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,shakirmd@verizon.net

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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>

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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)358-8090shakirmd@verizon.net