Latest Advances in the Art and Science of Depression
• Pharmacological Treatment
• Non-Pharmacological Trans-Cranial Magnetic Stimulation; FDA approved, Non-Invasive Treatment
• Silicon Valley TMS,www.siliconvalleytms.com
Neuro-Psychiatry in Transition
• “From Shock Therapy and Psychoanalysis to the MAGNET(TMS) and the Highways in between
Saad A. Shakir, MD, DFAPA, FACIP and Associates,(www.siliconvalleytms.com)
(408)358-8090,[email protected]
Integrated Clinical Neuro-Sciences and Silicon Valley TMS,Los Gatos,
Formerly Adjunct Clinical Associate Professor Emeritus of Psychiatry and Behavioral Medicine.
Stanford University,California.
Transcranial Magnetic Stimulation (TMS)
The treatment coil produces MRI-strength magnetic field pulses.
Magnetic field pulses pass unimpeded through the cranium for 2-3 cm. and induce a small electric current.
Induced electric currents stimulate the firing of nearby neurons, causing the release of neurotransmitters and clinical effects.
Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet
4
AProven
Approach
In the 21st century depression will surpass all other medical disorders as the number one illness in the world
Why Depression is so Important
W.H.O., 2001.
0
20
40
60
80
100
MDD is Disabling and an Economic Burden
Rank* 1990 2020 (est)
1Lower respiratory infections
Ischemic heart disease
2 Perinatal conditions
Major depressive disorder
3 HIV/AIDS Road traffic accidents
4Major depressive disorder
Cerebro-vascular disease
5 Diarrheal diseases
Chronic obstructive pulmonary disease
1.Murray CJ, et al. Science. 1996;274:740-743.2.Greenberg PE, et al. J Clin Psychiatry. 2003;64:1465-1475.
US
$ B
illio
ns
Economic Burden of MDD2
US (2000)
*Rank based on a composite measure of Disability-Adjusted Life Year (DALY) in 15-44 year olds
Workplace
Suicide-related
Direct Medical
$83.1
62%
7%
31%
All Costs
Disability1
1. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4 Suppl):1-45.
AMERICAN PSYCHIATRIC ASSOCIATION1
“The goal of treatment with antidepressant medications in the acute phase is the remission of major depressive
disorder symptoms.”
THE CANADIAN PSYCHIATRIC ASSOCIATION in conjunction with THE CANADIAN NETWORK FOR MOOD AND ANXIETY
TREATMENTS1
“In clinical practice, it behooves us to adequately assess and treat depressive and anxiety disorders to remission.”
1. O’Donovan C. Can J Psychiatry. 2004;49(March Suppl 1):5S-9S.
1. Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression. Aust N Z J Psychiatry. 2004;38:389-407.
AUSTRALIAN AND NEW ZEALAND CLINICAL PRACTICE GUIDELINES1
“The aim of treatment is to achieve and maintain remission.”
1. Möller HJ. WHO Regional Office for Europe. Health Evidence Network report. 2005.
WORLD HEALTH ORGANIZATION REGIONAL OFFICE FOR EUROPE1
“The goal of acute treatment should always be the complete remission of
the episode and not just partial improvement.”
Challenges1.Poor Recognition
2.Underdiagnosis and misdiagnosis
3.Overutilization of healthcare resources(non-Psychiatric)
1.Poor RecognitionDepressed Patient Population
70% of depressed healthcare seekers are seen by primary care M.D(limited training in mental health)
50% recognized as “mood disorder”10% appropriately treated with correct:
2/3 never see M.D.
1/3 see M.D.
Drug
Duration
Diagnosis
Dosage
2.Why are Mental Health issues Undiagnosed or Underdiagnosed?
• Mental illness stigma • Crisis in health care financing(Time constraints: 7-
11 minutes/patient )• Clinical diagnosis is difficult
– Clinical picture varies: sad, angry, anhedonic– Disease is cyclical– Many criteria on which to judge diagnosis
• Primary care patients/physicians focus on somatic complaints(on avg.have 1-2 months training in MH)– Sleep disturbances Weight loss/gain– Fatigue Headache– Back pain Gastrointestinal
symptoms
3.Overutilization of wrong resources
10% of highest utilizers of PC consumed 50% of $$$(Top 10% Visitors to Primary Care Physicians)
Top 10% use 50% of financial resources(50% have Mental Health Issues)
Consequences• Premature Death from
Health Decline• Complications,suicide,
alcohol and substance use/abuse
• Quality of life issues
• Impact of family and Community
• Employment and financial productivity
• Other
Phases of Treatment
Adapted from: Kupfer DJ. J Clin Psychiatry. 1991(May);52(suppl):28-34
MaintenanceContinuationAcute
Full Recovery
Sev
erit
y
Time
Response
RelapseRecurrence
Treatment Phases
Symptoms
Remission
Syndrome
Relapse
Progression
to disorder
No Depression
50%
80%90%
Depression Is a Chronic Illness
0
50
100
Pro
bab
ilit
y o
f R
ecu
rren
t E
pis
od
es (
%)
After 1 Episode
After 2 Episodes
After 3 Episodes
Kupfer DJ. J Clin Psychiatry. 1991(May);52(suppl):28-34
RISK FACTORS FOR DEPRESSION AND ANXIETY
GENETIC
SOMATIC
PSYCHOLOGICAL
ENVIRONMENTAL
e.g.,SYSTEMIC ILLNESS CHRONIC PAIN,
ENDOCRINE DISORDER
FAMILY HISTORY
e.g., LOW SELF-ESTEEM, POOR COPING SKILLS
e.g., UNEMPLOYMENT, DIVORCE, ABUSE,
BEREAVEMENT
Crisis/Opportunity
Impact on Health and Wellness of untreated
Depression
Effects of Depression on Medical Disorders
• Depression increases likelihood of development of coronary artery disease(heart disease)
• Depression worsens outcome after myocardial infarction(heart attacks)
• Depression increases risk of stroke• Depression worsens outcome post-stroke• Depression may increase risk of other medical
disorders including diabetes, cancer,arthritis• Depression may worsen outcome of cancer, diabetes,
AIDS, and other disorders(Immune disorders ,allergies,etc.)
• Depression increases risk of cognitive issues and Dementia
The Science
Evidence of Hippocampal Atrophy and Loss in Patients With MDD
1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118.2. Sheline YI, et al. J Neurosci. 1999;19:5034-5043.3. Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93:3908-3913.4. Sheline YI, et al. Am J Psychiatry. 2003;160:1516-1518.
• Compared to controls, patients with depression had smaller hippocampal volumes (n=16)1
• Decreased hippocampal volume may be related to the duration of depression2-4
Images courtesy of JD Bremner.
Correlation Between Hippocampal Volume and Duration of Untreated Depression
Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.
38 Female Outpatients With Recurrent Depression in Remission
Days of Untreated Depression
Tot
al H
ippo
cam
pal V
olum
e (m
m3)
R2=.28 *P=.0006N=38
0 1000 2000 3000 40003000
3500
4000
4500
5000
5500
6000
• There was a significant inverse relationship between total hippocampal volume and the length of time depression went untreated
Reprinted with permission from APA.
Beyond the Synapse: Brain-derived Neurotrophic Factor (BDNF), Depression, and Antidepressants
• Neurogenesis (the birth of new neurons) continues postnatally and into adulthood
• BDNF is associated with production of new neurons and their growth and development1
• Data suggest that neurogenesis occurs in the hippocampus2
• The hippocampi appear to have important functions related to both mood and memory
• Data from depressed patients have shown reduced hippocampal volume3
• BDNF may influence regulation of mood4
• BDNF is downregulated in MDD and increased with successful antidepressant treatment4,5
• Both 5-HT and NE are believed to play roles in the modulation of BDNF1,5
1. Duman RS, et al. Arch Gen Psychiatry. 1997;54(7):597-606.2. Gould E, et al. Biol Psychiatry. 2000;48(8):715-720.3. Sheline YI, et al. Proc Natl Acad Sci U S A. 1996;93(9):3908-3913.4. Shimizu E, et al. Biol Psychiatry. 2003;54(1):70-75.
5. Maletic V, et al. Int J Clin Pract. 2007;61:2030-2040.
Image courtesy of RIKEN Institute.
The Role of BDNF in Neuronal Changes in Depression1-3
Stress
1. Duman RS, et al. Biol Psychiatry. 2000;59:732-739.2. Sapolsky RM. Arch Gen Psychiatry. 2000;57;925-935.3. Maletic V, et al. Int J Clin Pract. 2007;61:2030-2040.
Increased Secretion of Glucocorticoids
BDNF
Increased Activity of HPA Axis
• Normal Survival and Growth
HPA = hypothalamic pituitary adrenal axis
Production of Inflammatory Cytokines and Catecholamines
• Decreased DendriticBranching
• Atrophy/Death of Neurons
Antidepressants and Neurotrophic Factors May Help Restore Communication in MDD
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.
Hippocampal Pyramidal Neurons1,2
Reduced:
• Dendritic arborization
• BDNF expression
Increased:
• Dendritic arborization
• BDNF expression
Micrograph Micrograph
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The ART
““Designer Treatment of the 21st Designer Treatment of the 21st Century”Century”
Developments in the Medical Developments in the Medical Treatment of DepressionTreatment of Depression
“Black Bile” ECT/Analysis
TCAs MAOIs SSRI/SNRIs
Pharmacologic Refinements
1 st Century 1900 1930s 1950s 80/90’s TMS
Treatment Requires Understanding
Neurotransmitters offer a crucial conceptual bridge between the mind and the brain.
Axon Terminals Of Serotonergic Neurons Project To Virtually All Portions Of The Brain
Thalamus
Ventral Striatum
Amygdaloid Body
Hypothalamus
Olfactory And Entorhinal Cortices
Hippocampus
Rostral Raphe Nuclei
Striatum
Neocortex
Cingulum
To Hippocampus
Cerebellar Cortex
Intracerebellar Nuclei
Caudal Raphe Nuclei
To Spinal Cord
Cingulate Gyrus
Serotonergic Neurotransmission
TCA SSRI{
Reuptake
Postsynaptic Receptors
Presynaptic 5-HT Neuron
Synapse5-HT1A
5-HT1D
5-
HT1A
5-
HT1B
5-
HT1C
5-
HT1D
5-HT2
5-HT3
5-HT4
(rodentonly)
Autoreceptors
5-HT1D/1A
5-HT
5-HT1A
• Stimulation of:– 5-HT2A
• Behavioral activation, insomnia, anxiety, sexual dysfunction
– 5-HT2C
• Irritability, decreased appetite
– 5-HT3
• Nausea, headache and emesis
Side Effects Associated with Serotonin Receptor Stimulation
Kaplan and Sadock. Synopsis of Psychiatry, Behavioral Sciences, Clinical Psychiatry. 6th ed. 1991 (revised).
Norepinephrine Innervation Of The CNS
Cerebral Cortex
Fornix
NucleusAccumbens
Amygdala
Hypothalamus
Dorsal Bundle
Ventral Bundle
Stria Terminalis
Hippocampus Projection
Thalamic Projection
Locus Ceruleus
Medullary Cell BodiesAnd Spinal Pathways
Dopamine Neurotransmission Relative to ADHD
• Enhances signal• Improves attention
– Focus– On-task behavior– On-task cognition
Solanto. Stimulant Drugs and ADHD. Oxford; 2001.
Nigrostriatal Pathway
Mesolimbic Pathway
Substantia nigra
Ventral tegmental area
Mesocortical Pathway
DopamineDopamine
SEROTONINSEROTONIN NOREPINEPHRINE
DOPAMINEDOPAMINE
IMPAIRED IMPAIRED MODULATIONMODULATION
IMPAIRED IMPAIRED ACTIVATIONACTIVATION
DEPRESSIONDEPRESSION
Metzner, 2000
FatigueFatigue
ApathyApathy
AnhedoniaAnhedonia
HypersomniaHypersomnia
LackLack ofof initiativeinitiative
InabilityInability toto concentrateconcentrate
DecreasedDecreased productivityproductivity
AnxietyAnxiety
IrritabilityIrritability
HostilityHostility
ImpulsivityImpulsivity
AgitationAgitation
HypochondriasisHypochondriasis
SuicidalitySuicidality
Reduced Neurotransmission and Neural Adaptability
Current Depression Treatment Options
• Nonpharmacologic– Psychotherapy
• Cognitive behavioral therapy• Interpersonal therapy• Psychodynamic therapy
– Electroconvulsive therapy– Phototherapy
– Rapid transcranial magnetic stimulation (RTMs)
– Vagus nerve stimulation
• Pharmacologic– Antidepressant medications
Depression Guideline Panel. Depression in Primary Care: Vol 1. Detection and Diagnosis. Clinical Practice Guideline No. 5. 1993
Classes of Classes of AntidepressantsAntidepressants
• TCAs• MAOIs• SSRIs• SNRIs• Others
Selective AntidepressantsTypes 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
But Wait Do We Have Perfect Well-Tolerated Anti-
Depressants?That are well tolerated?
And Work often?
Nemeroff (1996/1997) Depress Anxiety; Oquendo (2003) J Clin Psychiatry; Oquendo (1999) Am J Psychiatry.
Adequate Treatment Is Difficult to Achieve
• Adequacy of treatment has been estimated to be as low as 18%, regardless of agent used
• The ratio of inadequate-to-adequate treatment attempts is 4:1
…adequate treatment in depression is the exception, not the norm
Adequate Dosage
Adequate Dosage
Adequate Duration
Adequate Duration
Poor tolerability
Poor tolerabilityLack of adherence
to recommended treatment
Lack of adherence to recommended
treatment
Lack of efficacyLack of efficacyMedical and Psychiatric
Comorbidities
Medical and Psychiatric
Comorbidities
Factors contributing to inadequate treatment include:
Unmet Medical Needs
STAR*D Study demonstrates that current treatment has limited effectiveness
Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry
Unmet Medical Needs
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)
Unmet Medical Needs
Solutions?
Technology (to the rescue)
• Education
• Recognition
• Effective treatment that is well received
• Medically based Treatment
• Short term and successful
• No systemic side effects
NeuroStar TMS Therapy
A Proven Approach
Best Practices Treatment Guideline for DepressionBased on 2010 APA practice 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
Treating the Brain as an Electrochemical Target
Major brain regions known to be involved in mood regulation
Amygdala
VentromedialPrefrontal Cortex
PrefrontalCortex
Anterior Cingulate Gyrus
Brain activity can be altered:
• Chemically (eg, via drugs) or,
• Electrically (eg, via TMS)
– Drug action is anatomically diffuse and systemic
– TMS is focused, non-invasive and non-systemic
Pizzigalli (2011) Neuropsychopharmacology
AProven
Approach
Transcranial Magnetic Stimulation (TMS)
The treatment coil produces MRI-strength magnetic field pulses.
Magnetic field pulses pass unimpeded through the cranium for 2-3 cm. and induce a small electric current.
Induced electric currents stimulate the firing of nearby neurons, causing the release of neurotransmitters and clinical effects.
Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet
52
AProven
Approach
Activation of fronto-cingulate brain circuit following a course of TMS applied to the left dorsolateral prefrontal cortex in patients with Major Depression
Targeted Effects on Mood Circuits in Brain
Kito (2008) J Neuropsychiatry Clin Neurosci
TMS CoilL
L
R
R
53
AProven
Approach
NeuroStar TMS Therapy Demonstration
Video
TMS Therapy in Clinical Practice
• Only TMS device FDA-cleared for the treatment of depression
• Non-invasive and non-systemic
• The most common side effect associated with treatment is scalp pain or discomfort – generally mild to moderate
• Outpatient procedure, can be performed in a psychiatrist’s office; no anesthesia or sedation
• 37 minute treatment, administered daily for 4-6 weeks
• Observed therapy facilitates adherence with treatment
• Available by prescription only 55
AProven
Approach
NeuroStar TMS Therapy:
Role of NeuroStar TMS in the Treatment for Major
Depression
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); Institute for Clinical Systems Improvement (2010); American Psychiatric Association (2010)
Guideline SourcesWorld Federation of Societies for
Biological Psychiatry (2009)
Canadian Network for Mood and
Anxiety Treatments (2009)
Institute for Clinical Systems
Improvement (2010)
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…”
Where It
Fits
Private Practices
Institutions
NeuroStar TMS Practice Locations>300 Systems Installed as of December 2011
SILICON VALLEY TMSWWW.SILICONVALLEYTMS.COM
• Fastest growing and busiest center in Northern California
• 2nd Treatment system recently added• Center of Excellence• S.A.Shakir,MD medical director(founder)• 20 clinicians/technical integrated team including
MD,NP’s,Psychology,Counselors,Nursing etc.• Many Patients already treated very successfully
TMS Express:Brain Booster Depression Buster Therapy(BBDBT)Available in 5 or 10 Treatment Package
Used for quick control of breakthrough or residual depression in patients already under treatment as an adjunctive depressionDissolving therapy
Developed by Silicon Valley TMS
Silicon Valley TMSwww.siliconvalleytms.com“International Center of
excellence”• National Presentations (Numerous)• International Presentations• Nazareth,Palestine Nov.2011• Dubai,UAE, April 2012• Istanbul,Turkey July 2012• Beirut,Lebanon,July 2012• Others in the horizon?
For more informationwww.siliconvalleytms.com.
or www.NeuroStar.com
Thank you!
THANK YOU QUESTIONS????
(408)[email protected]