al. Am J Psychiatry. 2006;163(7):1161-1172; 6. McGrath PJ et al. Am J Psychiatry. 2006;163(9):1531-1541.
30
Where Do We Go From Here?
• Available antidepressant medications are effective
for a significant number of MDD patients
• However, approximately one-third of MDD patients
don’t adequately benefit from, or can’t tolerate, the
available antidepressant medications
• Various combinations and augmentation strategies
are frequently utilized to treat resistant MDD
31
Beyond Pills – What are our Options?
• Lifestyle modifications: Exercise, nutrition,
environment manipulations
• Phototherapy
• Psychotherapy
• Biomedical treatments
– Electroconvulsive Therapy (ECT)
– Vagus Nerve Stimulation (VNS)
– Deep Brain Stimulation (DBS)
– Transcranial Magnetic Stimulation (TMS) Therapy
32
Psychotherapy
• “You should see a
therapist, it helps!”
33
Psychotherapy
• Cognitive Behavioral Therapy
CBT offers a practical approach, focusing on
managing symptoms rather than on origins of
symptom-causing conflicts:
Patients gain insight to their cognitive distortions
and learn to control automated negative thoughts,
learn relaxation and breathing techniques.
• Supportive therapy focuses on emotional support
and finding practical solutions to everyday problems.
34
Psychotherapy: improve coping
skills and instill hope
35
Psychotherapy
• Interpersonal therapy focuses on the here-and-now of
interpersonal problems which are worked through the
relationship with the psychotherapist and may
involve understanding of past transference reactions.
• Psychodynamic therapy has its origin in
Psychoanalysis and focuses mainly on the origins of
conflict, childhood events and psychic determinism
stemming from those early events and attachment
patterns. The resolution of symptoms occurs when
the conflict is brought to light and worked through in
therapy.
36
Mind-Body Interventions
37
Life Style Changes and Mind-body
Interventions:
• Yoga classes for 5 weeks may reduce depression and
anxiety
• Tai chi may reduce depressive symptoms in elderly
• Relaxation may reduce self-rated depressive symptoms,
but appears less effective than psychological treatment
• Mindfulness-based cognitive therapy may delay relapse
for patients with recurrent depression
• Music therapy may be effective for improving mood in
depression
• Spirituality education program (8-week audio-taped
program) associated with reductions in depression,
tension, anger and fatigue
38
Phototherapy
• Light therapy is used in Seasonal Affective Disorder
(winter depression) and non-Seasonal Affective
Disorders.
• It is generally safe in treating depressed persons,
pregnant women and also elderly
• Daily treatments of 30 min and above
• May cause eye strain and headaches
• Relapse rates are high after treatment is stopped
• Study indicates better treatment response to Vitamin
D, than light therapy.
39
Case Presentation
• 40 y/o male patient with recurrent MDD; he was tx’d
with SSRIs, SNRI, SNRI+Abilify, SNRI+Wellbutrin (off
label), SNRI+Wellbutrin+Methylphenidate (off label).
• He has been in therapy for several months, along
with medication therapy.
• He doesn’t want ECT because of his cognitively
demanding job.
• What else is there?
• Neuro-modulation methods:
Convulsive and Non-convulsive techniques.
40
Electroconvulsive Therapy (ECT)
• Introduced in 1930s; first use in US in 1940s
• Most effective treatment for resistant depression
• Works by inducing whole brain “seizure” pattern of
neural activation through application of direct
electrical current to scalp
• Modern ECT is controlled and painless with
anesthesia
• Common adverse events:
temporary confusion and
memory loss
• Long-term cognitive
dysfunction possible
Sackeim HA, et al. Neuropsychopharmacology. 2007;32(1):244-254.
41
Vagus Nerve Stimulation (VNS)
• Approved by FDA in 2005 as adjunct to
antidepressant medications
• Electrodes implanted on vagus nerve, pulse
generator in chest wall (indirect stimulation of
the brain)
• It may take up to 1 year to achieve results
• Response rate 27-45%, remission 16-29%
• Invasive procedure required (surgery) with
risks from anesthesia
• MRI contraindication
42
Deep Brain Stimulation (DBS)
• Deep brain stimulation (DBS)
is a neurological treatment in
which mild electrical signals
stimulate the brain, causing
improved symptoms of MDD,
PD and Essential Tremors.
• Invasive procedure: requires
Neurosurgery to place leads,
neurostimulator (like a heart
pacemaker) and an extension.
• Complications and risks could
include bleeding in your brain,
stroke or infection.
43
Transcranial Magnetic Stimulation (TMS)
• Application of electromagnetic
induction described by Michael
Faraday in 1839
– Faraday’s Law: a time-varying
magnetic field induces an
electric current
• Clinical application:
Pulsed magnetic fields
can induce electrical
currents in brain tissues
and neurons; causing
neuromodulation effects
44
.
TMS History
• At first, TMS, was developed to use as a brain mapping
tool, as a tool to measure cortical excitability, as a probe
of neuronal networks, and as a modulator of brain
function.
• In 1995, first documented human case report of rTMS in
MDD
TMS History
46
NeuroStar TMS Therapy System
Treatment Coil
Head Support Unit
Touchscreen
Mobile Console
Treatment Chair
NeuroStar TMS Therapy System User Manual. Neuronetics, Inc: Malvern, PA; 2008.
47
Effect of TMS on the Brain
Acute Effects
– Induces electric current
– Depolarizes neurons in superficial cortex
– Leads to local and trans-synaptic changes in brain
activity
• Alteration of monoamine concentrations (salivary
cortisol)
• Induction of neurotrophin genes (e.g. BDNF)
• Stimulation of DLPFC alters functional activity of deeper
regions (anterior cingulate cortex, ACC)
48
Effect of TMS on the Brain
• Example:
Left prefrontal TMS; 23 depressed individuals
Activation demonstrated at site of stimulation and
also at synaptically connected cortical and
subcortical regions
49
Effect of TMS on the Brain
50
Transcranial Magnetic Stimulation
• Brain reorganization takes place by
mechanisms such as “axonal sprouting” in
which undamaged axons grow new nerve
endings to reconnect neurons whose links
were injured or severed.
• Undamaged axons can also sprout nerve
endings and connect with other undamaged
nerve cells, forming new neural pathways to
accomplish a needed function.
• In order to reconnect, the neurons need to be stimulated through
activity.
• Neuroplasticity allows us to compensate for irreparably damaged or
dysfunctional neural pathways by strengthening or rerouting our
remaining ones.
51
Key TMS Therapy Terms
• Pulse Train: group of
Single
Magnetic
Pulse
electromagnetic pulses
followed by non-pulse
interval
time
• Stimulation Time:
.2 msec
duration of pulse train,
measured in seconds
Pulse
Train
(10 pulses/sec)
time
• Interval: time period
between pulse trains,
measured in seconds
1 sec
Treatment
Session
4 sec
26 sec
~ 40 min
52
Low Frequency vs. High Frequency
TMS
Concept of Depolarization Function
• Low Frequency Stimulation- inhibitory, more focal effect
• High Frequency Stimulation - facilitatory, multiple, spread out,
global “dendritic, axonal effect”.
High frequency rTMS when applied, a longer lasting effect can be
induced which is thought to result from a long term potentiation (LTP),
or depression (LTD) at the neuronal level.
53
Understanding Motor Threshold
(MT)
• Location: position on
motor cortex that
stimulates thumb
• Level: minimum
stimulation that induces
observable motor
response in 50% of
applied pulses
• % MT: pulse output used
for treatment, relative to
MT level
54
TMS Therapy Treatment Parameters
• Treatment sessions
– 37.5 minutes
• Treatment course
– 5x/week for 4 to 6 weeks
– Then taper over 3 weeks
• Treatment magnetic field strength = 120% of MT
• Treatment parameters
–
–
–
–
Stimulation time = 4 seconds
Pulses per second = 10
Interval = 26 seconds
Number of pulses = 3000
NeuroStar TMS Therapy System User Manual. Neuronetics, Inc: Malvern, PA; 2008.
55
APA Depression Treatment
Guidelines
56
TMS Data and Studies
• Early Clinic Studies (prior to 2003):
Provided guidance on dosing, dose dependency of
effect, and safety of TMS
Limitations included small sample sizes,
heterogeneous populations, wide ranging parameters
• Later Studies (2006 and later):
Modified and improved study designs and treatment
parameters (higher number of pulses) for stimulation
Recent meta-analysis studies found more robust
effects with later vs earlier studies (2009-2010)
(example: prozac study at 5 mg qday, 2 weeks vs 20 mg qday x 8 weeks)
57
NeuroStar TMS Therapy:
Clinical Development Program
Randomized,
Controlled Study1,2,4
‘101’
Improved
Maintenance of
Effect Study2,4,5
‘103’
Not
Improved
Open-Label
Crossover Study 2,3,4
‘102’
Improved
1. O’Reardon JP et al. Biol Psychiatry. 2007;62(11):1208-1216; 2. Janicak PG et al. J Clin
Psychiatry. 2008;69(2):222-232; 3. Avery DH et al. J Clin Psychiatry. 2008;69(3):441-451;
4. Lisanby SH et al. Neuropsychopharm, 2009;34(1):522-534; 5. Data on file: Study 103.
Neuronetics, Inc: Malvern, PA; 2008.
58
NeuroStar TMS Produced Significant
Improvements in Depressive Symptoms
MADRS Total Score
(Baseline to Endpoint Change)1
Baseline
Week 2
Week 4
HAMD-24 Total Score
(Baseline to Endpoint Change)2
Baseline
Week 6
-2
-4
-6
Week 4
Week 6
**
**
P=.0006
P=.0041
0
**
P=.0018
**
**
P=.0006
P=.0063
-8
Change From Baseline
Change From Baseline
0
Week 2
-2
-4
-6
P=.007
-8
NeuroStar TMS
Therapy (n=88)
**
Sham (n=76)
** P<.01.
LOCF analysis of evaluable study population.
1. Lisanby SH et al. Neuropsychopharmacology. 2009;34(2):522-534; 2. Data on file.
Neuronetics, Inc: Malvern, PA; 2008.
59
Analysis of Effect Size:
TMS vs. Antidepressant Medications
[95% CI
0.21–0.83]
N=164
1. Data on file. Neuronetics, Inc: Malvern, PA; 2008.
2. Turner EH et al. N Engl J Med. 2008;358(3):252-260.
Antidepressant
Medication2
Standardized Effect Size
(HAMD-17)
Standardized Effect Size
(HAMD-17)
NeuroStar TMS
Therapy1
[95% CI
0.26–0.36]
N=12,564
60
Clinically Meaningful Response and
Remission Rates
HAMD-24 Response Rates
HAMD-24 Remission Rates
(>50% Improvement from Baseline)
(HAMD-24 Total Score <11)
Data on file: Study 102. Neuronetics, Inc: Malvern, PA; 2008.
61
NeuroStar TMS Therapy:
Safety Overview
More than 10,000 active treatments performed across all studies
• No seizures
• No systemic side effects such as
weight gain, sexual dysfunction,
nausea, dry mouth, or sedation
• No adverse effect on cognition
• Most common adverse events
were headache and scalp
discomfort during active treatment
• <5% of patients discontinued due
to adverse events
Sham (n=146)
Prestudy 1
Janicak PG et al. J Clin Psychiatry. 2008;69(2):222-232.
2
3
NeuroStar TMS
Therapy (n=155)
4
5
Week
6
7
8
9
62
No Evidence of Emergent Suicidal Ideation
With TMS Therapy
•4.0
•HAMD Item 3 Suicidal Ideation
•Shift Score (%)*
•No adverse effect on cognitive
function
•Tested across several cognitive
function outcome measures
•No evidence of emergent
suicidal ideation
•NeuroStar TMS Therapy (n=155)
•3.5
•Sham TMS (n=146)
•3.0
•2.5
•2.0
•1.5
•1.0
•0.5
•0.0
•Baseline
•Week 2
•Week 4
•Week 6
* 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.
O’Reardon JP et al. Biol Psychiatry. 2007;62(11):1208-1216; Avery DH et al. J Clin Psychiatry.
2008;69(3):441-451; Janicak PG et al. J Clinical Psychiatry. 2008;69(2):222-232.
63
Summary of TMS Therapy Clinical
Evidence
• Efficacy established in largest multi-site, randomized,
sham-controlled TMS clinical trial conducted to date:
– Primary outcome (MADRS): 22.1% reduction in MADRS
total score with active NeuroStar TMS vs 9.1% on sham
– Clinically meaningful effect size = 0.52
• In open label extension study, 1 in 2 patients reached
response, 1 in 3 patients achieved remission
• In a 6 month, open-label follow up study that allowed
TMS reintroduction if needed, <10% of patients
experienced relapse of illness
• Safety and tolerability shown to be excellent
64
TMS Therapy in Clinical Practice
• Non-invasive
• No anesthesia or sedation
• Outpatient procedure easily performed
in psychiatrists’ offices
• Approximately 40-minute daily
procedure
• 4-6 week treatment course
• Contraindication considerations
• Non-removable metallic objects in or
near the head
• Conductive, ferromagnetic, or other
magnetic sensitive metals that are
implanted or are
non-removable within 30 cm of
treatment coil
NeuroStar TMS Therapy System User Manual. Neuronetics, Inc: Malvern, PA; 2008.
65
Quality of Life and Economic
Benefits
• TMS therapy shows improvements in standard measures
of functional status and quality of life
• When TMS is compared to current standard of care
using complex combination antidepressant medications
– TMS results in decreased number of days lost due to
illness, and increased work productivity,
– TMS results in a net cost savings relative to current
pharmaceutical standard of care
Simpson, KN, Welch, MJ, Kozel, FA, et al. Adv in Therapy 2009; 29(3):346-368; Neuronetics, Inc,
data on file.
66