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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)
                                                                                                                              A
                                                                                                                           Proven
                                                                                                                          Approach

                                                                                                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.

                                                                                                                               4
Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet
Why Depression is so
       Important

In the 21st century depression will
surpass all other medical disorders
as the number one illness in the
world


W.H.O., 2001.
MDD is Disabling and an Economic Burden

                                Disability1                                             Economic Burden of MDD2
                                                                                              US (2000)
  Rank*            1990                             2020 (est)
                   Lower                                                          100
       1           respiratory                    Ischemic heart
                   infections                     disease                                  $83.1
                                                                                  80
                   Perinatal                      Major
       2           conditions                     depressive




                                                                   US$ Billions
                                                  disorder                        60
                                                  Road traffic
                                                                                            62%
       3           HIV/AIDS                       accidents
                                                                                  40                  Workplace
                   Major                          Cerebro-
       4           depressive                     vascular                                  7%        Suicide-related
                   disorder                       disease                         20
                                                                                                      Direct Medical
                                                  Chronic                                   31%
       5           Diarrheal                      obstructive
                   diseases                       pulmonary                        0
                                                  disease                                 All Costs
 *Rank based on a composite measure of Disability-
 Adjusted Life Year (DALY) in 15-44 year olds


1.Murray CJ, et al. Science. 1996;274:740-743.
2.Greenberg PE, et al. J Clin Psychiatry. 2003;64:1465-1475.
Dr. Shakir's CTF Presentation - Depression Treatment
AMERICAN PSYCHIATRIC
                                                                ASSOCIATION1
                                                  “The goal of treatment with antidepressant
                                                      medications in the acute phase is
                                                     the remission of major depressive
                                                             disorder symptoms.”




1. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4 Suppl):1-45.
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.
AUSTRALIAN AND NEW ZEALAND CLINICAL PRACTICE
                                              GUIDELINES1
                       “The aim of treatment is to achieve and maintain remission.”




1. Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression. Aust N Z J
Psychiatry. 2004;38:389-407.
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.”




1. Möller HJ. WHO Regional Office for Europe. Health Evidence Network report. 2005.
Dr. Shakir's CTF Presentation - Depression Treatment
Challenges
        1.Poor Recognition
2.Underdiagnosis and misdiagnosis
  3.Overutilization of healthcare
    resources(non-Psychiatric)
1.Poor Recognition
            Depressed Patient Population
 2/3                                            1/3 see
 never                                          M.D.
 see M.D.


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:
              Diagnosis        Drug
              Dosage           Duration
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     • Impact of family and
  Health Decline             Community
• Complications,suicide,   • Employment and
  alcohol and substance      financial productivity
  use/abuse                • Other
• Quality of life issues
Phases of Treatment
                                       Full Recovery
                                              Remission                 Recurrence
                   No Depression                          Relapse

                                              Relapse
        Severity




                   Symptoms             Response
                   Syndrome
                           Pro
                         to

                               gre
                                 d is

                                  ss
                                     ord

                                      ion
                                         er




                                                Acute ContinuationMaintenance
                     Treatment Phases
                                                 Time
Adapted from: Kupfer DJ. J Clin Psychiatry. 1991(May);52(suppl):28-34
Depression Is a Chronic Illness
       Recurrent Episodes (%)
                                100                       90%
                                                  80%
           Probability of




                                        50%
                                50



                                 0
                                       After 1 After 2  After 3
                                      Episode Episodes Episodes

Kupfer DJ. J Clin Psychiatry. 1991(May);52(suppl):28-34
RISK FACTORS FOR
DEPRESSION AND ANXIETY
      GENETIC   FAMILY HISTORY

                   e.g.,SYSTEMIC ILLNESS
       SOMATIC             CHRONIC PAIN,
                   ENDOCRINE DISORDER

        PSYCHOLOGICAL
                     e.g., LOW SELF-ESTEEM,
                        POOR COPING SKILLS

         ENVIRONMENTAL
                     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




                                                                     • 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




1.   Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118.                           Images courtesy of JD Bremner.
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.
Correlation Between Hippocampal Volume and Duration
  of Untreated Depression

                                                38 Female Outpatients With Recurrent Depression in Remission
        Total Hippocampal Volume (mm3)


                                         6000                                                          R2=.28
                                                                                                       *P=.0006
                                                                                                       N=38
                                         5500

                                         5000

                                         4500

                                         4000

                                         3500

                                         3000
                                                0           1000            2000           3000                   4000
                                                               Days of Untreated Depression
 • There was a significant inverse relationship between total hippocampal
   volume and the length of time depression went untreated

Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.                                    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.            5. Maletic V, et al. Int J Clin Pract. 2007;61:2030-2040.
 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.                                                            Image courtesy of RIKEN Institute.
The Role of BDNF in Neuronal Changes in Depression1-3

                                                            Stress
                       Production of                                 Increased Activity
                       Inflammatory Cytokines                          of HPA Axis
                       and Catecholamines
                                                                          Increased Secretion of
                                                                          Glucocorticoids



                                                            BDNF
                                                                                      • Decreased
                                                                                        Dendritic
• Normal Survival                                                                       Branching
  and Growth
                                                                                      • Atrophy/Death of
                                                                                        Neurons

HPA = hypothalamic pituitary adrenal axis

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.
Antidepressants and Neurotrophic Factors
  May Help Restore Communication in MDD
Micrograph                                                                                                           Micrograph
                                       Hippocampal Pyramidal                Neurons1,2

                                                  Reduced:            Increased:

                                                                      • Dendritic
                                                                        arborization   >
                                            < • Dendritic
                                                arborization




                                                                      • BDNF
                                                                        expression     >
                                             < • BDNF
                                                 expression



1. Adapted from: Nestler EJ, et al. Neuron. 2002;34:13-25.                                 Images reprinted with permission from Elsevier.
2. Adapted from: Manji HK, et al. Biol Psychiatry. 2003;53:707-742.
The ART
“Designer Treatment of the 21st
                      Century”
               Developments in the Medical
                Treatment of Depression
                                         Pharmacologic
                                          Refinements
  “Black                        TCAs
   Bile”                       MAOIs
                    ECT/Analysis        SSRI/SNRIs

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                    Cingulum
                                                    Cingulate Gyrus
        Striatum                                    To Hippocampus
   Neocortex

Ventral Striatum
Amygdaloid Body
          Hypothalamus                             Cerebellar Cortex
                                                 Intracerebellar Nucle
  Olfactory And Entorhinal
          Cortices                             Caudal Raphe Nuclei
               Hippocampus
                                          To Spinal Cord
                   Rostral Raphe Nuclei
Serotonergic Neurotransmission
                            Postsynapt
                                           ic
                                    TCA
                               {    SSRI
                                            Receptors
                                            5-
                Reuptake
Presynaptic 5-HT                            HT1A
Neuron                                             (rodent
                                            5-
                                                   only)
                                            HT1B
                               5-HT
                                            5-
                                            HT1C
                                            5-
 5-HT1A            5-HT1D/1A
                                            HT1D

                                   Synapse 5-HT2
Autoreceptors 5-HT1A                       5-HT3
              5-HT1D
Dr. Shakir's CTF Presentation - Depression Treatment
Side Effects Associated with
Serotonin Receptor Stimulation

• Stimulation of:
   – 5-HT2A
      • Behavioral activation, insomnia, anxiety, sexual
        dysfunction
   – 5-HT2C
      • Irritability, decreased appetite
   – 5-HT3
      • Nausea, headache and emesis
Norepinephrine Innervation Of The CNS

            Cerebral Cortex               Stria Terminalis
                                                          Hippocampus
                                                          Projection
     Fornix
                                                          Thalamic Projection
 Nucleus
Accumbens
                                                         Locus Ceruleus

     Amygdala

            Hypothalamus                         Medullary Cell Bodies
                  Dorsal Bundle                  And Spinal Pathways

                            Ventral Bundle

     Kaplan and Sadock. Synopsis of Psychiatry, Behavioral Sciences, Clinical
                      Psychiatry. 6th ed. 1991 (revised).
Dopamine Neurotransmission
      Relative to ADHD
  Dopamine
                                      Nigrostriatal Pathway
• Enhances signal
• Improves attention                          Mesolimbic Pathway
   – Focus                                              Substantia
   – On-task behavior                                   nigra
   – On-task cognition Mesocortical
                       Pathway              Ventral
                                            tegmental
                                            area




                                  Solanto. Stimulant Drugs and ADHD. Oxford; 2001.
Reduced Neurotransmission and Neural
           Adaptability
       SEROTONIN                       NOREPINEPHRINE

IMPAIRED                                        IMPAIRED
MODULATION                                    ACTIVATION
        Anxiety                                    Fatigue
        Irritability
                        DEPRESSION                  Apathy
        Hostility                               Anhedonia
        Impulsivity                          Hypersomnia
        Agitation                         Lack of initiative
        Hypochondriasis           Inability to concentrate
        Suicidality                             Decreased
                         DOPAMINE              productivity
Metzner, 2000
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
•   TCAs
                  •   MAOIs
  Classes of      •   SSRIs
Antidepressants
                  •   SNRIs
                  •   Others
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
But Wait Do We Have Perfect
    Well-Tolerated Anti-
       Depressants?
     That are well tolerated?
       And Work often?
Adequate Treatment Is Difficult to
                    Achieve
                                                                                                                       Unmet
                                                                                                                       Medical
                                                                                                                       Needs
                      Adequate                               Adequate
                                                                                                 • Adequacy of treatment
                       Dosage                                Duration
                                                                                                   has been estimated
     Factors contributing to inadequate treatment include:                                         to be as low as 18%,
                                                                                                   regardless of agent used
        Lack of adherence                                          Poor
        to recommended                                          tolerability                     • The ratio of inadequate-
            treatment
                                                                                                   to-adequate treatment
                                                     Medical and                                   attempts is 4:1
                         Lack of efficacy            Psychiatric
                                                    Comorbidities




                                                 …adequate treatment in depression
                                                      is the exception, not the norm
Nemeroff (1996/1997) Depress Anxiety; Oquendo (2003) J Clin Psychiatry; Oquendo (1999) Am J Psychiatry.
STAR*D Study demonstrates that current
            treatment has limited effectiveness
                                                                                                                           Unmet
                                                                                                                           Medical
                                                                                                                           Needs




Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry
Likelihood of discontinuing treatment increases
              with each new medication attempt
                                                                                                                                     Unmet
                                                                                                                                     Medical
                                                                                                                                     Needs

                                                                                                     Systemic Drug Side Effects
                                                                                                   Weight Gain       Fatigue

                                                                                                   Constipation      Headache/
                                                                                                                       Migraine
                                                                                                   Diarrhea
                                                                                                                      Abnormal
                                                                                                   Nausea             Ejaculation

                                                                                                   Drowsiness        Impotence

                                                                                                   Insomnia          Sweating

                                                                                                   Decreased         Tremor
                                                                                                    Libido
                                                                                                                      Treatment
                                                                                                   Nervous            Discontinuation
                                                                                                    Anxiety            Side Effects

                                                                                                   Increased         Weakness
                                                                                                    Appetite
                                                                                                                      Dry Mouth
                                                                                                   Decreased
                                                                                                    Appetite          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)
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 Depression
            Based on 2010 APA practice guidelines and NeuroStar TMS
                           Therapy® indication for use.

                                                                                                                         Unmet
                                                                                                                         Medical
                                                                                                                         Needs




Adapted from: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd Edition, APA (2010)
Treating the Brain as an
                            Electrochemical Target
                                                                                       A
                                                                                    Proven
                                            Anterior Cingulate Gyrus               Approach


                                            Prefrontal
                                            Cortex
 Brain activity can be altered:
    • Chemically (eg, via
       drugs) or,
    • Electrically (eg, via TMS)
                                               Ventromedial
                                               Prefrontal Cortex
 – Drug action is anatomically                                     Amygdala
   diffuse and systemic
 – TMS is focused, non-invasive
   and non-systemic                                  Major brain regions known to be
                                                        involved in mood regulation

Pizzigalli (2011) Neuropsychopharmacology
Transcranial Magnetic Stimulation
                     (TMS)
                                                                                                                              A
                                                                                                                           Proven
                                                                                                                          Approach

                                                                                                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.

                                                                                                                             52
Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet
Targeted Effects on Mood Circuits in Brain
                                                                         A
                                                                      Proven
                                                                     Approach
                                        L                R




                                              TMS Coil
                                        L                R




  Activation of fronto-cingulate brain circuit following a course of
    TMS applied to the left dorsolateral prefrontal cortex in patients
    with Major Depression                                                53
Kito (2008) J Neuropsychiatry Clin Neurosci
NeuroStar TMS
Therapy Demonstration
        Video
TMS Therapy in Clinical
              Practice                                                A
                                                                   Proven
                                                                  Approach




•   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
NeuroStar TMS
    Therapy:
Role of NeuroStar TMS in
 the Treatment for Major
       Depression
TMS is Included in Practice Guidelines
                    Following Failure of Initial Treatment                                                                     Where
                                                                                                                                 It
                                                       Guideline Sources                                                        Fits


                                 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…”

                                                            Guideline Sources
     World Federation of                                   Canadian Network                               Institute for Clinical
         Societies for                                       for Mood and                                       Systems
     Biological Psychiatry                                 Anxiety Treatments                                Improvement
            (2009)                                               (2009)                                          (2010)


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)
NeuroStar TMS Practice Locations
     >300 Systems Installed as of December 2011




               Private
               Practices      Institutions
SILICON VALLEY TMS
WWW.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 depression
Dissolving therapy



Developed by Silicon Valley TMS
Silicon Valley TMS
      www.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 information
www.siliconvalleytms.com.
  or www.NeuroStar.com




             Thank you!
THANK YOU
  QUESTIONS????
    (408)358-8090
shakirmd@verizon.net
Dr. Shakir's CTF Presentation - Depression Treatment

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Dr. Shakir's CTF Presentation - Depression Treatment

  • 1. 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
  • 2. Neuro-Psychiatry in Transition • “From Shock Therapy and Psychoanalysis to the MAGNET(TMS) and the Highways in between
  • 3. 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.
  • 4. Transcranial Magnetic Stimulation (TMS) A Proven Approach  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. 4 Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet
  • 5. Why Depression is so Important In the 21st century depression will surpass all other medical disorders as the number one illness in the world W.H.O., 2001.
  • 6. MDD is Disabling and an Economic Burden Disability1 Economic Burden of MDD2 US (2000) Rank* 1990 2020 (est) Lower 100 1 respiratory Ischemic heart infections disease $83.1 80 Perinatal Major 2 conditions depressive US$ Billions disorder 60 Road traffic 62% 3 HIV/AIDS accidents 40 Workplace Major Cerebro- 4 depressive vascular 7% Suicide-related disorder disease 20 Direct Medical Chronic 31% 5 Diarrheal obstructive diseases pulmonary 0 disease All Costs *Rank based on a composite measure of Disability- Adjusted Life Year (DALY) in 15-44 year olds 1.Murray CJ, et al. Science. 1996;274:740-743. 2.Greenberg PE, et al. J Clin Psychiatry. 2003;64:1465-1475.
  • 8. AMERICAN PSYCHIATRIC ASSOCIATION1 “The goal of treatment with antidepressant medications in the acute phase is the remission of major depressive disorder symptoms.” 1. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4 Suppl):1-45.
  • 9. 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.
  • 10. AUSTRALIAN AND NEW ZEALAND CLINICAL PRACTICE GUIDELINES1 “The aim of treatment is to achieve and maintain remission.” 1. Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression. Aust N Z J Psychiatry. 2004;38:389-407.
  • 11. 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.” 1. Möller HJ. WHO Regional Office for Europe. Health Evidence Network report. 2005.
  • 13. Challenges 1.Poor Recognition 2.Underdiagnosis and misdiagnosis 3.Overutilization of healthcare resources(non-Psychiatric)
  • 14. 1.Poor Recognition Depressed Patient Population 2/3 1/3 see never M.D. see M.D. 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: Diagnosis Drug Dosage Duration
  • 15. 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
  • 16. 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)
  • 17. Consequences • Premature Death from • Impact of family and Health Decline Community • Complications,suicide, • Employment and alcohol and substance financial productivity use/abuse • Other • Quality of life issues
  • 18. Phases of Treatment Full Recovery Remission Recurrence No Depression Relapse Relapse Severity Symptoms Response Syndrome Pro to gre d is ss ord ion er Acute ContinuationMaintenance Treatment Phases Time Adapted from: Kupfer DJ. J Clin Psychiatry. 1991(May);52(suppl):28-34
  • 19. Depression Is a Chronic Illness Recurrent Episodes (%) 100 90% 80% Probability of 50% 50 0 After 1 After 2 After 3 Episode Episodes Episodes Kupfer DJ. J Clin Psychiatry. 1991(May);52(suppl):28-34
  • 20. RISK FACTORS FOR DEPRESSION AND ANXIETY GENETIC FAMILY HISTORY e.g.,SYSTEMIC ILLNESS SOMATIC CHRONIC PAIN, ENDOCRINE DISORDER PSYCHOLOGICAL e.g., LOW SELF-ESTEEM, POOR COPING SKILLS ENVIRONMENTAL e.g., UNEMPLOYMENT, DIVORCE, ABUSE, BEREAVEMENT
  • 22. Impact on Health and Wellness of untreated Depression
  • 23. 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
  • 25. Evidence of Hippocampal Atrophy and Loss in Patients With MDD • 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 1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118. Images courtesy of JD Bremner. 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.
  • 26. Correlation Between Hippocampal Volume and Duration of Untreated Depression 38 Female Outpatients With Recurrent Depression in Remission Total Hippocampal Volume (mm3) 6000 R2=.28 *P=.0006 N=38 5500 5000 4500 4000 3500 3000 0 1000 2000 3000 4000 Days of Untreated Depression • There was a significant inverse relationship between total hippocampal volume and the length of time depression went untreated Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518. Reprinted with permission from APA.
  • 27. 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. 5. Maletic V, et al. Int J Clin Pract. 2007;61:2030-2040. 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. Image courtesy of RIKEN Institute.
  • 28. The Role of BDNF in Neuronal Changes in Depression1-3 Stress Production of Increased Activity Inflammatory Cytokines of HPA Axis and Catecholamines Increased Secretion of Glucocorticoids BDNF • Decreased Dendritic • Normal Survival Branching and Growth • Atrophy/Death of Neurons HPA = hypothalamic pituitary adrenal axis 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.
  • 29. Antidepressants and Neurotrophic Factors May Help Restore Communication in MDD Micrograph Micrograph Hippocampal Pyramidal Neurons1,2 Reduced: Increased: • Dendritic arborization > < • Dendritic arborization • BDNF expression > < • BDNF expression 1. Adapted from: Nestler EJ, et al. Neuron. 2002;34:13-25. Images reprinted with permission from Elsevier. 2. Adapted from: Manji HK, et al. Biol Psychiatry. 2003;53:707-742.
  • 31. “Designer Treatment of the 21st Century” Developments in the Medical Treatment of Depression Pharmacologic Refinements “Black TCAs Bile” MAOIs ECT/Analysis SSRI/SNRIs 1 st Century 1900 1930s 1950s 80/90’s TMS
  • 32. Treatment Requires Understanding Neurotransmitters offer a crucial conceptual bridge between the mind and the brain.
  • 33. Axon Terminals Of Serotonergic Neurons Project To Virtually All Portions Of The Brain Thalamus Cingulum Cingulate Gyrus Striatum To Hippocampus Neocortex Ventral Striatum Amygdaloid Body Hypothalamus Cerebellar Cortex Intracerebellar Nucle Olfactory And Entorhinal Cortices Caudal Raphe Nuclei Hippocampus To Spinal Cord Rostral Raphe Nuclei
  • 34. Serotonergic Neurotransmission Postsynapt ic TCA { SSRI Receptors 5- Reuptake Presynaptic 5-HT HT1A Neuron (rodent 5- only) HT1B 5-HT 5- HT1C 5- 5-HT1A 5-HT1D/1A HT1D Synapse 5-HT2 Autoreceptors 5-HT1A 5-HT3 5-HT1D
  • 36. Side Effects Associated with Serotonin Receptor Stimulation • Stimulation of: – 5-HT2A • Behavioral activation, insomnia, anxiety, sexual dysfunction – 5-HT2C • Irritability, decreased appetite – 5-HT3 • Nausea, headache and emesis
  • 37. Norepinephrine Innervation Of The CNS Cerebral Cortex Stria Terminalis Hippocampus Projection Fornix Thalamic Projection Nucleus Accumbens Locus Ceruleus Amygdala Hypothalamus Medullary Cell Bodies Dorsal Bundle And Spinal Pathways Ventral Bundle Kaplan and Sadock. Synopsis of Psychiatry, Behavioral Sciences, Clinical Psychiatry. 6th ed. 1991 (revised).
  • 38. Dopamine Neurotransmission Relative to ADHD Dopamine Nigrostriatal Pathway • Enhances signal • Improves attention Mesolimbic Pathway – Focus Substantia – On-task behavior nigra – On-task cognition Mesocortical Pathway Ventral tegmental area Solanto. Stimulant Drugs and ADHD. Oxford; 2001.
  • 39. Reduced Neurotransmission and Neural Adaptability SEROTONIN NOREPINEPHRINE IMPAIRED IMPAIRED MODULATION ACTIVATION Anxiety Fatigue Irritability DEPRESSION Apathy Hostility Anhedonia Impulsivity Hypersomnia Agitation Lack of initiative Hypochondriasis Inability to concentrate Suicidality Decreased DOPAMINE productivity Metzner, 2000
  • 40. 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
  • 41. TCAs • MAOIs Classes of • SSRIs Antidepressants • SNRIs • Others
  • 42. 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
  • 43. But Wait Do We Have Perfect Well-Tolerated Anti- Depressants? That are well tolerated? And Work often?
  • 44. Adequate Treatment Is Difficult to Achieve Unmet Medical Needs Adequate Adequate • Adequacy of treatment Dosage Duration has been estimated Factors contributing to inadequate treatment include: to be as low as 18%, regardless of agent used Lack of adherence Poor to recommended tolerability • The ratio of inadequate- treatment to-adequate treatment Medical and attempts is 4:1 Lack of efficacy Psychiatric Comorbidities …adequate treatment in depression is the exception, not the norm Nemeroff (1996/1997) Depress Anxiety; Oquendo (2003) J Clin Psychiatry; Oquendo (1999) Am J Psychiatry.
  • 45. STAR*D Study demonstrates that current treatment has limited effectiveness Unmet Medical Needs Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry
  • 46. Likelihood of discontinuing treatment increases with each new medication attempt Unmet Medical Needs Systemic Drug Side Effects  Weight Gain  Fatigue  Constipation  Headache/ Migraine  Diarrhea  Abnormal  Nausea Ejaculation  Drowsiness  Impotence  Insomnia  Sweating  Decreased  Tremor Libido  Treatment  Nervous Discontinuation Anxiety Side Effects  Increased  Weakness Appetite  Dry Mouth  Decreased Appetite  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)
  • 48. Technology (to the rescue) • Education • Recognition • Effective treatment that is well received • Medically based Treatment • Short term and successful • No systemic side effects
  • 49. NeuroStar TMS Therapy A Proven Approach
  • 50. Best Practices Treatment Guideline for Depression Based on 2010 APA practice guidelines and NeuroStar TMS Therapy® indication for use. Unmet Medical Needs Adapted from: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd Edition, APA (2010)
  • 51. Treating the Brain as an Electrochemical Target A Proven Anterior Cingulate Gyrus Approach Prefrontal Cortex Brain activity can be altered: • Chemically (eg, via drugs) or, • Electrically (eg, via TMS) Ventromedial Prefrontal Cortex – Drug action is anatomically Amygdala diffuse and systemic – TMS is focused, non-invasive and non-systemic Major brain regions known to be involved in mood regulation Pizzigalli (2011) Neuropsychopharmacology
  • 52. Transcranial Magnetic Stimulation (TMS) A Proven Approach  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. 52 Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet
  • 53. Targeted Effects on Mood Circuits in Brain A Proven Approach L R TMS Coil L R Activation of fronto-cingulate brain circuit following a course of TMS applied to the left dorsolateral prefrontal cortex in patients with Major Depression 53 Kito (2008) J Neuropsychiatry Clin Neurosci
  • 55. TMS Therapy in Clinical Practice A Proven Approach • 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
  • 56. NeuroStar TMS Therapy: Role of NeuroStar TMS in the Treatment for Major Depression
  • 57. TMS is Included in Practice Guidelines Following Failure of Initial Treatment Where It Guideline Sources Fits 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…” Guideline Sources World Federation of Canadian Network Institute for Clinical Societies for for Mood and Systems Biological Psychiatry Anxiety Treatments Improvement (2009) (2009) (2010) 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)
  • 58. NeuroStar TMS Practice Locations >300 Systems Installed as of December 2011 Private Practices  Institutions
  • 59. SILICON VALLEY TMS WWW.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
  • 60. 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 depression Dissolving therapy Developed by Silicon Valley TMS
  • 61. Silicon Valley TMS www.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?
  • 62. For more information www.siliconvalleytms.com. or www.NeuroStar.com Thank you!
  • 63. THANK YOU QUESTIONS???? (408)358-8090 shakirmd@verizon.net

Editor's Notes

  1. School of Medicine
  2. This slide shows a schematic example of the targeted action of a TMS coil.   At a practical level, a TMS coil generates strong, MRI-strength, rapidly pulsed magnetic fields. The magnetic field remains sufficiently strong to a depth of about 2-3 centimeters into the brain as it extends away from the face of the TMS magnetic coil. This rapid magnetic pulsing in turn induces an electrical current in an adjacent electrical conductor.   The target electrical conductor in the case of TMS is the surface layers of the cerebral cortex of the brain.   This scientific principle is known as the ‘Law of Electromagnetic Induction’ and was formally described by the English experimenter, Michael Faraday in the late 1800’s, and is sometimes referred to as ‘Faraday’s Law’.   TMS therapy is a noninvasive method of stimulating areas of the brain thought to be involved in mood regulation.   References : Faraday M. In: Experimental Research in Electricity . Vol 1. London Quaritch; 1839:1-15 Barker AT. An introduction to the basic principles of magnetic nerve stimulation. J Clin Neurophysiol . 1991;8(1):26-37 Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet . 1985;11(8437):1106-1107.
  3. Slide 2 For individuals to be diagnosed with GAD, symptoms of excessive anxiety/worry and difficulty controlling the worry must both be present. In patients with GAD, the intensity, duration, or frequency of the anxiety and worry generally far outweigh the actual possibility or effect of the circumstance. Considerable variation occurs among individuals in how they express anxiety. Some patients with GAD may not focus on their anxiety or worry, but describe considerable nonspecific distress. Adults with GAD routinely worry about everyday life circumstances such as job responsibilities, finances, the health of a family member, misfortune to their children, or minor matters (e.g., household chores, car repairs, being late for appointments). In addition, individuals with GAD suffer from significant distress or have great impairment in social, occupational, and other important areas of functioning. In addition, symptoms of GAD must not be the direct physiologic effects of a substance (e.g., a drug being abused, a prescription medication) or a general medical condition (e.g., hyperthyroidism) and must not occur exclusively during a mood, psychotic, or pervasive developmental disorder.
  4. PURPOSE OF THE SLIDE Emphasize that major depressive disorder (MDD) is among the most disabling illnesses in the world, and will likely become more burdensome in the coming decade. 1 Highlight that MDD is also costly, especially in the workplace—workplace costs including absenteeism and presenteeism represent two-thirds of all economic costs associated with depression. 2 SPEAKER DIRECTION MDD is costly in many ways: Unipolar major depression (major depressive disorder) is among the most costly illnesses in the world, and it is becoming more prevalent. In 1990, unipolar major depression was ranked the number 4 cause of disability-adjusted life years (DALYs) among 15-44 year olds. 1 By 2020, it is predicted that unipolar major depression may be the second leading cause of disability-adjusted life years (DALYs) among 15-44 year olds. 1 In 2001, major depressive disorder (unipolar major depression) was already the number 2 cause of disability-adjusted life years (DALYs) among women. 3 In the US alone in 2000, depression accounted for more than $83 billion dollars in economic burden. 2 The most significant portion of that economic burden represented workplace costs such as lost work hours from absenteeism and lost productivity from presenteeism (at work, but not fully functioning). 2 BACKGROUND DALYs for a disease are the sum of the years of life lost due to premature mortality and the years of life lived with the disability, adjusted for the severity of the disability. One DALY can be thought of as one lost year of “healthy” life, and the burden of disease as a measurement of the gap between current health status and an ideal situation where everyone lives into old age free of disease and disability. 1 2020 projections are based on a simple model that relates cause-specific mortality rates to income per capita, average years of schooling, duration of disability, and tobacco use. Cause of death data from 47 countries for the period from 1950 to 1990 were used. Main drivers of the economic burden of MDD are prevalence, treatment rates, and degree of debilitation. Economic burden of MDD includes cost of treatment (direct costs), suicide-related costs, and workplace costs that account for both absenteeism and presenteeism. 2 REFERENCES Murray CJ, Lopez AD. Evidence-based health policy: lessons from the Global Burden of Disease Study. Science. 1996;274:740-743. Greenberg PE, Kessler RC, Birnbaum HG, et a. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003:64:1465-1475. Michaud CM, Murray CJ, Bloom BR. Burden of disease—implications for future research. JAMA. 2001;285:535-539.
  5. PURPOSE OF THE SLIDE This slide begins the “Remission is the goal” section of the presentation. This is the first of five slides in a “build” sequence that shows that several entities around the world have publicly stated that the goal of treating depression is remission. SPEAKER DIRECTION Since 2000, the importance of treating depression to remission has been advanced by several entities around the world. As you proceed through the next four slides, statements will appear regarding treating depression to remission from the American Psychiatric Association, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety, the Royal Australian and New Zealand College of Psychiatrists Clinical Practice, and the World Health Organization Regional Office for Europe.
  6. PURPOSE OF THE SLIDE This is the second of five slides in a “build” sequence that shows that several entities around the world have publicly stated that the goal of treating depression is remission. This slide places an emphasis on targeting remission as the goal for treatment in the acute phase of major depression by showing a direct quote from the American Psychiatric Association practice guideline for the treatment of major depressive disorder. 1 SPEAKER DIRECTION Per the American Psychiatric Association, “The goal of treatment with antidepressant medications in the acute phase is the remission of major depressive disorder symptoms.” 1 REFERENCE Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry . 2000;157(4 Suppl):1-45.
  7. PURPOSE OF THE SLIDE This is the third of five slides in a “build” sequence that shows that several entities around the world have publicly stated that the goal of treating depression is remission. This slide places an emphasis on targeting remission as the goal for treatment of major depression by showing a direct quote from the Canadian Psychiatric Association. 1 SPEAKER DIRECTION In 2004, the Canadian Psychiatric Association in its publication, The Canadian Journal of Psychiatry, released a supplement that focused on achieving and sustaining remission in depression and anxiety disorders that was produced in conjunction with the Canadian Network for Mood and Anxiety. This publication stated, “In clinical practice, it behooves us to adequately assess and treat depressive and anxiety disorders to remission.” 1 REFERENCE O’Donovan C. Achieving and sustaining remission in depression and anxiety disorders: introduction. Can J Psychiatry . 2004;49(March Suppl 1):5S-9S.
  8. PURPOSE OF THE SLIDE This is the fourth of five slides in a “build” sequence that shows that several entities around the world have publicly stated that the goal of treating depression is remission. This slide places an emphasis on targeting remission as the goal for the treatment of major depression by showing a direct quote from the Australian and New Zealand Clinical Practice Guidelines. 1 SPEAKER DIRECTION Per the Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines, “The aim of treatment is to achieve and maintain remission.” 1 The Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression performed meta-analyses, conducted literature reviews, and consulted with patients and practitioners. 1 REFERENCE Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression. Australian and New Zealand clinical practice guidelines for the treatment of depression. Aust N Z J Psychiatry . 2004;38:389-407.
  9. PURPOSE OF THE SLIDE This is the fifth of five slides in a “build” sequence that shows that several entities around the world have publicly stated that the goal of treating depression is remission. This slide emphasizes the importance of targeting remission as the goal for the treatment of major depression by showing a direct quote from the World Health Organization regional office for Europe. SPEAKER DIRECTION Per the World Health Organization Regional Office for Europe, “The goal of acute treatment should always be the complete remission of the episode and not just partial improvement.” 1 This quote comes from a report by the Health Evidence Network (an information service for public health in the World Health Organization Europe Region). 1 REFERENCE 1. Möller HJ, Henkel V (2005). What are the most effective diagnostic and therapeutic strategies for the management of depression in specialist care? Copenhagen, WHO Regional Office for Europe (HealthEvidence Network report; http://www.euro.who.int/Document/E86602.pdf, accessed 21 February 2007).
  10. PURPOSE OF THE SLIDE Show that remission, while the desired goal of acute treatment, means different things to different people. SPEAKER DIRECTION In a published summary of recommendations from the American College of Neuropsychopharmacology (ACNP) Task Force on Response and Remission in Major Depressive Disorder, Rush and colleagues noted that remission was the desired goal of acute treatment, and sustained remission was the desired goal of long-term treatment. 1 But different parties hold different views of remission: Patient’s view: While symptom relief is important, patients also see remission as a state of positive mental health, marked by optimism and self-confidence; a feeling that one has returned to one’s usual normal self; and a usual level of functioning. 2 Family’s view: Remission of depression in mothers may have a positive effect on their children. One study suggests that remission of maternal depression is associated with a reduction in their children’s current diagnoses. 3 Employer’s view: Major depression can substantially reduce worker performance, accounting for 48% of lost productive time at work. To employers, remission of depression may mean improved worker job performance. 4 BACKGROUND Rush and colleagues published a summary of recommendations from the American College of Neuropsychopharmacology (ACNP) Task Force on Response and Remission in Major Depressive Disorder. 1 They noted the importance and clinical relevance of remission as an end point for both practitioners and investigators. 535 outpatients being treated for a major depressive episode were asked to complete a questionnaire to examine what they considered important in defining remission. 2 One hundred fifty-one children (aged 7 to 17) whose depressed mothers were being treated with medication as part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were assessed to determine whether effective treatment of their mothers was associated with reduction of symptoms and diagnoses in the children. 3 A survey of 692 depressed individuals by Stewart et al found that workers with depression reported significantly more total health-related lost productive time: a mean of 5.6 hours per week vs an expected 1.5 hours per week. Extrapolation of survey results suggests that US workers with depression cost employers an estimated $44 billion a year. 4 REFERENCES Rush AJ, Kraemer HC, Sackheim HA, et al. Report by the ACNP task force on response and remission in major depressive disorder. Neuropsychopharmacology . 2006;31:1841-1853. Zimmerman M, McGlinchey JB, Posternak MA, et al. How should remission from depression be defined? The depressed patient’s perspective. Am J Psychiatry . 2006;163:148-150. Weissman W, Pilowsky D, Wickramaratne P, et al. Remissions in maternal depression and child psychopathology: A STAR*D-Child report. JAMA . 2006;295(12):1389-1398. Stewart W, Ricci J, Chee E, et al. Cost of lost productive work time among US workers with depression. JAMA . 2003;289(23):3135-3144.
  11. C. Brendan Montano, M.D. 2000 Forest PCP T1 Depression is frequently misdiagnosed as an anxiety disorder
  12. 50% Psychiatric Illness 66% Recurrent Major Depressive Illness Katon W, Sullivan MD. J Clin Psychiatry. 1990(Jun);51(suppl):3-11 (Discussion 12-14)
  13. C. Brendan Montano, M.D. 2000 Forest PCP T1 J ay D. Fawver, M.D. Lilly 2000 PMDD Core- Talk l WO2903 Obstacles in Treating Depression: Treatment Issues and Current Strategies
  14. C. Brendan Montano, M.D. 2000 Forest PCP T1
  15. Under normal circumstances, stress has a temporary effect on mood. Depression may be viewed as a failure of mood to return to normal after exposure to stress.
  16. Depression may increase the risk for various medical conditions, including coronary heart disease, stroke, and cancer. When depression is accompanied by non-psychiatric medical conditions (e.g., coronary artery disease, diabetes), the outcome of these concurrent medical disorders is likely to be worse than if depression was not present.
  17. PURPOSE OF THE SLIDE Atrophy of the hippocampus, a region of the brain involved in conscious memory, may be associated with depression. SPEAKER DIRECTION Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis of depression. These studies demonstrated that stress and antidepressant treatment may exert opposing actions on the expression of specific neurotrophic factors in limbic brain regions involved in the regulation of mood and cognition. 1 Most notable are studies of BDNF. The functional significance of altered neurotrophic factor expression was highlighted by studies demonstrating that stress and depression can lead to neuronal atrophy and cell loss in key limbic brain regions implicated in depression, including the amygdala, prefrontal cortex, and hippocampus (which expresses high levels of receptors for glucocorticoids, the major stress reactive adrenal steroid). 1 Several studies have associated depression with decreased hippocampal volume. 2,3 Furthermore, this reduction in volume has been related to the duration of depression. 3-5 BACKGROUND The hippocampus is one of several limbic structures that have been implicated in mood disorders. Included in the functions of hippocampal circuitry are control of learning and memory and regulation of the hypothalamic-pituitary-adrenal (HPA) axis, both of which are altered in depression. The hippocampus has connections with the amygdala and prefrontal cortex, regions that are more directly involved in emotion and cognition and thereby contribute to other major symptoms of depression. 1 Bremner et al studied 16 patients with a history of depression based on the Structured Interview for DSM-IV, finding hippocampal volume loss and memory deficits. 2 In a sample of 24 women age 23 to 86 years with histories of recurrent major depression, Sheline et al found that post-depressives scored lower in verbal memory, suggesting that the hippocampal volume loss was related to an aspect of cognitive functioning. The study also found duration of depressive episode to be a predictor of hippocampal volume loss. 3 REFERENCES Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116-1127 . Bremner JD, Narayan M, Anderson ER, et al. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157(1):115-118 . Sheline YI, Sanghavi M, Mintun MA, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. Neurosci. 1999;19:5034-5043. Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA . 1996;93:3908-3913. Sheline YI, Gado MH, Kraemer HC, et al. Untreated depression and hippocampal volume loss. Am J Psychiatry . 2003;160:1516-1518.
  18. PURPOSE OF THE SLIDE Illustrate the potential correlation between the duration of untreated depression and changes in hippocampal volume. Emphasize the urgency to treat depression early. SPEAKER DIRECTION In this study, depression that had gone untreated was found to have deleterious effects on overall neuronal health. The duration of time that depression was untreated was significantly inversely related to hippocampal volume, with longer periods of untreated depression correlated with lower total hippocampal volume. BACKGROUND 38 outpatient female subjects with recurrent depression in remission were recruited for this study. Subjects were screened for medical problems and were specifically screened for incipient dementia. DSM-IV criteria were used to determine past episodes of major depression as well as for exclusion of other psychiatric diagnoses. Hippocampal volumes were measured using MRI scans. Total time treated was not found to be correlated with hippocampal volume. REFERENCE Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516-1518.
  19. PURPOSE OF THE SLIDE Stress the importance of BDNF in depression and connect depression and antidepressants with neuronal health through interaction with BDNF. SPEAKER DIRECTION Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. One specific area where neurons continue to be born throughout life is in the dentate gyrus of the hippocampus. 1,2 Neurogenesis is regulated by growth factors, including brain derived neurotrophic factor (BDNF), that can lead to the development of new cells and help keep them alive. The hippocampi appear to have important functions related to both mood and memory. Sheline compared hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity (n=10) to matched normal controls (n=10) by using volumetric magnetic resonance imaging. 3 BDNF is expressed throughout the brain in glia, monoamine neurons including monoaminergic, GABA, and glutamate neurons. 4 Neurotrophic factors such as BDNF are critical for growth and guidance of the developing nervous system, the survival and function of the adult learning system, learning, and memory. 4 Depression, in part, results from a loss of neurotrophic support, which leads to atrophy and loss of neurons in the brain. This suggests a role for structural and neurochemical changes in depression. BDNF has been shown to be associated with regulation of mood, 5 and in preclinical studies, to be influenced by stress and perception of pain. 6 In one study, patients with major depressive disorder (MDD) had significantly lower levels of BDNF compared to control subjects. 5 Antidepressant treatment was shown to raise BDNF levels back to normal levels. Both 5-HT and NE are believed to play roles in the modulation of BDNF. 1 Antidepressants act in part by inducing neurotrophic effects that reverse the structural changes that may have occurred. 4 Antidepressants increase the synaptic levels of NE and 5-HT over the course of weeks or months, suggesting that adaptation or plasticity is necessary for therapeutic response. BACKGROUND Most neurons in the mammalian brain and spinal cord are generated during the pre- and perinatal periods of development. Nevertheless, neurons continue to be born throughout life in the olfactory bulb , which processes scents, and in the dentate gyrus of the hippocampus. 1 Most existing neurons in the adult brain cannot divide. Some progenitor cells, however, remain, and they retain the capability for further division into new neurons. Apparently, in most parts of the adult brain, something inhibits progenitor cells from dividing to produce new neurons. No one knows exactly why neurogenesis continues in some areas and not others. In a study of 33 patients with MDD, patients who had not received antidepressant treatment (n=16) had significantly lower BDNF levels than treated patients (n=17) as well as control subjects (n=50). 5 In an animal study, both stress as well as acute and chronic pain states significantly lowered levels of BDNF mRNA in the rat hippocampus. 5 5-HT and/or NE activate intracellular cascades that can independently lead to activation of transcription factor (CREB) and eventual synthesis of BDNF. BDNF interacts with TrkB receptor to enhance neuroplasticity and neurogenesis. By facilitating synthesis of a neuroprotective factor, Bcl-2, BDNF helps improve cellular resilience. 7,8 REFERENCES Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54(7):597-606. Gould E, Tanapat P, Rydel T, Hastings N. Regulation of hippocampal neurogenesis in adulthood. Biol Psychiatry. 2000;48(8):715-720. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA. 1996;93(9):3908-3913. Duman RS. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromol Med. 2004;5:11-25. Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70-75. Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience. 2005;133(4):999-1006. Maletic V, Robinson M, Oakes T, et al. Neurobiology of depression: an integrated view of key findings. Int J Clin Pract. 2007;61:2030-2040. Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry. 2003;53:707-742.
  20. PURPOSE OF THE SLIDE Show the importance of the HPA axis and BDNF in some of the neuronal changes that may be involved in depression. SPEAKER DIRECTION Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis of depression. Stress has been shown to decrease levels of BDNF in the hippocampus, as well as produce neuronal atrophy and decrease neurogenesis, which may contribute to a depression-like state. 1,2 A mechanism by which the brain reacts to stress and depression is activation of the hypothalamic-pituitary-adrenal (HPA) axis. Sustained elevations of glucocorticoids may be seen under conditions of prolonged, severe stress and possibly in patients with depression, hippocampal neurons may be damaged and reduction of neurogenesis may occur. Patients with major depression who are otherwise medically healthy have also been observed to have activated inflammatory pathways. Activation of macrophages due to inflammatory challenges (infection, tissue damage, or destruction) may cause release of proinflammatory cytokines. These cytokines enter several areas of the afferent sensory systems and can lead to increased activity. Once in the brain, cytokines can cause altered metabolism of serotonin (5-HT) and dopamine (DA), activation of corticotrophin-releasing hormone (CRH) leading to increased serum glucocorticoid levels, and disruption of synaptic plasticity through changes in growth factors such as BDNF. 3 Severe stress can cause several changes in these neurons, including a reduction in their dendritic branching, and a reduction in BDNF expression (which could be one of the factors mediating the dendritic effects). The reduction in BDNF is thought to be mediated partly by excessive glucocorticoids, which could interfere with the normal transcriptional mechanisms that control BDNF expression and therefore damage hippocampal pyramidal neurons. 2 BACKGROUND The requirement for long-term, chronic antidepressant treatment has led to the hypothesis that alterations in functional and structural plasticity may be necessary for a therapeutic response. 1 Antidepressants are thought to produce the opposite effects: they increase dendritic branching and BDNF expression of these hippocampal neurons. By these actions, antidepressants may reverse and prevent the actions of stress on the hippocampus, and therefore may ameliorate certain symptoms of depression. 4 Antidepressants have been shown to increase levels of BDNF (as well as other neurotrophic/growth factors). The reversal of neuronal atrophy, increased neurogenesis, and antidepressant response may potentially be regulated by increases in growth factors such as BDNF. REFERENCES Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116-1127 . Sapolsky RM Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57;925-935. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunol. 2006;27:24-31. Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13-25.
  21. PURPOSE OF THE SLIDE Illustrate the role that antidepressants and neurotrophic factors, such as BDNF, play in restoring communication within depressed patients. SPEAKER DIRECTION The neurotrophic hypothesis of depression states that a deficiency in neurotrophic support may contribute to hippocampal pathology during the development of depression, and that reversal of this deficiency by antidepressant treatments may contribute to the resolution of depressive symptoms. 1 Acute and chronic stress decreases levels of BDNF expression in the dentate gyrus and pyramidal cell layer of hippocampus in rodents. 2 This reduction appears to be mediated partly via stress-induced glucocorticoids. The two illustrations above show hippocampal pyramidal neurons and their innervation by glutamatergic, monoaminergic, and other neurons. Their regulation by BDNF (derived from hippocampus or other brain areas) is also shown. 1 Severe stress can cause several changes in these neurons, including a reduction in their dendritic branching, and a reduction in BDNF expression (which could be one of the factors mediating the dendritic effects). 1 Antidepressants are thought to produce the opposite effects: they increase dendritic branching and BDNF expression of these hippocampal neurons. By these actions, antidepressants may reverse and prevent the actions of stress on the hippocampus, and therefore may ameliorate certain symptoms of depression. 1 Treatment of depression is attained by providing both trophic and neurochemical support; the trophic support restores normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. BDNF also facilitates the release of neurotransmitters that act on this restored, intact circuit. BACKGROUND Neuronal atrophy and reduced neurotrophic factor expression that are observed in preclinical models, as well as decreased expression of BDNF in depressed subjects, suggest that there could be structural alterations in mood disorder patients. Brain imaging studies have addressed this question and demonstrate a reduction in the volume of the hippocampus of depressed subjects. 1,3,4 In addition, the reduction of hippocampal volume may be reversed by antidepressant treatment. 3,6 Administration of antidepressant treatments increases BDNF expression in these regions, 7 and can prevent the stress-induced decreases in BDNF levels. There is also evidence that antidepressants increase hippocampal BDNF levels in humans. 8 Antidepressant induction of BDNF is at least partly mediated via the transcription factor CREB (cAMP response element binding protein). Antidepressant-induced up regulation of BDNF could help repair some stress-induced damage to hippocampal neurons and protect vulnerable neurons from further damage increased BDNF levels induced by antidepressants may promote hippocampal function. The findings could also explain why an antidepressant response is delayed: it would require sufficient time for levels of BDNF to gradually rise and exert their neurotrophic effects. REFERENCES Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13-25. Smith MA, Makino S, Kvetnansky R, et al. Stress alters the express of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995;15:1768-1777. Sheline Y, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. 2003. Am J Psychiatry. 160:1516-1518. Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry. 2004; 56:140-145. Duman RS. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med. 2004;5:11-25. Vermetten E, Vythilingam M, Southwick SM, et al. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry. 2003;54:693-702. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15:7539-7547. Chen B, Dowlatshahi D, MacQueen GM, et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry. 2001;50:260-265.
  22. Slide 2 Treatment requires understanding -- the neurotransmitters serotonin, norepinephrine and dopamine offer a crucial conceptual link between the mind and the brain.
  23. In states of reduced serotonin neurotransmission and neuroplasticity impaired modulation can cause anxiety, irritability hostility, impulsivity, agitation, hypochondria and suicidal behavior. On the other hand, when catecholaminergic function is compromised, impaired activation can lead to fatigue, apathy, loss of ability to experience pleasure, sleeping too much, and lack of initiative, concentration and productivity. REFERENCE Metzner, RJ, American Psychiatric Association Annual Meeting, Chicago, 2000.
  24. Developed by Larry Culpepper, M.D., M.P.H. 2000 Forest/Parke-Davis PCP T2
  25. In the U.S. there are now six serotonergic, one catecholaminergic and two dual mechanism antidepressants.  
  26. I’d like to expand a bit on the problem of antidepressant treatment adherence. As indicated on the previous slide, as a patient shows increasing levels of treatment resistance, the likelihood that they will keep taking the prescribed treatment also begins to decline. In fact, the occurrence of intolerable adverse events, and discontinuation of patient adherence to the treatment regimen, can become a major challenge in clinical management when treatment resistance worsens.   The iceberg image on this slide portrays the nature of the problem. Clearly, getting to a defined and effective acute treatment (the tip of the iceberg) is the goal: effective treatment with the prescribed antidepressant at an adequate dose for an adequate length of time.   Unfortunately, for the majority of patients, this does not occur, and is an especially significant challenge for the patient with a treatment resistant form of depression.   Below the water line, are shown some of the potential factors that can confound achieving the goal of treatment adequacy.   When looked at in rigorous research studies, adequate antidepressant treatment occurs in the minority of patients. Typically, only one in every four antidepressant treatments is able to achieve the ‘’tip of the iceberg’’ due to lack of efficacy, intolerance and other factors as shown here   An effective and, most important, a tolerable treatment option is a critical goal in the setting of treatment resistance .   References  : Nemeroff CB. Depress Anxiety . 1996/1997;4(4):169-181 Oquendo MA, A, et al. J Clin Psychiatry . 2003;64(7):825-833 Oquendo MA, et. al. Am J Psychiatry . 1999;156(2):190-194 Prudic J, et. al. Psychol Med . 2001;31(5):929-934. Osterberg, L, et. al., NEJM , 2009 ; 353 5): 487-497
  27. Let’s take a closer look at the evidence generated in the STAR*D Study. The design of this study involved four treatment Levels. These Levels were pre-specified by expert consensus, and were intended to reflect the general approach taken in clinical practice at the time STAR*D was constructed, which was about 10 years ago.   Patients treated in STAR*D were either first episode patients, or treatment-responsive patients. To get into the study, the patient could not have previously been treated with and failed to benefit from any of the options offered in either Level 1 or 2. Patients were recruited from both primary care and specialty psychiatric treatment settings in the United States. About 4,000 patients entered into this study.   The first Level results showed that in response to an adequate course of treatment with an SSRI (in this study, citalopram was the option used) only about 28% of patients were able to achieve remission as measured using the 17 Item Hamilton Depression Rating Scale.   At Level 2, the results are shown for those patients who were offered a switch to another antidepressant of the same or a different class (these options included sertraline, bupropion SR, or venlafaxine SR). You can already observe the drop in likelihood of remission, here at about 21% after failure of only one prior adequate antidepressant treatment.   At Level 3, the switch options offered were either mirtazapine or nortriptyline, and again the remission likelihood degrades further.   Finally, at Level 4, the switch option offered was the MAOI tranylcypromine. Here the likelihood of remission after failure of three prior adequate treatments was 6.9%.   References : Fava, M., A. J. Rush, et al. (2006). &amp;quot;A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A Star*D Report.&amp;quot; Am J Psychiatry 163 (7): 1161-1172. McGrath, P. J., J. W. Stewart, et al. (2006). &amp;quot;Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report.&amp;quot; Am J Psychiatry 163 (9): 1531-1541. Nierenberg, A. A., M. Fava, et al. (2006). &amp;quot;A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report.&amp;quot; Am J Psychiatry 163 (9): 1519-1530. Rush, A. J. (2007). &amp;quot;STAR*D: What have we learned?&amp;quot; Am J Psychiatry 164 (2): 201-204. Rush, A. J., M. H. Trivedi, et al. (2006). &amp;quot;Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report.&amp;quot; Am J Psychiatry 163 (11): 1905-1917. Trivedi, M. H., M. Fava, et al. (2006). &amp;quot;Medication Augmentation after the Failure of SSRIs for Depression.&amp;quot; New England Journal of Medicine 354 (12): 1243-1252. Trivedi, M. H., A. J. Rush, et al. (2006). &amp;quot;Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D Implications for Clinical Practice.&amp;quot; Am J Psychiatry 163 (1): 28-40.
  28. What about antidepressant tolerability and treatment adherence? A close look at the reported results of STAR*D reveals some important findings.   We have learned from the STAR*D Study, that the likelihood of a patient dropping out of treatment because of side effects rises dramatically, nearly tripling in the transition from Level 1 ( about 9% ) to Level 2 ( about 23% ). By the time a patient had failed to benefit from three prior treatment attempts, the likelihood of their discontinuing due to adverse events from the next offered antidepressant monotherapy (in this case the MAOI tranylcypromine), was quite notable: slightly greater than 41% .   There are many reasons why the intolerance to treatment rises with progressive levels of treatment resistance, and a full consideration of this is beyond the scope of this presentation. In general, this finding is both a reflection of how physically uncomfortable depression is as a disease, as well as the fact that each next treatment offering in this study brought the potential for an even greater degree of uncomfortable adverse events.   Shown on the right side of this diagram is a list of those adverse events reported in product labels for all contemporary antidepressant medications, including the augmentation agents such as the atypical antipsychotics. The list specifically shows those adverse events that in each product’s labeling were observed to occur at an incidence of at least 5% in the antidepressant-treated group, and occurred at a rate at least twice as high as the incidence of that event reported in the placebo group.   References : Fava, M., A. J. Rush, et al. (2006). &amp;quot;A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A Star*D Report.&amp;quot; Am J Psychiatry 163 (7): 1161-1172. McGrath, P. J., J. W. Stewart, et al. (2006). &amp;quot;Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report.&amp;quot; Am J Psychiatry 163 (9): 1531-1541. Nierenberg, A. A., M. Fava, et al. (2006). &amp;quot;A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report.&amp;quot; Am J Psychiatry 163 (9): 1519-1530. Rush, A. J. (2007). &amp;quot;STAR*D: What have we learned?&amp;quot; Am J Psychiatry 164 (2): 201-204. Rush, A. J., M. H. Trivedi, et al. (2006). &amp;quot;Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report.&amp;quot; Am J Psychiatry 163 (11): 1905-1917. Trivedi, M. H., M. Fava, et al. (2006). &amp;quot;Medication Augmentation after the Failure of SSRIs for Depression.&amp;quot; New England Journal of Medicine 354 (12): 1243-1252. Trivedi, M. H., A. J. Rush, et al. (2006). &amp;quot;Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D Implications for Clinical Practice.&amp;quot; Am J Psychiatry 163 (1): 28-40. Product Labeling for currently marketed antidepressants (Neuronetics, Inc., data on file)
  29. In the following section of my talk, I’d like to discuss TMS in more detail. I will review its mechanism of action, and then discuss some of the most recent randomized clinical trial evidence supporting its efficacy and safety. I will also discuss recent outcomes in real-world practice settings obtained from an ongoing large, prospective outcomes study.
  30. In 2010, the American Psychiatric Association updated their Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, now in its 3 rd Edition.   This slide depicts the general conclusions in that document for the next treatment steps in patients who have failed initial acute phase antidepressant medication. There are several points that I would like to comment on:   As I mentioned above, the APA notes the progressive sequence of steps along the bottom as the next choice for antidepressant medications. As you can see, these options include both medication switches within and across pharmacologic classes, as well as augmentation options. While these options have some scientific evidence base for their support, very few have actually withstood FDA scrutiny in large, multisite, randomized controlled trials. The few that have been studied in this manner and are approved for use in treatment resistant depression are the atypical antipsychotic medications, as augmentation agents. As is also noted in this diagram and as you are well aware, each medication trial can take up to 2 months to clearly understand its potential benefits. Finally, in many instances, ongoing treatment may involve continuation of multiple antidepressant medications.   TMS is now included as an accepted treatment option for patients who have failed to benefit from first line treatment attempts. As we will discuss later in this presentation, placing TMS at this earlier stage in treatment planning is consistent with the strength of the clinical trial evidence that led to the FDA clearance of the NeuroStar TMS Therapy system device. The NeuroStar TMS system is current the only TMS device in the US which has been cleared by the FDA for use in the treatment of major depression.   A treatment course of TMS, as recommended in product labeling, is usually 4 to 6 weeks in duration, and when effective, has been safely followed by a course of a single antidepressant medication.   References : American Psychiatric Association (2010) (eds: Gelenberg, AJ, Freeman, MP, Markowitz, JC, Rosenbaum, JF, Thase, ME, Trivedi, MH, Van Rhoads, RS). Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, 3 rd Edition.
  31. The underlying rationale for the use of TMS exploits the fact that neurons are elecrochemical cells. This means that neuronal activity can be affected either chemically, via the use of drugs, or electrically, via interventions like TMS.   In general, while the action of drugs may be directed at a certain neurochemical receptor or protein, they are by virtue of their method of administration anatomically diffuse, and after oral ingestion, circulate systemically throughout the body, and affect any tissue of the body that possesses that neurochemical target, whether relevant to the disease being treated or not.   In contrast, TMS’s effects are anatomically focused, and by design are non-invasive and non-systemic in action. Under normal conditions of use, TMS therefore incurs far fewer adverse events, and is devoid of undesired systemic adverse events commonly observed with antidepressant medications.   As a targeted treatment, where should TMS be directed in the brain? The right hand side of this figure shows several key brain regions involved in the regulation of mood. Accessible on the surface of the cortex of the brain is the dorsolateral prefrontal cortex (shown in green ). Deeper underlying structures including the anterior cingulate gyrus (shown in red ) and areas of limbic system, such as the amygdala (shown in blue ) also play important roles. The arrows connecting these different brain regions indicate that these various regions (and others) communicate with each other. As a targeted treatment, TMS’s actions are directed at the surface areas of the left dorsolateral prefrontal cortex. TMS can then indirectly exert effects to reach these underlying deeper brain structures through these regional, trans-synaptic connections.   In short, TMS exerts its effects (directly and indirectly) through targeted action on brain circuits involved in the regulation of mood.   References : Pizzigalli, DA. (2011) Frontocingulate Dysfunction in Depression: Toward Biomarkers of Treatment Response. Neuropsychopharmacology 36 :183-206.
  32. This slide shows a schematic example of the targeted action of a TMS coil.   At a practical level, a TMS coil generates strong, MRI-strength, rapidly pulsed magnetic fields. The magnetic field remains sufficiently strong to a depth of about 2-3 centimeters into the brain as it extends away from the face of the TMS magnetic coil. This rapid magnetic pulsing in turn induces an electrical current in an adjacent electrical conductor.   The target electrical conductor in the case of TMS is the surface layers of the cerebral cortex of the brain.   This scientific principle is known as the ‘Law of Electromagnetic Induction’ and was formally described by the English experimenter, Michael Faraday in the late 1800’s, and is sometimes referred to as ‘Faraday’s Law’.   TMS therapy is a noninvasive method of stimulating areas of the brain thought to be involved in mood regulation.   References : Faraday M. In: Experimental Research in Electricity . Vol 1. London Quaritch; 1839:1-15 Barker AT. An introduction to the basic principles of magnetic nerve stimulation. J Clin Neurophysiol . 1991;8(1):26-37 Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet . 1985;11(8437):1106-1107.
  33. This slide shows all of these scientific principles in action in a group of patients (N=12 males) with major depression who have received a course of TMS to their left prefrontal cortex. These pictures represent images from a SPECT (single photon emission computed tomography) scan of the aggregate results in these patients, looking at the areas of the brain that showed changes in cerebral blood flow that correlated with improvement in symptom ratings, as measured by the Hamilton Depression Rating Scale.   On the left of the slide are the image slices showing the left side of the brain, and the right side of the brain are on your right, as labeled. The top row of images show tranverse sections moving from lower in the brain to higher in the brain, as you read from left to right. Similarly, the bottom row of images show coronal sections through the brain moving from back to front in the head as you move from left to right.   You can see the approximate position of the TMS coil on the left side of the head.   The area just underneath the coil is the left dorsolateral prefrontal cortex, which is showing increased metabolic activity as a direct result of the magnetic stimulation. In other panels you can also see that the increase in metabolism reaches secondarily to reach many of the deeper brain regions important in mood regulation that I mentioned earlier. For example in the middle panel on the bottom coronal section, areas of the cingulate cortex show increased activation.   References : Kito, S, Fujita, K, Koga, Y. (2008) Changes in Regional Cerebral Blood Flow After Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Treatment-Resistant Depression. J Neuropsychiatry Clin Neurosci 20(1) :74-80.
  34. The following video provides a brief overview of the key operating features of the NeuroStar TMS system.   NOTE TO PRESENTERS:   The video is silent, and is presented in this manner to allow you to provide commentary in your own words on the video as it is being shown.   The video begins with a presentation of the label language of the indication for use, and then reviews some of the major features of TMS treatment, including the fact that it is non-invasive, is not associated with the development of systemic side effects, and that the patient can transport themselves to and from the treatment on their own.   The treatment shown is a brief summary of the essential components of:   A Motor Threshold procedure Treatment Localization Treatment Session Patient Exit   The final screen refers the viewer to the www.NeuroStar.com website for complete safety information.
  35. The NeuroStar TMS Therapy system is the only FDA-cleared TMS device for the treatment of adult patients with major depression who have failed to benefit from initial treatment.   In clinical practice, TMS Therapy is:   An outpatient procedure, It is non-invasive and non-systemic in action, Shows a safety profile of few side effects, Is typically performed in an outpatient setting, without need for sedation or anesthesia, A standard treatment session is 37 minutes long, and a treatment course consists of daily (5 days per week) treatments for 4 to 6 weeks, A physician or other clinical professional is in attendance during the treatment session, which facilitates adherence with the prescribed treatment   References : NeuroStar TMS Therapy System User Manual. Neuronetics, Inc: Malvern, PA; 2008.
  36. I’d like to conclude my presentation with some comments on the role of NeuroStar TMS Therapy in the treatment of major depression, and remind you of some of the comments I mentioned at the outset of my talk.
  37. As I noted previously, TMS is now incorporated as an accepted treatment option for patients who have failed to benefit from initial antidepressant medication treatment for their illness.   This is reflected in a growing body of published consensus. I mentioned earlier the recent publication of the APA Practice Guidelines, and you can read the quote from the Executive Summary of that document on this slide.   Several other organizations have also acknowledged the scientific evidence for the safety and efficacy of TMS, including the World Federation of Societies for Biological Psychiatry (2009), the Canadian Network for Mood and Anxiety Treatments (CANMAT, 2009), and in the payor community, the Institute for Clinical Systems Improvement (2010), which is a new technology review panel.   References : American Psychiatric Association (2010) (eds: Gelenberg, AJ, Freeman, MP, Markowitz, JC, Rosenbaum, JF, Thase, ME, Trivedi, MH, Van Rhoads, RS). Practice Guidelines for the Treatment of Patients with Major Depressive Disorder, 3 rd Edition. Kennedy, SH, Milev, R, Giacobbe, P, Ramasubbu, R, Lam, RW, Parikh, SV, Patten, SB, Ravindran, AV. (2009) Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. IV. Neurostimulation therapies. J Aff Disorders 117:S44-S53. Institute for Clinical Systems Improvement (ICSI) Health Care Guideline: Major Depression in Adults in Primary Care (13 th Edition, May 2010). Schlaepfer, TE, George, MS, Mayberg, H. (2009) WFSBP Guidelines on Brain Stimulation Treatments in Psychiatry. World J Biol Psychiatry Aug 26:1-7.
  38. NeuroStar TMS Therapy is available as a clinical treatment option in practice at over 250 locations in the United States. References : Neuronetics, Inc., data on file.
  39. Please visit www.NeuroStar.com for full safety and prescribing information. Please consult the Find-A-Provider page also to identify a TMS practitioner in your area.   Thanks for your attention. 44-02214-000, rev C